Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic Properties
Pharmacotherapeutic group: Intestinal anti-inflammatory agents, aminosalicylic acid and similar agents
Mesalazine is the active component of sulphasalazine, which has been used for a long time in the treatment of ulcerative colitis and Crohn's disease. The therapeutic value of mesalazine appears to be due to local effect on the inflamed intestinal tissue, rather than to systemic effect. There is information suggesting that severity of colonic inflammation in ulcerative colitis patients treated with mesalazine is inversely correlated with mucosal concentrations of mesalazine.
Increased leucocyte 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.
The mechanism of action of mesalazine is not fully understood although mechanisms such as activation of the γ-form of peroxisome proliferator-activated receptors (PPAR-γ) and inhibition of nuclear factor-kappa B (NF-κB) in the intestinal mucosa have been implicated. Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leucocyte chemotaxis, decrease cytokine and leukotriene production and scavenge for free radicals. It is currently unknown which, if any of these mechanisms play a predominant role in the clinical efficacy of mesalazine.

Pharmacokinetic Properties

5.2     Pharmacokinetic Properties
General characteristics of the active substance:
Disposition and local availability:
The therapeutic activity of mesalazine most likely depends on a local contact of the drug with the diseased area of the intestinal mucosa. PENTASA enemas are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. The enemas have been shown to reach and cover the descending colon.

Absorption:
The absorption following rectal administration is low, but depends on the dose, the formulation and the extent of spread. Based on urine recoveries in healthy volunteers under steady-state conditions given a daily dose of 2g (1g x 2), about 15-20% of the dose is absorbed after administration of enemas.

Distribution:
Mesalazine and acetyl mesalazine do not cross the blood-brain barrier. Protein binding of mesalazine is approximately 50% and of acetyl mesalazine about 80%.
Metabolism:
Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl mesalazine (acetyl mesalazine) principally by NAT-1. . The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria. The acetylation seems to be independent of the acetylator phenotype of the patient.
Acetyl mesalazine is thought to be clinically as well as toxicologically inactive, although this remains to be confirmed.

Elimination:
The plasma half-life of pure mesalazine is approximately 40 minutes and for acetyl mesalazine approximately 70 minutes. Both substances are excreted in urine and faeces. The urinary excretion consists mainly of acetyl mesalazine.

Characteristics in patients:
The systematic absorption following administration of PENTASA has been shown to be significantly decreased in patients with active ulcerative colitis compared to those in remission.