PENTASA Tablets and Sachets NAME OF THE MEDICINE Mesalazine (5-ASA) Synonyms: 5-aminosalicylic acid 5-amino 2-hydroxybenzoic acid
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PHARMACOLOGY Pharmacotherapeutic group: Intestinal anti-inflammatory agents (A07 EC02). Actions: It has been established that mesalazine is the active component of sulfasalazine, which is used for the treatment of ulcerative colitis and Crohn’s disease. Based on clinical results, the therapeutic value of mesalazine after oral as well as rectal administration appears to be due to a local effect on the inflamed intestinal tissue, rather than to systemic effects. 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. Mesalazine has in vitro pharmacological effects that inhibit leukocyte chemotaxis, decrease cytokine production, scavenge for free radicals and also reduce leukotriene production via inhibition of the lipo-oxygenase pathway. Prostaglandin production is reduced via inhibition of the cyclo-oxygenase pathway. It is currently unknown which, if any, of these mechanisms play a predominant role in the clinical efficacy of mesalazine. Observed effects of mesalazine in experimental models show downregulation of both inflammation dependent and non-inflammation dependent signalling pathways involved in the development of colitis-associated colorectal cancer (CRC) (see CLINICAL TRIALS). Pharmacokinetics: The therapeutic activity of mesalazine appears to depend on local contact of the drug with the diseased area of the intestinal mucosa. PENTASA prolonged release granules and tablets consist of ethylcellulose-coated microgranules of mesalazine. Following administration and tablet disintegration, mesalazine is continuously released from the individual microgranules throughout the gastrointestinal tract in any enteral pH conditions. The microgranules enter the duodenum within an hour of administration, independent of food co-administration. The average small intestinal transit time is approximately 3-4 hours in healthy volunteers. Absorption: Based on urinary recovery in healthy volunteers, 30-50% of the ingested dose is absorbed following oral administration, predominantly from the small intestine. Mesalazine is detectable in plasma 15 minutes after administration. Maximum plasma concentrations are seen 1-4 hours postdose. After a gradual decrease, mesalazine will no longer be detectable 12 hours post-dose. The plasma concentration curve for acetyl-mesalazine follows the same pattern, but the concentrations are generally higher and the elimination is slower. The metabolic ratio of acetyl-mesalazine to mesalazine in plasma after oral administration ranges from 3.5 to 1.3 after daily doses of 500mg x 3 and 2g x 3, respectively, implying a dose dependent acetylation which may be subject to saturation. Mean steady-state plasma concentrations of mesalazine are approximately 0.3μg/mL, 1.2μg/mL and 1.9μg/mL after 1.5g, 4g and 6g daily dosages, respectively. For acetylmesalazine the corresponding concentrations are approximately 1.1μg/mL, 2.5μg/mL and 3.1μg/mL. The transit and release of mesalazine after oral administration are independent of food co-administration, whereas the systemic absorption will be reduced. Metabolism: Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl mesalazine (acetyl-mesalazine). 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 but this still remains to be confirmed. Distribution: Protein binding of mesalazine is approximately 50% and of acetyl-mesalazine about 80%. Excretion: After intravenous administration, the plasma half-life of mesalazine is approximately 40 minutes and for acetylmesalazine approximately 80 minutes. Due to the continuous release of mesalazine from PENTASA throughout the gastrointestinal tract, the elimination half-life cannot be determined after oral administration. However, steady-state is reached after a treatment period of 5 days following oral administration. Both substances are excreted in the urine and faeces. The urinary excretion consists mainly of acetyl-mesalazine and the faecal excretion consists mainly of mesalazine. Characteristics in patients: The delivery of mesalazine to the intestinal mucosa after oral administration is only slightly affected by pathophysiologic changes such as diarrhoea and increased bowel acidity observed during active inflammatory bowel disease. A reduction in systemic absorption to 20-25% of the daily dose has been observed in patients with accelerated intestinal transit. Likewise, a corresponding increase in faecal excretion has been seen. In patients with impaired liver and kidney function, the resultant decrease in the rate of elimination and increased systemic concentration of mesalazine may constitute an increased risk of nephrotoxic adverse reactions.
منابع مشابه
Pharmacokinetics for Balsalazide and Key Metabolites (5—ASA and N-Ac-5- ASA) with Administration of COLAZAL Following a Fast, a High-Fat Meal, and Drug Contents
COLAZAL (balsalazide disodium) Capsules (kôl a zal) DESCRIPTION: Each COLAZAL capsule contains 750 mg of balsalazide disodium, a prodrug that is enzymatically cleaved in the colon to produce mesalamine (5-aminosalicylic acid or 5-ASA), an antiinflammatory drug. Each daily dose of COLAZAL (6.75 grams) is equivalent to 2.4 grams of mesalamine. Balsalazide disodium has the chemical name (E)-5-[[-4...
متن کاملRelease of 5-Aminosalicylic Acid (5-ASA) from Mesalamine Formulations at Various pH Levels
INTRODUCTION Oral formulations of 5-aminosalicylic acid (5-ASA) for treatment of ulcerative colitis have been developed to minimize absorption prior to the drug reaching the colon. In this study, we investigate the release of 5-ASA from available oral mesalamine formulations in physiologically relevant pH conditions. METHODS Release of 5-ASA from 6 mesalamine formulations (APRISO®, Salix Phar...
متن کاملDissolution of Commercially Available Mesalamine Formulations at Various pH Levels
INTRODUCTION Mesalamine (5-aminosalicylic acid; 5-ASA) is recommended first-line therapy for mild-to-moderate ulcerative colitis. Many mesalamine formulations employ a pH-dependent release mechanism designed to maximize drug release in the colon. This study compared the in vitro release of 5-ASA from six commercially available mesalamine formulations at pH levels similar to those typically enco...
متن کاملSystematic review: does concurrent therapy with 5-ASA and immunomodulators in inflammatory bowel disease improve outcomes?
BACKGROUND With greater use of immunomodulators in inflammatory bowel disease (IBD), it is uncertain whether concurrent therapy with both 5-aminosalicylic acid [5-ASA, mesalazine (mesalamine)] and an immunomodulator is necessary. AIM To determine whether concurrent therapy with both 5-ASA and immunomodulator(s) improves outcomes in IBD. METHODS Systematic review with search terms 'azathiopr...
متن کاملLittle benefit from mesalazine taken prophylactically after surgery for Crohn's disease.
Commentary The main disadvantage of surgery for Crohn’s disease is postoperative recurrence of disease even when all macroscopically involved bowel is removed. Risk factors for early recurrence are ileal or ileocolonic resection with ileocolonic anastomosis, heavy smoking, especially in females, and perforating type of disease. Within weeks to months after resection, new lesions can be visualis...
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تاریخ انتشار 2014