MELANEZ

Indications

• Treatment of mild to moderate ulcerative colitis
• Maintenance of remission in ulcerative colitis
• Acute exacerbations of ulcerative colitis

Dosage

Adults: For adults, mesalazine is typically dosed at 2.25 g three times a day until remission occurs, or as 1.5 g twice daily (maximum per dose

Mechanism of action

Mesalazine's mechanism of action is not completely understood, but it is believed to exert a topical anti-inflammatory effect on colonic epithelial cells. It may block cyclooxygenase and inhibit prostaglandin production in the colon, thereby diminishing inflammation. Additionally, mesalazine may inhibit the activation of Nuclear Factor kappa B (NFkB) and the production of pro-inflammatory cytokines. It is also thought to activate PPAR gamma receptors and inhibit inducible NO synthase (iNOS), contributing to its anti-inflammatory properties.

Pharmacodynamics

As an active component of sulphasalazine, mesalazine plays a crucial role in the management of ulcerative colitis by inhibiting prostaglandin and leukotriene synthesis, which subsequently reduces leukocyte migration to the inflamed tissue. It acts mainly topically in the gastrointestinal tract, which is significant for its therapeutic efficacy while minimizing systemic side effects. Mesalazine is also noted for its ability to scavenge free radicals, further supporting its role in controlling intestinal inflammation.

Pharmacokinetics

Mesalazine is absorbed in varying degrees depending on the formulation, with some preparations designed for delayed release to target the colonic region specifically. It undergoes extensive metabolism in the liver, with renal excretion of its metabolites. The pharmacokinetics can be influenced by the route of administration, with oral formulations typically achieving peak plasma concentrations within a few hours. The half-life of mesalazine can vary, and renal function should be monitored during treatment due to potential nephrotoxicity.

Contra-indications

• Severe renal impairment
• Hypersensitivity to mesalazine or any of the excipients

Adverse effects

• Diarrhoea
• Nausea
• Headache
• Abdominal pain
• Vomiting
• Skin reactions
• Alopecia
• Leucopenia
• Arthralgia
• Depression
• Dizziness
• Fever
• Gastrointestinal discomfort
• Dyspnoea

Interactions

• Anticoagulants may have an increased risk of bleeding
• Other aminosalicylates may have additive effects
• Azathioprine and mercaptopurine may increase the risk of bone marrow suppression

Precautions

• Caution in patients with a history of asthma
• Monitor renal function before and during treatment
• Use with caution in hepatic impairment
• Pregnancy and breastfeeding considerations

Pregnancy

Manufacturer advises to avoid use during pregnancy.

Breast-feeding

Diarrhoea may develop in the infant; monitor breast-fed infants for diarrhoea.

Storage

Store below 25°C. Protect from moisture. Keep out of reach of children.

Formulations

• 400 mg tablets (Asacol)
• 250 mg suppositories
• Granules (Pentasa)

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.