COLISTICOL 1200

Indications

• Ulcerative colitis
• Mild to moderate Crohn's disease

Dosage

Children: Refer to the BNF for Children for specific paediatric dosing recommendations.

Adults: Refer to the BNF for specific adult dosing recommendations.

Mechanism of action

The precise mechanism of action of mesalamine is not fully elucidated, but it is believed to exert a topical anti-inflammatory effect on colonic epithelial cells. It likely diminishes inflammation by blocking cyclooxygenase activity and inhibiting prostaglandin production in the colon. Furthermore, mesalamine may inhibit the activation of Nuclear Factor kappa B (NFkB), leading to decreased production of pro-inflammatory cytokines. It is also proposed to activate PPAR gamma receptors in the colonic epithelium and inhibit inducible nitric oxide synthase (iNOS), contributing to its anti-inflammatory effects in inflammatory bowel diseases.

Pharmacodynamics

Mesalamine is recognized as the active moiety in the treatment of ulcerative colitis, effectively reducing inflammation through inhibition of prostaglandin and leukotriene synthesis, thereby decreasing leukocyte migration. Its effects are primarily topical rather than systemic, and it has shown similar efficacy to corticosteroids and sulfasalazine in various experimental models of colitis. Mesalamine also acts as a free radical scavenger, further contributing to its therapeutic profile.

Pharmacokinetics

Mesalamine is absorbed in the gastrointestinal tract, but its site of action is primarily in the colon. The drug undergoes acetylation in the liver, resulting in the formation of its active metabolite, which is excreted in urine. The half-life of mesalamine varies, and its pharmacokinetics can be influenced by factors such as formulation and patient characteristics. Due to its topical action, systemic exposure is generally lower than other anti-inflammatory agents.

Contra-indications

• Hypersensitivity to mesalamine or any component of the formulation
• Severe renal impairment

Adverse effects

• Headache
• Nausea
• Abdominal pain
• Diarrhea
• Rash
• Fever
• Hepatic dysfunction
• Pancreatitis
• Interstitial nephritis

Interactions

• May increase the risk of nephrotoxicity when combined with other nephrotoxic drugs
• Risk of additive effects with other anti-inflammatory agents

Precautions

• Monitor renal function prior to and during treatment
• Use caution in patients with a history of gastrointestinal obstruction or colitis
• Assess for hypersensitivity reactions

Pregnancy

Mesalazine is classified as category B; studies in animals have not shown any risk, but there are limited studies in pregnant women. Use only if clearly needed.

Breast-feeding

Mesalazine is excreted in breast milk, therefore caution should be exercised when administered to nursing women.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral tablets
• Rectal suppositories
• Enema formulations

Mechanism of action

Although the mechanism of action of mesalazine is not fully understood, it is believed to possess a topical anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalazine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon. Furthermore, mesalazine also has the potential to inhibit the activation of Nuclear Factor kappa B (NFkB) and consequently the production of key pro-inflammatory cytokines. It has been proposed that reduced expression of PPAR gamma nuclear receptors (gamma form of peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis, and that mesalazine produces pharmacodynamic effects through direct activation of PPAR gamma receptors in the colonic/rectal epithelium. Other research also showed the potential involvement of inducible NO synthase (iNOS) and that mesalazine can inhibit this enzyme to amiliorate the enteropathy in inflammatory bowel diseases. Moreover, since increased leukocyte migration, abnormal cytokine production, increased production of arachidonic acid metabolites, particularly leukotriene B4, and increased free radical formation in the inflamed intestinal tissue are all present in patients with inflammatory bowel disease it is also believed that mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leukocyte chemotaxis, decrease cytokine and leukotriene production and scavenge for free radicals. Mesalamine is effective in the treatment of inflammatory bowel diseases. However, the mechanisms of action of mesalamine remain unclear. IEC-6 and IRD-98, nontransformed rat small intestinal epithelial cell lines, were used to examine the effect of mesalamine on the expression of manganese superoxide dismutase (MnSOD). Rats were given mesalamine enemas to determine the effect on colonic MnSOD expression. Treatment with mesalamine at 0.02 or 2 mg/mL induced MnSOD mRNA levels 2.67-fold or 5.66-fold, respectively. Inhibition of 5-lipoxygenase activating protein with MK-886 or cyclooxygenase with indomethacin did not influence the level of MnSOD mRNA. Nuclear run-on experiments demonstrated an increase in de novo transcription following treatment with mesalamine. MnSOD protein levels were induced 2-fold at 24 hr and 4.23-fold at 48 hr following treatment with 1 mg/mL mesalamine. Mesalamine increased MnSOD 1.7-fold in vivo. Pretreatment with mesalamine significantly protected IRD-98 cells from tumor necrosis factor-alpha cytotoxicity. This is the first example of transcriptional gene regulation by mesalamine. The induction of MnSOD by mesalamine may contribute to the therapeutic mechanism of mesalamine. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, is increased in patients with inflammatory bowel disease. Mesalamine appears to diminish inflammation by inhibiting cyclooxygenase and lipoxygenase, thereby decreasing the production of prostaglandins, and leukotrienes and hydroxyeicosatetraenoic acids (HETs), respectively. It is also believed that mesalamine acts aas a scavenger of oxygen-derived free radicals, which are produced in greater numbers in patients with inflammatory bowel disease. Derivatives of 5-aminosalicylic acid (mesalamine) represent a mainstay in inflammatory bowel disease therapy, yet the precise mechanism of their therapeutic action is unknown. Because tumor necrosis factor (TNF)-alpha is important in the pathogenesis of inflammatory bowel disease, we investigated the effect of mesalamine on TNF-alpha-regulated signal transduction and proliferation in intestinal epithelial cells. Young adult mouse colon cells were studied with TNF-alpha, epid

Pharmacodynamics

Mesalazine is one of the two components of sulphasalazine, the other being sulphapyridine. It is the latter responsible for most of the side effects associated with sulphasalazine therapy, while mesalazine is known to be the active moiety in the treatment of ulcerative colitis. Mesalazine is thought to dampen the inflammatory process through its ability to inhibit prostaglandin synthesis, interfere with leukotriene synthesis, and consequent leukocyte migration as well as act as a potent scavenger of free radicals. Regardless of the mode of action, mesalazine appears to be active mainly topically rather than systemically. Intraperitoneally administered mesalazine at 30 and 340 mg/kg daily had similar efficacy in attenuating colitis as prednisolone 4 to 550 mg/kg daily given intraperitoneally or sulphasalazine 0.34 to 5 mg/kg given orally in immune complex-induced colitis mice. Mesalazine at 5 mmol/L and sulphasalazine 1.5 mmol/L also reversed the increase in water and chloride secretion and decrease the sodium in dinitrochlorbenzene-induced colitis guinea pig.