It combines an antibacterial agent sulfapyridine with an anti-inflammatory component 5-ASA. The sulfonamide moiety acts as a carrier to deliver the active component 5-ASA to the colon where it is released by bacterial action. Sulfasalazine is metabolized by colonic bacterial enzymes to produce the two active byproducts. Sulfapyraidine is metabolized by the liver and excreted in the urine whereas the 5-ASA component is acetylated by the colonic epithelium Rochester and Abreu The original indication for 5-ASA was for rheumatoid arthritis, however it was subsequently found to be efficacious in ulcerative colitis.
Misiewicz et al published the first placebo controlled maintenance trial in randomizing patients to receive sulfasalazine or placebo for one year. Due to the intolerance of sulfasalazine being a restrictive factor in optimizing the therapeutic dosage, more tolerable mesalamine-based drugs have been developed void of the sulphur component.
These new formulations are composed of 5-ASA, the active moiety of sulfasalazine, without the poorly tolerated sulfapyridine carrier molecule. The newer generation aminosalicylates allow for targeted delivery with reduced side effects observed with sulfasalazine.
These new formulations also allow for earlier release more proximally in the small intestine. An added benefit also includes variablility in the pH dependent site of release of various aminosalicylates see Table 2. A variety of different mechanisms have been proposed by which aminosalicylates work in inflammatory bowel disease.
The main mechanism includes the inhibition of cyclooxygenase and lipoxygenase pathways to reduce the production of prostaglandins and leuokotrienes, respectively Kaiser et al Mesalamine also reverses the antiproliferative effects of TNF-alpha thus disrupting the effect of cytokines by reducing intestinal cell transcription of inflammatory mediators Kaiser et al Other processes described include inhibition of platelet activating factor and production of oxygen radicals and other anti-inflammatory factors Egan et al ; Hanauer By reducing inflammatory prostaglandin production and the formation of other potent chemotactic substances including leukotriene B4 and certain hydroxy fatty acids Grisham , mesalamine plays a significant role in halting the perpetuation of a chronic inflammatory state.
Different preparations have been designed in accordance to delivery site depending where the highest activity of disease is located. There have been two major forms of delivery systems currently available. One method is coating 5-ASA with a pH sensitive resin or a semipermeable membrane.
An alternative approach is a prodrug system which is to link the 5-ASA with another molecule by an azo bond Figure 2. Pentasa Shire US, Inc. Olsalazine Dipentum; Celltech Parmaceuticals, Inc.
Variability may exist in the absorption of 5-ASA, most commonly due to the failing of the active drug to reach the appropriate pH in the small intestine. The therapeutic effect of these compounds is dependent on releasing of active drug in the colon which will therefore improve clinical response. Because of adherence issues, a newer high-strength 1. Once dissolved above pH of 7. With this higher concentration tablet and slow dissolution, the aim is to increase adherence by minimizing the number of tablets required.
Another improved delivery method is a micropellet formulation, provided as individual sachets containing granules, with less frequent 2 packets twice a day dosing. Studies have shown non-inferiority of the micropellet formulation compared to tablets in terms of clinical remission within 8 weeks Cohen Two studies have shown that delayed — release mesalamine showed significant benefit compared with placebo Schroeder et al ; Sninsky et al It was demonstrated that mesalamine 4.
The clinical response was based on predetermined criteria that included stool frequency, rectal bleeding, sigmoidoscopic appearance of the mucosa. A complete response was defined as total resolutions of all symptoms, whereas a partial response was a substantial but incomplete improvement in clinical parameters. The absolute benefit increase ABI based on overall response for mesalamine 4.
Studies employing doses of 1. According to the American College of Gastroenterology practice guidelines on ulcerative colitis, mild-to moderate extensive colitis should be treated with oral sulfasalazine titrated up to 4—6 g per day or an alternative aminosalicylate dose up to 4.
Patients with only moderately active ulcerative colitis treated with 4. This result was based on a double-blinded, controlled trial of patients randomized to either 2. The primary endpoint was the proportion of patients in each arm achieving overall improvement from baseline at week 6. Overall improvement was defined as either complete resolution of signs and symptoms or a clinical response to therapy. Double blinded controlled trial of patients randomized to either 2.
Overall improvement defined as either complete resolution of signs and symptoms or a clinical response to therapy. Results demonstrated improvement in clinical parameters in Patients were randomized to either receiving 1 g mesalamine enema nightly versus placebo and disease activity was assessed at 4 and 8 weeks.
Disease activity was assessed using endoscopic signs of improvement and clinical features of response. Briefly, clinical and endoscopic features of response include decrease stool frequency, decrease episodes of rectal bleeding, physician global assessment, and decreased erythema, friability, and ulcerations on endoscopy.
Objective scoring system was established for different stages of the clinical features and accordingly the endpoints of remission and clinical improvement were defined. The combination therapy of oral and enema mesalamine treatment was shown to be superior to oral alone in terms of both remission and improvement. Improvement was defined by objective scoring method based on disease activity. Adapted from data: Marteau et al There is very little data evaluating the efficacy of 5-ASA for treatment of steroid dependent ulcerative colitis.
Ardizzone et al compared the efficacy of 5-aminosalicylic acid and azathioprine in inducing remission of steroid dependent ulcerative colitis. Success in treatment was defined by clinical and endoscopic remission with steroid discontinuation, with azathioprine being more effective than 5-ASA in inducing clinical and endoscopic remission and avoiding long term steroid dependence. Balsalazide, which is pH-dependent, delayed release and slow release mesalamine preparation has also shown improvement in clinical symptoms in acute mild to moderate ulcerative colits Pruitt et al Data has revealed that in newly diagnosed patients with less than 40 cm involvement improvement of symptoms occurred in a median time of 11 days.
However, overall no statistically significance differences between mesalamine and balsalazide were detected at the end of week 8 of treatment. Mansfield et al compared the safety and efficacy of sulfasalazine 3 g with balsalazide 6. Seventy percent of patients with ulcerative colitis given no treatment can expect to experience a relapse over a month period. As early as it was shown that sulfasalazine is effective in maintenance therapy in ulcerative colitis Misiewicz et al , and newer generation 5-ASAs including olsalazine and balsalazine have shown relapse prevention properties virtually the same as, but not greater than, those of equivalent doses of sulfasalazine Kornbluth and Sachar A Cochrane Database analysis of 2, patients Sutherland and MacDonald showed 5-ASA to be superior to placebo with regard to all measured outcome variables.
There was no statistical difference in maintenance of remission between 2. Although the increased dose did not appear to reduce the incidence of relapse of UC over a period of 1 year, the authors report that the increase dose was beneficial in overall delaying relapses. Most comparison studies of mesalamine have shown increased efficacy in remission with higher doses up to 4 g per day of aminosalicylates Kornbluth and Sachar There is overwhelming data to support the use of topical formulations of 5-ASA in distal left sided colitis.
The question arises whether topical therapy alone is efficacious or if topical therapy combined with oral mesalamine would produce higher response rates. A study to compare the efficacy of mesalamine rectal suspension enema, Rowasa Solvay Pahramceuticals, Inc.
However, it has not been clearly defined whether this is a dose response effect or independently a benefit of topical therapy. The combination of oral and rectal mesalamine therapy produced earlier and more complete relief of rectal bleeding than oral and rectal therapy alone.
Adapted from data: Safdi et al However, a comprehensive meta-analysis performed of 67 studies reported that the therapeutic approach in left-sided ulcerative colitis and proctitis was dose dependent and topical mesalamine was superior to oral therapies and topical steroids Cohen et al The meta-analysis also found topical mesalamine was superior in achieving remission compared to topical steroids with overall decreased patient costs.
In the setting of left-sided distal colitis proctitis , topical rectal formulations were found to be superior to oral aminosalicylates at inducing remission Cohen et al and the therapeutic effect of mesalamine was strongly correlated with its mucosal concentration Frieri et al A meta-analysis of five controlled trials comparing rectal mesalamine with placebo for distal colitis showed superiority of mesalamine over placebo Marshall and Irvine Slow release 1 g mesalamine suppositories used three times per week was compared with placebo in maintaining remission in patients with proctitis and the data reveled that slow release suppositories were also effective for preventing relaspses in ulcerative proctitis Marteau et al There is sufficient data to demonstrate long-term safety with mesalamine at doses of up to 5 g daily Cunliffe and Scott The most commonly reported adverse events with the 5-ASA formulations include headache, GI symptoms such as diarrhea, bloating, nausea.
Other rare side effects include interstitial nephritis, hepatitis, pericarditis, pancreatitis, pneumonitis, dermatitis, myocarditis, and hematological disturbances Ransford and Langman Table 3. On occasion, drug holidays may be initiated until diarrheal symptoms resolve.
Nephrotoxicity can be seen with any of the 5-ASA compounds. Considering that IBD affects younger population, it is reasonable to also evaluate its safety profile in pregnancy. There has been no evidence of teratogenic effect or fetal toxicity with mesalamine Diav-Citran et al , placing it into a FDA category B for pregnancy. A prospective controlled cohort study of pregnancy exposure to mesalamine in women with IBD was performed.
Although the mean daily dose used by the cohort was 2. This is in part due to case report of severe fetal nephropathy during renal morphogenesis Colombel et al It works by stopping the body from producing a certain substance that may cause inflammation. Mesalamine comes as a delayed-release releases the medication in the intestine where its effects are needed tablet, a delayed-release releases the medication in the intestine where its effects are needed capsule, a controlled-release releases the medication throughout the digestive system capsule, and as an extended-release long-acting capsule to take by mouth.
Your doctor will tell you how often to take your medication, depending on your condition and how well your symptoms are controlled. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take mesalamine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.
Swallow the delayed-release tablets and delayed-release capsules whole; do not split, chew, or crush them. Be careful not to break the protective coating on the delayed-release tablets. Continue to take mesalamine until you finish your prescription, even if you feel better at the beginning of your treatment. Do not stop taking mesalamine without talking to your doctor. This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.
Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one. Mesalamine may cause other side effects. Call your doctor if you have any unusual problems while you are taking this medication.
Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat, light, and moisture not in the bathroom. It is important to keep all medication out of sight and reach of children as many containers such as weekly pill minders and those for eye drops, creams, patches, and inhalers are not child-resistant and young children can open them easily.
To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location — one that is up and away and out of their sight and reach. Mesalamine is used to treat and prevent mild to moderately active ulcerative colitis an inflammatory bowel disease. It works inside the bowels to reduce inflammation and other symptoms of the disease. All rights reserved. Information is for End User's use only and may not be sold, redistributed or otherwise used for commercial purposes.
Mayo Clinic does not endorse companies or products.
0コメント