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Review article: monitoring for drug side-effects in inflammatory bowel disease.

The side-effects suitable for monitoring in patients with inflammatory bowel disease being treated with the four main groups of drugs (5-aminosalicylic acid preparations, azathioprine and 6-mercaptopurine, methotrexate, and corticosteroids) are reviewed. On the basis of the reported frequency, severity and timing of side-effects, a practical scheme of monitoring is recommended. This includes a baseline measurement of full blood count, creatinine and liver function tests in all patients. In the absence of worrying symptoms, we recommend the following: (i) no monitoring for sulfasalazine; (ii) for other 5-aminosalicylic acid preparations, the measurement of creatinine at 6 and 12 months and then annually; (iii) for azathioprine/6-mercaptopurine, thiopurine methyltransferase genotype/phenotype determination has no role in treatment monitoring, but a full blood count at 2 weeks, 1 month, 3 months and then every 3 months should be performed; (iv) for methotrexate, a full blood count and liver function tests should be performed every 3 months; (v) for steroids, dual energy X-ray absorptiometry bone scanning should be performed at the start of therapy, every year in which steroids are used if the T score is < 0, and every 3-5 years if the T score is > 0.

Adrenal Cortex Hormones↗

[Local or systemic treatment of inflammatory bowel diseases?].

Standard therapy of inflammatory bowel disease is based on the treatment with corticosteroids, sulfasalazine and 5-aminosalicylic acid. Depending on localization, extent and activity of the bowel inflammation, these drugs are administered topically, systemically or in combination. The advantage of the topical therapy is the lack of non allergic side effects. Ulcerative proctitis and left-sided colitis should, in the first approach, be treated topically with suppositories or enemas. In severe colitis, a combined systemic and topical therapy is useful. In Crohn's disease topical agents are of minor importance. 5-aminosalicylic acid is efficient in mildly active Crohn's disease and prevents relapse for some patients in remission. In severely active Crohn's disease, systemic corticosteroids have to be administered. Azathioprine, cyclosporin A and metronidazole are considered to be reserve drugs because of significant side effects. The clinical usefulness of new topical corticosteroids showing both high antiinflammatory effect and no systemic side effects is presently investigated.

Administration, Oral↗

[Crohn disease: prevention and drug therapy].

In view of a high recurrence rate of Crohn's disease after surgical resection prophylaxis is desirable. The value of various medical therapies to maintain remission after surgery has thus far only partially been established in clinical trials. Therefore, no clear guidelines are presently available. In patients with complete resection and a low risk of recurrence prophylactic treatment seems not to be necessary. In patients with a high risk of recurrence prophylactic treatment is recommended. This recommendation is supported by some clinical trials, although major trials are still ongoing. 5-Aminosalicylic acid in a daily dose of ca. 2-3 g is the primary choice for prophylaxis of recurrence. It reduces the risk of recurrence presumably by about 50%. In patients with a complicated course of the disease who have undergone several previous resections immunosuppressive treatment with azathioprine (1-2 mg/kg body weight/day) is recommended to avoid further recurrences. Conventional corticosteroids are not effective for postoperative prophylaxis. Ongoing studies evaluate the non-systemic steroid budesonide as prophylactic treatment. There is no specific nutritional therapy to prevent recurrences; however, patients are advised to avoid nutrients which they do not tolerate. When patients have a clinical relapse systemic or topical corticosteroids are the treatment of choice. In moderately active disease and in patients who refuse to take corticosteroids high dose 5-aminosalicylic acid (at least 4 g/day) may be used alternatively. In patients with chronic complicated disease azathioprine is recommended.

Aminosalicylic Acids↗

New salicylate therapies for ulcerative colitis.

Since the development of sulfasalazine about a half century ago, the prognosis for patients with ulcerative colitis has improved significantly. Very recently, the active moiety of oral sulfasalazine, 5-aminosalicylic acid, has been made available as a topical (enema) preparation. In this article, Dr. Bruckstein reviews the advantages of the enemas in the treatment of ulcerative colitis and briefly examines the potential benefits of the new oral salicylate preparations.

Administration, Oral↗

Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis.

OBJECTIVE: Balsalazide is a novel azo-bonded 5-aminosalicylic acid treatment for mild-to-moderate ulcerative colitis. The study objective was to compare symptomatic remission rates with balsalazide and mesalamine while controlling for extent of disease and time since diagnosis in patients with active, mild-to-moderate ulcerative colitis. METHODS: A total of 173 patients with sigmoidoscopically verified ulcerative colitis were randomized to 8 wk of double-blind treatment with balsalazide 6.75 g/day or mesalamine 2.4 g/day. Both treatments provided 2.4 g/day of oral 5-aminosalicylic acid. Patients maintained symptom diaries throughout the treatment period. RESULTS: Overall, 46% of balsalazide- and 44% of mesalamine-treated patients achieved symptomatic remission. Higher response rates were noted in newly diagnosed patients with < or = 40 cm of disease (68% vs 61%) than in recently relapsed patients with >40 cm of disease (36% vs 25%). The median time to symptomatic remission was 12 days shorter with balsalazide (25 days) than with mesalamine (37 days). Significantly more balsalazide patients showed sigmoidoscopic (p = 0.002), stool frequency (p = 0.006), rectal bleeding (p = 0.006), and physician's global assessment score (p = 0.013) improvement by 14 days than did mesalamine patients. Similar proportions of patients reported adverse events (54% vs 64%), which were most commonly related to the gastrointestinal and central and peripheral nervous systems. CONCLUSIONS: Balsalazide is an effective and safe treatment for mild-to-moderate ulcerative colitis. Improvement of symptoms occurs considerably earlier with balsalazide than with mesalamine.

Acute Disease↗

Clinical experience of the tolerance of mesalazine and olsalazine in patients intolerant of sulphasalazine.

We assessed the tolerance and safety of two new preparations designed to release 5-aminosalicylic acid in the colon in patients with ulcerative colitis who were intolerant of sulphasalazine. Twenty-eight of 37 patients (76%) given mesalazine and 18 of 21 patients (86%) given olsalazine tolerated the new preparations with no adverse effects. No haematologic or biochemical abnormalities were detected. Adverse reactions to the new preparations were usually but not always similar to those they had previously encountered with sulphasalazine, but a few patients experienced rash and diarrhoea. In some patients intolerant of one of the new preparations, their tolerance of the other was assessed. Three patients intolerant of mesalazine tolerated olsalazine. Similarly, three other patients intolerant of olsalazine tolerated mesalazine. We conclude that not all adverse effects of sulphasalazine are due to the sulphapyridine part of the molecule. Some are due to the released 5-aminosalicylic acid and some to the parent compound. Both drugs are likely to prove useful in the management of patients intolerant of sulphasalazine.

Adult↗

Low Pentasa dosage versus hydrocortisone in the topical treatment of active ulcerative colitis: a randomized, double-blind study.

OBJECTIVES: To compare a low dosage (1 g/day) rectal preparation of 5-aminosalicylic acid in slightly acidic, buffered suspension (Pentasa) with a hydrocortisone 100 mg/day enema (Cortenema). METHODS: Fifty-two patients with mild to moderate distal ulcerative colitis were randomized under double-blind conditions to receive a rectal preparation of either Pentasa (1 g/day) or Cortenema (100 mg/day) for 3 wk. RESULTS: After 3 wk, both types of treatment resulted in statistically significant improvements in clinical and endoscopic activity. No significant difference was observed between the two drugs in any of the parameters considered, although a statistical trend in favor of Pentasa was evident when analysis was limited to clinical activity (p = 0.07). No side effects were reported in either group. CONCLUSIONS: Our experience confirms that short term topical treatment with a low dosage 5-aminosalicylic acid is at least as effective as 100-mg hydrocortisone enemas in treating mild to moderate distal ulcerative colitis and is generally well tolerated.

Administration, Rectal↗

Modulation of cytokine release from human monocytes by drugs used in the therapy of inflammatory bowel diseases.

BACKGROUND: Cytokines produced in the gut mucosa play an important role in the pathogenesis of inflammatory bowel diseases (IBD). To determine whether drugs used in the treatment of these diseases modulate cytokine synthesis, we investigated their effects on endotoxin-induced tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6 release by elutriation-purified human monocytes in vitro. METHODS: Drugs tested were dexamethasone, 5-aminosalicylic acid, sulphapyridine and zileuton (a 5-lipoxygenase inhibitor). Monocytes were isolated and stimulated with endotoxin, and TNF, IL-1 and IL-6 levels were determined using an enzyme-linked immunosorbent assay. RESULTS: Monocyte stimulation with endotoxin resulted in an average TNF release of 2464 +/- 64 pg/10(6) cells, IL-1 release of 616 +/- 47 pg/10(6) cells and IL-6 release of 2259 +/- 148 pg/10(6) cells. Addition of dexamethasone resulted in a reduction of TNF, IL-1 and IL-6 release to below background levels. Sulphapyridine significantly reduced TNF and induced IL-1 release in a dose-dependent fashion, but had no significant effect on IL-6 release. 5-Aminosalicylic acid did not modulate IL-6 synthesis, but significantly reduced IL-1 and enhanced TNF synthesis. Zileuton reduced TNF and IL-6 release, but enhanced IL-1 release. CONCLUSION: We conclude that these anti-inflammatory drugs are able to modulate cytokine release by human monocytes. Further studies are needed to determine whether these effects are related to their therapeutic efficacy in IBD.

Aminosalicylic Acids↗

Intraluminal colonic release of immunoreactive tumour necrosis factor in chronic ulcerative colitis.

1. Tumour necrosis factor is a proinflammatory macrophage-derived polypeptide cytokine. Its participation in disease processes has been usually inferred from data obtained from experiments in vitro or from measurements of its plasma circulating levels. To investigate its role in chronic ulcerative colitis, we have quantified in vivo the steady-state release of tumour necrosis factor into the colonic lumen. 2. We studied 19 patients with untreated active ulcerative colitis and seven patients with irritable bowel syndrome as controls. A group of seven patients with active ulcerative colitis were studied before and after 4 weeks on treatment with oral 5-aminosalicylic acid. By means of an intracolonic double-lumen perfusion tube, an isotonic solution was continuously infused 50 cm from the anal verge at a rate of 5 ml/min, and was recovered 30 cm distally by siphonage. Effluents were assayed for tumour necrosis factor by a specific e.l.i.s.a. and for prostaglandin E2 and leukotriene B4 by specific r.i.a.s. 3. The intracolonic release of tumour necrosis factor was undetectable in patients with irritable bowel syndrome, whereas measurable release occurred in 15 out of 19 patients with active ulcerative colitis (P < 0.01). Prostaglandin E2 and leukotriene B4 release were also increased in active ulcerative colitis by comparison with irritable bowel syndrome (P < 0.01). Five out of seven patients with colitis improved with 5-aminosalicylic acid treatment, and tumour necrosis factor release became undetectable or decreased markedly (P < 0.05 compared with before treatment). However, tumour necrosis factor release remained high in the non-responder patients. 4. These findings indicate that intracolonic immunoreactive tumour necrosis factor release is enhanced in active chronic ulcerative colitis, becoming undetectable when mucosal lesions are healed. These results suggest that the luminal release of tumour necrosis factor may serve as an objective index of inflammatory activity in patients with chronic ulcerative colitis.

Adolescent↗

Intracolonic release in vivo of interleukin-1 beta in chronic ulcerative colitis.

1. To investigate the role of interleukin-1 beta in chronic ulcerative colitis, we quantified interleukin-1 beta steady-state release into the colonic lumen. 2. We studied 26 patients with untreated chronic ulcerative colitis and seven patients with irritable bowel syndrome who served as disease controls. In seven ulcerative colitis patients, the disease was inactive and in 19 it was mild to moderately active, according to clinical and colonoscopic criteria. Seven patients with active colitis were studied before and after 4 weeks of treatment with oral 5-aminosalicylic acid. 3. Colonic perfusions were performed using a double-lumen technique. An isotonic solution was continuously infused 50 cm from the anal verge at 5 ml/min, and was recovered 30 cm distally by siphonage. Interleukin-1 beta was measured by ELISA, polymorphonuclear elastase by immunoactivation and leukotriene B4 by specific RIA. 4. All control patients and five out of seven patients with inactive colitis had undetectable interleukin-1 beta release. In active colitis, the release of interleukin-1 beta was detected in 17 out of 19 patients (median 500 pg/min, interquartiles 270-1582 pg/min, P < 0.01 compared with control subjects and patients with inactive colitis). Elastase and leukotriene B4 release were also significantly increased in active colitis compared with inactive colitis and controls. Leukotriene B4 release was similar in inactive colitis and controls, whereas elastase release was higher in inactive colitis than in controls. Five out of seven patients with colitis improved after treatment with 5-aminosalicylic acid. In all responder patients, interleukin-1 beta became undetectable or declined. 5. Our results demonstrate under conditions in vivo that active colitis is associated with enhanced interleukin-1 beta release into the colonic lumen whereas such release does not occur in remission, supporting the concept that ulcerative colitis flare-ups involve increased interleukin-1 beta production.

Adolescent↗

Canadian survey to determine the rate of drug resistance to isoniazid, PAS and streptomycin in newly detected untreated tuberculosis patients and retreatment cases.

In 1975, a survey was carried out in Canada to determine the primary and acquired drug resistance of M. tuberculosis isolates to isoniazid (INH), para-aminosalicylic acid (PAS) and streptomycin. The results of this investigation were compared with those of the primary drug resistant study of Armstrong, undertaken in 1963-64. It revealed that primary drug resistance has increased from 4.9% to 6.3%. The increase is mainly due to immigrants having arrived in this country during the last 12 years. In these newcomers the primary resistance rate was 11.5%. Moreover, 57.8% of the immigrants examined in the survey were of Asian origin, with a drug resistance rate of 11.7%, while 15.6% had arrived from South Europe with a resistant ratio of 16.7%. In retreatment cases, the national average of drug resistance was 26.4%. Among the Canadian provinces, the highest drug resistance rate in retreatment patients (40%) was found in Quebec. While in primary resistance Streptomycin exhibited the highest incidence, in retreatment cases isoniazid resistance proved to be more frequent. In natives, the rates and patterns of primary and acquired resistance were very similar to those observed in other Canadian born patients.

Aminosalicylic Acid↗

Inhibition of binding of interferon-gamma to its receptor by salicylates used in inflammatory bowel disease.

5-Aminosalicylic acid (5ASA), 4ASA, their N-acetylated metabolites N-acetyl-5ASA and N-acetyl-4ASA, olsalazine, and colchicine impair interferon-gamma (IFN gamma) induced HLA-DR expression on a colonic cell line, HT-29. The mechanism of this effect is now reported. HT-29 cells were cultured with 50 U/ml IFN gamma with or without drug, and northern blot analysis was performed using a probe for the beta chain of the DR molecule. IFN gamma led to a noticeable increase in HLA-DR mRNA which was attenuated by the drugs. Analysis of the specific binding of increasing concentrations of 125I-IFN gamma by non-linear regression showed a Kd of 1.35 x 10(-10) M and 2.3 x 10(5) binding sites per HT-29 cell. Binding of 125I-IFN gamma was reduced by incubation with increasing concentrations of unlabelled IFN gamma but not with IFN alpha. Incubation with therapeutic concentrations of drugs led to the following reductions in binding: 10 mM 5ASA, 20% (p < 0.001); 10 mM N-acetyl-5ASA, 24% (p < 0.01); 10 mM 4ASA, 21% (p < 0.005); 10 mM N-acetyl-4ASA, 29% (p < 0.001); and 1 mM olsalazine, 29% (p < 0.001). Colchicine (10(-7) M) and 10(-5) M prednisolone had no effect. Incubation with higher concentrations of the drugs revealed a dose-response effect on binding with complete inhibition by 100 mM 4ASA and 10 mM olsalazine, and lesser degrees of inhibition by 100 mM 5ASA, N-acetyl-5ASA, and N-acetyl-4ASA. At concentrations found in the rectal lumen, the salicylates used in inflammatory bowel disease impair the binding of IFN gamma to its receptor on colonic epithelial cells.

Aminosalicylic Acid↗

Use of pharmaceuticals by inflammatory bowel disease patients: a population-based study.

OBJECTIVES: In 1996 we created the population-based University of Manitoba Inflammatory Bowel Disease (IBD) Database. In 1994, Manitoba Health established the Drug Program Information Network (DPIN), which identified all ambulatory prescription drugs dispensed to each individual resident of the province. All residents have a personal health identification number, and use of this number allowed linkage of the IBD database with the DPIN database. Our aim was to use the linkage of these databases to describe prescription drug use by patients with IBD in Manitoba in 1997. METHODS: We analyzed all prescriptions and costs for fiscal year 1997, and stratified our analysis by age, sex, urban versus nonurban residence, income, and disease (Crohn's disease vs ulcerative colitis). We also extracted all subjects diagnosed with IBD in 1984-1987 and those diagnosed in 1994-97 and compared any differences in prescribing patterns in 1997 for these two cohorts. RESULTS: A total of 87.5% of IBD subjects received prescriptions in 1997. There was a direct, significant relationship between increasing age and number of different prescriptions per IBD drug user and total prescription costs per IBD drug user (in adults only), particularly for alimentary drugs. Female patients used a greater number of different prescriptions, but there was no difference between sexes in costs per user. Only 7.8% of patients used immunomodulatory drugs, but these accounted for the greatest cost ($1404) per user. Patients whose disease was diagnosed in 1994-1997 were significantly more likely to be prescribed oral or rectal 5-aminosalicylic acid and steroids than were those whose disease was diagnosed in 1984-1987. In addition, prescriptions for rectal 5-aminosalicylic acid were significantly increased in those patients whose diagnoses were made later over those whose diagnoses were made earlier. Male patients and Crohn's disease patients were more likely to use oral steroids and immunomodulatory medications. Based on the decade of diagnosis, there was no difference in prescribing patterns for immunomodulatory medications. CONCLUSIONS: The linkage of the University of Manitoba IBD Database and the Manitoba DPIN Database allowed a description of patterns of prescription use in a population-based sample of IBD patients. Among the important findings are the lack of effect of gender and urban residence on prescription use in IBD patients; however the decade of diagnosis did affect prescribing patterns. Furthermore, only 7.8% overall receive immunomodulatory medications, but this was independent of the decade of diagnosis.

Adjuvants, Immunologic↗

Interaction between azathioprine and aminosalicylates: an in vivo study in patients with Crohn's disease.

BACKGROUND: The inhibition of thiopurine methyltransferase activity, one of the enzymes responsible for azathioprine metabolism, by aminosalicylates has been described in an in vitro study. This could result in a higher risk of bone marrow depression when using the two drugs together. AIM: To investigate the in vivo interaction between azathioprine and aminosalicylates in quiescent Crohn's disease by measuring 6-thioguanine nucleotide levels, thiopurine methyltransferase activity and the plasma levels of the acetylated metabolite of 5-aminosalicylic acid. METHODS: Sixteen patients taking a stable dose of azathioprine, plus sulfasalazine or mesalazine, were enrolled and completed the study. They were not taking any drugs interfering with azathioprine metabolism. Four visits every 4 weeks were held over a 3-month period. Aminosalicylate administration was withdrawn after the second visit. At each visit, the blood cell count, inflammatory parameters, levels of 6-thioguanine nucleotide and the acetylated metabolite of 5-aminosalicylic acid and thiopurine methyltransferase activity were determined. RESULTS: After aminosalicylate withdrawal, mean 6-thioguanine nucleotide levels decreased significantly from 148 pmol (57-357 pmol) to 132 pmol (56-247 pmol) per 8 x 10(8) red blood cells (P=0.027), without significant changes in thiopurine methyltransferase activity or biological parameters. CONCLUSIONS: This in vivo study favours the existence of an interaction between azathioprine and aminosalicylates through a mechanism which remains unclear. This drug-drug interaction should be taken into account when using azathioprine and aminosalicylates simultaneously.

Adult↗

[Therapeutic efficacy of the principal antitubercular drugs: an evaluation by antibiogram].

Pulmonary and extrapulmonary tuberculosis is still encountered in clinical practice, sometimes in forms that are difficult to categorize nosographically. In this study, the therapeutic efficacy of the 6 main antitubercular drugs (rifampicin, streptomycin, isoniazide, ethambutol, kanamycin, para-aminosalicylic acid) in 20 patients with early TB of the lungs was assessed on the basis of antibiogram findings. Para-aminosalicylic acid was found to be the least effective; isoniazide, rifampicin and streptomycin were reasonably so; both kanamycin and ethambutol were extremely effective.

Adult↗

Review article: chronic active disease and maintaining remission in Crohn's disease.

The clinical management of Crohn's disease can be considered in relation to the treatment of acute disease and the maintenance of remission. The medication used to achieve these two goals may or may not be the same. Some patients with mildly active disease may respond to high-dose (4 g/day) mesalazine (mesalamine), and 5-aminosalicylic acid may also be helpful in weaning a patient off steroids after treatment for a flare-up. However, the value of 5-aminosalicylic acid in maintaining remission in Crohn's disease remains controversial. Subgroups of patients may be helped: for example, patients with Crohn's disease who have experienced a relapse within the last 2 years may benefit. Steroids form the first-line therapy for acute episodes of inflammation but do not maintain remission. Azathioprine and mercaptopurine are the first-line drugs for the maintenance of remission in moderate to severe Crohn's disease, and by titrating the dose up from 2 mg/kg daily, some previously resistant patients will be brought into remission. One-half of patients who do not tolerate azathioprine will tolerate mercaptopurine. Methotrexate is effective in inducing and maintaining remission, and is useful for patients who fail azathioprine treatment. Thalidomide is not proven in controlled studies, but two open studies have demonstrated its efficacy. The optimal dose, however, remains to be defined. Purified liquid diets with food exclusion can induce remission in patients with active disease, but food exclusion is difficult to maintain long term. Infliximab can induce and maintain remission in patients resistant to other therapies, with two-thirds of patients initially responding to treatment. One-third go into remission and, of those who respond to a single treatment, approximately one-half maintain remission when treated regularly for a year. Infliximab is, however, associated with an increased risk of infection, and its effect on cancer incidence is uncertain. The development of antibodies against the drug is associated with a loss of effect and allergic infusion reactions. In summary, simple proven therapies should be used first, because of their safety and benefit in some patients. However, aggressive therapy should be used when needed.

Anti-Inflammatory Agents, Non-Steroidal↗

The role of the gastric mucosal sulfhydryls in the ulcer-protecting effects of sulphasalazine.

The role of gastric mucosal sulfhydryls in gastric ulceration, produced by restraint at 4 degrees C (stress) for 2 h, and in the ulcer-protecting effects of sulphasalazine and its constituents (sulphapyridine and 5-aminosalicylic acid), have been studied in rats. Stress significantly raised the mucosal sulphydryl content, but sulphasalazine and sulphapyridine did not influence these changes; only 5-aminosalicylic acid decreased the mucosal sulphydryl concentration. These results indicate that depletion of mucosal sulfhydryls does not occur in stress-induced ulceration, in contrast to what has been shown in other experimental ulcer models. The antiulcer effects of sulphasalazine or of any of its constituents may, therefore, not involve the sulphydryl mechanism.

Animals↗