Aminosalicylates in inflammatory bowel disease
AminosaLiciLati pri vnetni črevesni bolezni
VojisLav N. Perisic 1
University Children's Hospital, Belgrade, Serbia
Korespondenca/ Correspondence:
VojisLav N. Perisic, MD, PhD, FRCPch (UK), University Children s Hospital, 10 Tirsova str, Belgrade, Serbia; Perisicvn@sezampro.rs
Ključne besede:
aminosalicilati, otroci, ulcerativni kolitis, Crohnova bolezen
Key words:
aminosalicylates, children, ulcerative colitis, Crohn's disease
Citirajte kot/Cite as:
Zdrav Vestn 2013; 82 supl 1: I-26-8
Prispelo: 21. maj 2013, Sprejeto: 11. jun. 2013
Izvleček
Mnogi klinični preskusi so potrdili učinkovitost aminosalicilatov pri zdravljenju vnetne črevesne bolezni, posebej še ulcerativnega kolitisa. Študij, ki obravnavajo bodisi farmakokinetične lastnosti ali učinkovitost pri pediatričnih bolnikih, je malo. Obstajajo številna deljena mnenja o njihovi klinični uporabnosti, ki se nanašajo na optimalni odmerek in interval odmerjanja za dosego in vzdrževanje remisije, najprimernejši pripravek glede na klinično sliko, splošno učinkovitost pri Crohnovi bolezni, učinkovitost pri preprečevanju pooperativne ponovitve Crohnove bolezni itd. Novi pripravek mezalamina za peroralno uporabo MMX (večplastna tableta) omogoča, da mezalamin doseže še posebej oddaljene dele širokega črevesa tudi ob aplikaciji enkrat dnevno. Oblika tablet pa izključuje uporabo pri majhnih otrocih.
Abstract
Numerous clinical trials have supported the efficacy of aminosalicylates in the treatment of inflammatory bowel disease, particularly ulcerative colitis. There are few studies in paediat-ric patients addressing either pharmacokinetic properties or efficacy. There are a number of controversies in their clinical use, including: the optimum dose and dosing interval for induction and maintenance of remission, the most appropriate preparation given the clinical setting, the overall efficacy in Crohn's disease, the efficacy in preventing post-operative recurrence of Crohn's disease etc. A new oral mesalamine formulation, MMX (multi-matrix tablet), delivers mesala-mine particularly to the distal colon even when given once daily. The tablet form still precludes use in small children.
Introduction
Aminosalicylates (5-aminosalicylates, 5-aminosalicylic acid, 5-ASA, mesalamine, mesalazine) are widelyused as first-line therapy in mild to moderate inflammatory bowel disease (IBD), particularly ulcerative colitis.1 Their efficacy in the treatment of active Crohn's disease is questionable.2 These drugs have a number of anti-inflammatory and immunomodulatory effects.
Pharmacokinetics
5-ASA, unless bound as prodrug or combined with another delivery system, is readily absorbed from the stomach and jejunum. Sulfasalazine delivered 5-ASA to the
colon by combining it with sulfapyridine via an azo bond which is cleaved by colonic bacteria. The dose- limiting side effects of sul-fapyridine were generating significant and frequent problems. Subsequent formulations have included pH-dependent and time-released preparations of 5-ASA. These drugs differ in the site of gastrointestinal tract in which the active drug is released.
Balsalazide and olsalazine (Dipentum) are prodrugs and have azo bonds that allow the release of 5-ASAin the colon. In olsala-zine, the azo bonds connect two 5-ASA molecules. All the active medications of these prodrugs are released in the colon.
Delayed release of 5-ASA in the distal small bowel and colon are achieved by pH--dependent delivery system as well. Coating
5-ASA with acrylic-based resin, Eudragit, dissolves formulation at specific pH. Eu-dragit-S releases 5-ASA at a pH of 7 (Asa-col, 5-ASA) initiating in the distal ileum and colon.
Preparations coated with Eudragit-L dissolve at pH 6 (Salofalk, Claversal) and release the drug starting from the mid-ileum, and continuing throughout the right colon.
Release of 5-ASA more proximally can provide active drug throughout the small bowel as well as the colon by time release mechanism (Pentasa). There is less active drug available in the distal colon.
Another new preparation utilizes a novel matrix system to deliver a high concentration of 5-ASA to the distal colon (multimatrix, MMX mesalamine). A dose of 1.2 g three times a day is effective as 5-ASA enemas (4gr/day) in inducing remission in patients with left-sided ulcerative colitis.3 Administration of MMX mesalamine once daily was as effective as when given in split-dose regimen.
Mechanism of action
These medications have both antiinflammatory and immunomodulatory properties.4'5 One of the most important effects is the inhibition of cyclo-oxigenase and 5-lipoxygenase which blocks the production of the proinflammatory activity of prosta-glandin E2 and leukotriens. Other effects are anti-oxidant and free radical scavenging, inhibition of antigen presentation, T--cell proliferation and antibody production of B-cells, inhibition of cellular function of NK cells, mast cells, neutrophils, mucosal lymphocytes, inhibition of expression of adhesion molecules and inhibition of IL-1 synthesis.4'5
Nuclear factor-kappa B activation is blocked as well.
Indications and efficacy Ulcerative colitis
The efficacy of sulfasalazine and the newer 5-ASA preparations in inducing and maintaining remission is established and
these medications remain the first-line therapy in treating mild-to-moderate ulcerative colitis.6 Although there are theoretical benefits of one 5-ASA preparation over another, based on the site of release and location of disease in the colon, this has not been consistently demonstrated clinically. Preparations that are not released until they reach the colon may have advantage in treating more distal disease. The combination of an oral and rectal preparation was shown to be effective.
The doses currently used in children are variable but tend to fall within the range of 50-100 mg/kg/day.3 In children who do no swallows pills, the preparations are limited to those in a form of microgranule formulations (Salofalk) and crushed tablets mixed with soft food (Pentasa).
Crohn's disease
The efficacy of mesalamine in the treatment of active Crohn's disease is questionable 7. The National Cooperative Crohn Disease Study from 1979 did show the benefit of sulfasalazine in ileocolonic and colonic disease.8 More recently Pentasa has been used with success as first-line therapy in mild-to-moderate Crohn's disease.9
5-ASA preparations are used for the induction and maintenance of remission in paediatric patients with Crohn's disease.The lack of rigorous pharmacokinetic studies and clinical trials in children makes decision about the use of these drugs in paedi-atric patents with Crohn's disease difficult. Until more conclusive evidence is available in children, continued use in this setting of mild or mild-to-moderate.ileal, ileo-colonic and colonic Crohn's disease may be reasonable. Doses are similar to those for ulcerative colitis.
The adults studies demonstrated that there may be some efficacy of 5-ASA in maintaining surgically-induced remission in Crohn's disease. However, this effect appears to be modest at best. There have been no published trials in paediatric patients.
Adverse efefcts
Therapy with sulfasalazine is accompanied by frequent side effects. The majority of these effects are related to sulfapyridi-ne: hypersensitivity reactions (fever, rash), agranulocytosis and haemolysis. The newer
References
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There are infrequent report of exacerbation of colitis due to these drugs.
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