Cyclosporine and inflammatory bowel disease: buying time.

Cyclosporine is an effective drug in acute exacerbations of corticosteroid resistant ulcerative colitis, but its efficacy to maintain disease remission is not clear. Cyclosporine may not be as effective in Crohn''s disease. However, being a rapidly acting immunosuppressant, cyclosporine may be a valuable therapeutic option in the short-term to treat corticosteroid resistant Crohn''s disease and ulcerative colitis.     

Randomised controlled trial of azathioprine withdrawal in ulcerative colitis.

OBJECTIVE--To determine whether azathioprine can prevent relapse in ulcerative colitis. DESIGN--One year placebo controlled double blind trial of withdrawal or continuation of azathioprine. SETTING--Outpatient clinics of five hospitals. SUBJECTS--79 patients with ulcerative colitis who had been taking azathioprine for six months or more. Patients in full remission for two months or more (67), and patients with chronic low grade or corticosteroid dependent disease (12) were randomised separately. 33 patients in remission received azathioprine and 34 placebo; five patients with chronic stable disease received azathioprine and seven placebo. MAIN OUTCOME MEASURE--Rate of relapse. Relapse was defined as worsening of symptoms or sigmoidoscopic appearance. RESULTS--For the remission group the one year rate of relapse was 36% (12/33) for patients continuing azathioprine and 59% (20/34) for those taking placebo (hazard rate ratio 0.5, 95% confidence interval 0.25 to 1.0). For the subgroup of 54 patients in long term remission (greater than six months before entry to trial) benefit was still evident, with a 31% (8/26) rate of relapse with azathioprine and 61% (17/28) with placebo (p less than 0.01). For the small group of patients with chronic stable colitis (six were corticosteroid dependent and six had low grade symptoms) no benefit was found from continued azathioprine therapy. Adverse events were minimal. CONCLUSIONS--Azathioprine maintenance treatment in ulcerative colitis is beneficial for at least two years if patients have achieved remission while taking the drug. Demonstration of the relapse preventing properties of azathioprine has implications for a large number of patients with troublesome ulcerative colitis, who may benefit from treatment with azathioprine.     

Toxigenicity and antimicrobial susceptibility ofClostridium difficile,a cause of antimicrobial agent-associated colitis

Fourteen of 16 strains ofClostridium difficile, a recently recognized cause of antimicrobial agent-associated ileocolitis in laboratory animals and colitis in man, were found to be toxigenic. The susceptibility of these isolates to a variety of antimicrobial agents provides information that may be of value in assessing the means by whichC. difficile may produce colitis, in developing selective bacteriologic media for diagnosis, and in selecting appropriate antimicrobial therapy for colitis.     

Combination therapy of mesenchymal stromal cells and sulfasalazine attenuates trinitrobenzene sulfonic acid induced colitis in the rat: The S1P pathway

Adipose derived mesenchymal stem cells (ASCs) transplantation is a novel immunomodulatory therapeutic tool to ameliorate the symptom of inflammatory bowel disease (IBD). The objective of this study was to investigate the therapeutic effects of combined sufasalazine and ASCs therapy in a rat model of IBD. After induction of colitis in rats, ASCs were cultured and intraperitoneally injected (3 × 10⁶cells/kg) into the rats on Days 1 and 5 after inducing colitis, in conjunction with daily oral administration of low dose of sulfasalazine (30 mg/kg). The regenerative effects of combination of ASCs and sulfasalazine on ulcerative colitis were assessed by measuring body weight, colonic weight/length ratio, disease activity index, macroscopic scores, histopathological examinations, cytokine, and inflammation markers profiles. In addition, western blot analysis was used to assess the levels of nuclear factor-kappa B (NF-κB) and apoptosis related proteins in colitis tissues. Simultaneous treatment with ASCs and sulfasalazine was associated with significant amelioration of disease activity index, macroscopic and microscopic colitis scores, as well as inhibition of the proinflammatory cytokines in trinitrobenzene sulfonic acid (TNBS)-induced colitis. Moreover, combined ASCs and sulfasalazine therapy effectively inhibited the NF-κB signaling pathway, reduced the expression of Bax and prevented the loss of Bcl-2 proteins in colon tissue of the rats with TNBS-induced colitis. Furthermore, combined treatment with ASCs and sulfasalazine shifted inflammatory M1 to anti-inflammatory M2 macrophages by decreasing the levels of MCP1, CXCL9 and increasing IL-10, Arg-1 levels. In conclusion, combination of ASCs with conventional IBD therapy is potentially a much more powerful strategy to slow the progression of colitis via reducing inflammatory and apoptotic markers than either therapy alone.     

Smoking and nicotine in inflammatory bowel disease: good or bad for cytokines?

Smoking has either a beneficial or harmful effect on the course and recurrence of ulcerative colitis and Crohn''s disease respectively. Transdermal application of nicotine had similar effects in ulcerative colitis and therefore was considered to be an effective basic drug which could be further developed in the search for new compounds in the treatment of acute exacerbations of corticosteroid resistant ulcerative colitis. In this communication the short-term use of nicotine in ulcerative colitis is reviewed.     

Effect of combination of thalidomide and sulfasalazine in experimentally induced inflammatory bowel disease in rats

Thalidomide provided significant protection against tri nitro benzene sulfonic acid induced colitis. Combination therapy also reduced colonic inflammation and all the biochemical parameters (myeloperoxidase assay, malondialdehyde assay and tumor necrosis factor-alpha, estimation) were significant as compared to control as well as thalidomide alone treated group. Combination therapy showed additive effect of thalidomide which restored lipid peroxidation as well as reduced myeloperoxidase and TNF-a towards the normal levels. Morphological and histological scores were significantly reduced in combination groups. In experimental model of colitis, oral administration of thalidomide (150 mg/kg) alone as well as its combination with sulfasalazine (360 mg/kg) significantly reduced the colonic inflammation. The results indicate the additive effect of thalidomide with sulfasalazine in rat colitis model which requires further confirmation in human studies.     

Inflammatory bowel disease.

An increasing number of options are available for the treatment of inflammatory bowel disease; the selection depends on the extent and severity of the disease. Experience with sulfasalazine and corticosteroids has led to a proliferation of 5-aminosalicylic acid (5-ASA) compounds and experimentation with alternative corticosteroid preparations. Given rectally 5-ASA is particularly effective in the treatment of distal ulcerative colitis, and experience is accumulating with several oral formulations. Metronidazole is useful in some cases, and immunosuppressive agents have a role in some patients with chronic refractory disease. A variety of measures, such as nutritional therapy, surgery and psychosocial support, are important elements of therapy. Further therapeutic innovations are expected as the etiology and pathogenesis are clarified.     

Synergistic effects of systemic trefoil factor family 1 (TFF1) peptide and epidermal growth factor in a rat model of colitis

Novel therapies for the treatment of colitis are required. We therefore examined the potential value of the trefoil factor family 1 (TFF1) peptide and epidermal growth factor (EGF) alone and in combination. Effects of TFF1- Cys58 +/- EGF on an in vitro HT29 cell wounding model of restitution showed synergistic activity when used in combination. In addition, animals had colitis induced by adding 4% dextran sulphate sodium (DSS) to the drinking water for 7 days and they also received twice daily subcutaneous injections of test peptides. Treatment with TFF1-Cys58 alone (100 microg/kg) reduced histological colitis score by 22%, but the TFF1-Ser58 variant was ineffective. In a second study, TFF1-Cys58 reduced histological colitis score by 15%, EGF (600 microg/kg) by 26%, and an additive response (42% reduction) was demonstrated when used together (P < 0.01 versus either peptide given alone). Similar results were found using tissue myeloperoxidase (MPO) activity as a marker of inflammation. Where clinical risk/benefit seems justified, these initial studies suggest that combination therapy of systemic EGF and TFF peptides may prove useful for treatment of colitis in patients with disease extending beyond the reach of topical (enema) therapy.     

Effect of Manuka honey and sulfasalazine in combination to promote antioxidant defense system in experimentally induced ulcerative colitis model in rats

Manuka honey (MH, 5g/kg) provided protection against trinitro-benzo-sulphonic acid induced colonic damage. Combination therapy (MH+sulfasalazine) also reduced colonic inflammation and all the biochemical parameters were significant compared to control and MH alone treated group. Combination therapy showed additive effect of the MH which restored lipid peroxidation and improvement of antioxidant parameters. Morphological and histological scores were significantly reduced in combination groups. In inflammatory model of colitis, oral administration of MH (5g/kg) and combination with sulfasalazine (360 mg/kg) with MH (5g/kg) significantly reduced the colonic inflammation. The results indicate the additive effect of Manuka honey with sulfasalazine in colitis.     

Azathioprine in Ulcerative Colitis: Final Report on Controlled Therapeutic Trial

Eighty patients, all of whom were suffering from a frank clinical attack of ulcerative colitis, were admitted to the trial. The attack was treated with a standard course of corticosteroids and the patients were immediately placed on treatment with either azathioprine in a dose of 2·5 mg/kg body weight or dummy tablets. The trial tablets were continued for one year while the patients were maintained under regular clinical, sigmoidoscopic, histological, haematological, and biochemical surveillance. If a patient relapsed during such maintenance treatment he or she was treated with a further course of corticosteroids without interrupting maintenance treatment.In the treatment of an actual attack of ulcerative colitis the results in the attacks which brought the 80 patients into the trial show that no benefit came from the addition of azathioprine to a standard course of corticosteroid therapy.Patients admitted in their first attack of ulcerative colitis showed no benefit from the one-year maintenance treatment with azathioprine, the benefits of which were confined to patients admitted in a relapse of established disease. Even in these the difference between the treated group and the control group failed to reach statistical significance, but the difference was big enough to suggest that there is a prima facie case for regarding azathioprine as of some benefit in this group of patients.     

A 21-Day of Adjunctive Corticosteroid Use May Not Be Necessary for HIV-1-Infected Pneumocystis Pneumonia with Moderate and Severe Disease

Background

The current guidelines recommend 21-day adjunctive corticosteroid therapy for HIV-1-infected pneumocystis pneumonia patients (HIV-PCP) with moderate-to-severe disease. Whether shorter adjunctive corticosteroid therapy is feasible in such patients is unknown.

Methods

We conducted a retrospective study to elucidate the proportion of patients with moderate and severe HIV-PCP who required adjunctive corticosteroid therapy for 21 days. The enrollment criteria included HIV-PCP that fulfilled the current criteria for 21-day corticosteroid therapy; PaO₂ on room air of <70mmHg or A-aDO₂ ≥35 mmHg.

Results

The median duration of corticosteroid therapy in the 73 study patients was 13 days (IQR 9–21). Adjunctive corticosteroid therapy was effective and discontinued within 10 and 14 days in 30% and 60% of the patients, respectively. Only 9% of the patients with moderate HIV-PCP (n = 22, A-aDO₂ 35–45 mmHg) received steroids for >14 days, whereas 35% of the patients with severe HIV-PCP (n = 51, A-aDO₂ ≥45 mmHg) required corticosteroid therapy for ≥21 days. Four (13%) of the severe cases died, whereas no patient with moderate disease died. Among patients with severe HIV-PCP, discontinuation of corticosteroid therapy within 14 days correlated significantly with higher baseline CD4 (p = 0.049).

Conclusion

Shorter adjunctive corticosteroid therapy was clinically effective and adjunctive corticosteroid could be discontinued within 14 days in 60% of moderate-to-severe HIV-PCP and 90% of moderate cases.     

Addition of Berberine to 5-Aminosalicylic Acid for Treatment of Dextran Sulfate Sodium-Induced Chronic Colitis in C57BL/6 Mice

Ulcerative colitis (UC) is a common chronic remitting disease but without satisfactory treatment. Alternative medicine berberine has received massive attention for its potential in UC treatment. Conventional therapies with the addition of berberine are becoming attractive as novel therapies in UC. In the present study, we investigated the preclinical activity of a conventional oral 5-aminosalicylic acid (5-ASA) therapy plus berberine in experimental colitis. A subclinical dose of 5-ASA (200 mg/kg/day) alone or 5-ASA plus berberine (20 mg/kg/day) was orally administered for 30 days to C57BL/6 mice with colitis induced by three cycles of 2% dextran sulfate sodium (DSS). The disease severity, inflammatory responses, drug accumulation and potential toxicity of colitis mice were examined. The results showed that comparing to 5-ASA alone, 5-ASA plus berberine more potently ameliorated DSS-induced disease severity, colon shortening, and colon histological injury. Further, the up-regulation in mRNA level of colonic TNF-α as well as NFκB and JAK2 phosphorylation caused by DSS were more pronouncedly reversed in animals treated with the combination therapy than those treated with 5-ASA alone. Moreover, the addition of berberine to 5-ASA more significantly inhibited lymphocyte TNF-α secretion of DSS mice than 5-ASA alone. In the meanwhile, no extra drug accumulation or potential toxicity to major organs of colitis mice was observed with this combination treatment. In summary, our studies provide preclinical rationale for the addition of berberine to 5-ASA as a promising therapeutic strategy in clinic by reducing dose of standard therapy.     

The Metabolic and Phagocytic Activities of Leukocytes from Patients Receiving Corticosteroid and Radiation Therapy,and Patients with Bacterial Infections

Peripheral blood leukocytes from patients given corticosteroid or radiation therapy, as well as patients with bacterial or viral infections, were studied with regard to the selected enzyme activities of the hexose monophosphate shunt (HMS). Glucose-6-phosphate dehydrogenase (G-6-PD), 6-phosphogluconate dehydrogenase (6-PGD) and reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase were assayed spectrophotometrically on mixed leukocyte suspensions in isotonic glycerol. Enzyme activities of G-6-PD and NADPH oxidase in patients receiving corticosteroid or radiation therapy were significantly lower than the enzyme activity of 6-PGD. In patients with bacterial infections, activities of the three enzymes increased but in patients with viral infections, only the activities of NADPH oxidase and G-6-PD were slightly decreased. Nitroblue tetrazolium (NBT) dye-reducing activities of neutrophils from patients receiving corticosteroid or radiation therapy were attenuated which coincides with the reduced activities of HMS enzymes. From these results, it is likely that the reduced activities of intraleukocytic HMS enzymes of patients receiving corticosteroid or radiation therapy are correlated with intracellular bactericidal activities which might result from the attenuated level of hydrogen peroxide production.     

The metabolic and phagocytic activities of leukocytes from patients receiving corticosteroid and radiation therapy, and patients with bacterial infections.

Peripheral blood leukocytes from patients given corticosteroid or radiation therapy, as well as patients with bacterial or viral infections, were studied with regard to the selected enzyme activities of the hexose monophosphate shunt (HMS). Glucose-6-phosphate dehydrogenase (G-6-PD), 6-phosphogluconate dehydrogenase (6-PGD) and reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase were assayed spectrophotometrically on mixed leukocyte suspensions in isotonic glycerol. Enzyme activities of G-6PD and NADPH oxidase in patients receiving corticosteroid or radiation therapy were significantly lower than the enzyme activity of 6-PGD. In patients with bacterial infections, activities of the three enzymes increased but in patients with viral infections, only the activities of NADPH oxidase and G-6PD were slightly decreased. Nitroblue tetrazolium (NBT) dyereducing activities of neutrophils from patients receiving corticosteroid or radiation therapy were attenuated which coincides with the reduced activities of HMS enzymes. From these results, it is likely that the reduced activities of intraleukocytic HMS enzymes of patients receiving corticosteroid or radiation therapy are correlated with intracellular bactericidal activities which might result from the attenuated level of hydrogen peroxide production.     

Beclomethasone dipropionate in asthma.

Beclomethasone dipropionate aerosol therapy can replace or diminish systemic corticosteroid therapy in the majority of asthmatics. In a clinical trial of 41 patients with perennial asthma, the 10 who had not required long-term corticosteroid therapy improved symptomatically and in pulmonary function. Of the 31 who had required prolonged systemic corticosteroid therapy 12 were able to discontinue oral prednisone therapy, 15 were able to decrease the maintenance dose of prednisone and only 4 were unable to decrease the dose; all maintained satisfactory lung function and some showed improvement. Discontinuation of systemic corticosteroid therapy was accomplished more readily in patients whose daily maintenance dose was less than 15 mg and who had been taking the drug for less than 3 years. Side effects consisted of a "dry throat" in seven patients, two of whom had throat infections with Candida albicans. Recurrence of rhinitis after discontinuation or reduction of systemic corticosteroid therapy was noted in 11 patients.     

The status of corticosteroid therapy in dermatology

Therapy with systemic corticosteroids, despite attendant serious risks, is mandatory in diseases such as pemphigus, acute disseminated lupus erythematosus and some cases of exfoliative dermatitis that are ordinarily fatal, for in such cases life may be prolonged and the patients made comfortable. If no contraindications exist, therapy with corticosteroids is desirable, for diseases of short duration-contact dermatitis, serum sickness reactions and drug eruptions of all kinds-provided the causative factors have been removed and the reactions are causing severe distress.On the basis of encouraging reports in the literature corticosteroid therapy may be instituted with justification for a group of unrelated, intractable and discomforting diseases such as maddening pruritus ani, sclerema neonatorum, dermatomyositis, certain cases of sarcoidosis, berylliosis, Behcet's syndrome, universal calcinosis, Reiter's disease and ulcers of sickle-cell anemia. One must always bear in mind the well-defined contraindications to corticosteroid therapy and the hazards of its use, particularly if therapy is to be prolonged. Results from topical hydrocortisone therapy are particularly pleasing in chronic eczematous otitis externa and especially when it is combined with an antibiotic drug. Results are excellent also in nuchal eczema, dermatitis of the eyelids and in pruritus ani. More often than not, hydrocortisone ointment and lotions benefit more than do other standard remedies such diseases as atopic eczema, contact dermatitis, lichen simplex-chronicus and eczematized phases of conditions such as psoriasis and superficial mycotic infections. Preparations containing a combination of hydrocortisone and an antibiotic are more useful than hydrocortisone alone. When used with discrimination, with full attention to the selection of cases and proper concentration in the correct vehicle, hydrocortisone preparations in combination with antibiotics are excellent antieczematous agents.     

Lack of correlation between in vitro corticosteroid effect on hemopoietic colony formation and response to corticosteroid therapy in aplastic anemia

We performed hemopoietic colony culture assays in 15 patients with aplastic anemia (AA) in order to test the effect of hydrocortisone (HC) on late erythroid colony (CFU-e) formation of the patients' marrow and to correlate the in vitro culture results with the clinical response to corticosteroid therapy. HC enhanced CFU-e growth in four patients. All four patients failed to respond to corticosteroid, but three improved with with androgens. The addition of HC did not increase CFU-e colony formation in 11 patients. However, two of them responded to corticosteroid therapy. Among the nine patients showing no HC effect in vitro, two subsequently improved with androgens and one each with anti-thymocyte globulin and anti-lymphocyte globulin. The results suggest that the in vitro corticosteroid effect may not necessarily correlate with responsiveness to corticosteroid therapy.     

Augmented reduction in colonic inflammatory markers of dextran sulfate sodium-induced colitis with a combination of 5-aminosalicylic acid and AD-lico™ from Glycyrrhiza inflata

The primary aim of this study was to determine whether the oral administration of AD-lico?, a functional extract from Glycyrrhiza inflata in combination with 5-aminosalicylic acid (5-ASA) could ameliorate the inflammatory symptoms in dextran sulfate sodium (DSS)-induced colitis in rodents. This DSS rodent model is used to study drug candidates for colitis, as part of the spectrum of diseases falling under the inflammatory bowel disease (IBD) category. Here, with oral AD-lico? administration, there was a substantial disruption of the colonic architectural changes due to DSS and a significant reduction in colonic myeloperoxidase (MPO) activity, a marker of colitis. In the same samples, there were also reduced levels of colonic and serum IL-6 in the oral AD-lico? treated rats. This study also addressed the possible mechanisms for AD-lico? mediated changes on colonic inflammation markers. These included the observations that AD-lico? dampened the IL-6 proinflammatory-signaling pathway in THP-1 human monocytic cells and reduced the TNFα-mediated upregulation of surface adhesion molecule ICAM-1 in human umbilical vein endothelial cells (HUVECs). Finally, it was shown that AD-lico? could be combined with 5-ASA in reducing the inflammatory markers for colorectal sites affected by colitis, a first study of its kind for a combination therapy.     

Orbital cobalt radiotherapy and systemic or retrobulbar corticosteroids for Graves' ophthalmopathy

Orbital radiotherapy and corticosteroids are two well-established medical treatments for severe Graves' ophthalmopathy. In this report we analyze the results obtained by the combination of orbital radiotherapy and systemic or retrobulbar corticosteroids in patients with severe Graves' ophthalmopathy. Orbital cobalt radiotherapy was carried out by a cobalt unit, delivering a total of 2,000 rads to each eye in 10 daily doses. Systemic corticosteroid treatment was started with 70-80 mg methylprednisolone/day for 2-3 weeks with subsequent progressive reduction of the dose until discontinuation of the drug after 5-6 months. Retrobulbar corticosteroid therapy was performed by 14 bilateral injections of 40 mg methylprednisolone acetate at 20- to 30-day intervals. Results were evaluated both on clinical grounds and by numerical scoring (ophthalmopathy index, OI). Excellent or good responses were obtained in the majority of 72 patients by combined treatment with orbital cobalt radiotherapy and systemic corticosteroids. Soft tissue changes, newly developed eye muscle dysfunction and optic neuropathy showed the most beneficial effects from treatment, whereas proptosis, corneal lesions and long-standing eye muscle abnormalities responded to a lesser extent. The results of a controlled clinical trial showed that the combined treatment was more effective than the administration of systemic methylprednisolone alone. Because relevant side effects of systemic corticosteroid therapy were observed in 4 cases, the clinical validity of retrobulbar corticosteroids in substitution for systemic corticosteroids was evaluated in 44 patients. Excellent or good responses were observed in 25% of these patients, slight responses being obtained in 55% and no change in 20%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytomegalovirus infection masquerading as an ulcerative colitis flare-up: case report and review of the literature.

We report the case of a patient with a case of cytomegalovirus (CMV) colitis, which presented as a flare-up of her ulcerative colitis. Standard treatment for the flare-up, which included intravenous corticosteroids, bowel rest, topical salicylates and ultimately colectomy were not effective. The patient did not improve until therapy with intravenous ganciclovir was initiated. There have been 26 previous reports of CMV colitis complicating inflammatory bowel disease (IBD). The diagnosis is not frequently entertained and, if not made, leads to a high rate of colectomy (67 percent) and mortality (33 percent). Appropriate antiviral therapy appears to eliminate these complications, thus a high index of suspicion for CMV superinfection in cases of IBD refractory to traditional therapy is warranted.