5-Aminosalicylic acid

153.14

153.14

2090421

201-919-1

4Q81I59GXC

759301|38877

DTXSID5024506

C29249

White to pinkish crystals

A07EC02|A - Alimentary tract and metabolism

2922509090

83.6

1.3

off-white to gray tablets

1.5±0.1 g/cm3

283 °C

403.9ºC at 760 mmHg

279-281°C

1.691

H2O: <0.1 g/100 mL at 21 ºC;soluble in dimethyl sulfoxide.

2-8°C

6.10X10-8 mm Hg at 25 deg C (est)

Peritoneal-mouse LD50: 5000 mg/kg; oral-mouse LDL0: 313 mg/kg

Flammable; burning produces toxic nitrogen oxide fumes

Henry's Law constant = 5.02X10-12 atm-cu m/mol at 25 °C (est)

Mesalamine's production and use in the manufacture of light-sensitive paper, azo and sulfur dyes and as a gastrointestinal medication may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 6.1X10-8 mm Hg at 25 °C indicates mesalamine will exist in both the vapor and particulate phases in the atmosphere. Vapor-phase mesalamine will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 18 hrs. Particulate-phase mesalamine will be removed from the atmosphere by wet or dry deposition. Mesalamine does contain chromophores that absorb at wavelengths >290 nm and therefore may be expected to be susceptible to direct photolysis by sunlight. If released to soil, mesalamine is expected to have very high mobility based upon an estimated Koc of 10. Estimated pKa values of 2.09, 5.26 and 13.64 indicate that this compound will dissociate to the zwitterion form in the environment. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 5.0X10-12 atm-cu m/mole. Mesalamine is considered completely biodegradable under anaerobic conditions as was indicated by 95.6% methane production following acclimation. If released into water, mesalamine is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to mesalamine may occur through inhalation and dermal contact with this compound at workplaces where mesalamine is produced or used. Use data indicate that the general population may be exposed to mesalamine via dermal contact with products containing this compound as well as via ingestion following administration of drugs containing mesalamine, a gastrointestinal anti-inflammatory. (SRC)

134.7 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Decomposes at approx 280 °C|Hydroxyl radical reaction rate constant = 2.09X10-11 cu cm/molec-sec at 25 °C (est)

Sensitive to moisture. Water insoluble.

Acids, Carboxylic

5-AMINOSALICYLIC ACID is incompatible with acids, acid chlorides, acid anhydrides, chloroformates and strong oxidizers. (NTP, 1992)

IRRITANT

NONH for all modes of transport

2

36/37/38-52/53

26-36-24/25-61-37/39

VO1400000

Xi

Warehouse ventilated, low temperature and dry

Stable. Incompatible with acids, acid anhydrides, acid chlorides, chloroformates, strong oxidizing agents.

P261-P305 + P351 + P338

H315-H319-H335

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl mesalamine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)

|Warning|H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]|P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.|H315 (95.18%): Causes skin irritation [Warning Skin corrosion/irritation]|P261, P264, P271, P272, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P333+P313, P337+P313, P362, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 229 companies from 19 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. A water spray may also be used. (NTP, 1992)

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should store this chemical under refrigerated temperatures, and protect it from moisture. If possible, it would be prudent to store this compound under inert atmosphere. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Mesalamine was detected not quantified in municipal landfill waste(1). Mesalamine was not detected in munitions wastewater from a former ammunition plant in Stadtallendorf, Germany as part of study of nitroaromatic compounds in munition wastewater(2).

moderately

Oral, mouse: LD50 = 3370 mg/kg; Oral, rat: LD50 = 2800 mg/kg; Skin, rabbit: LD50 = >5 gm/kg [MSDS]. There have been no documented reports of serious toxicity in man resulting from massive overdosing with mesalamine. Under ordinary circumstances, mesalazine absorption from the colon is limited. Although there is little to no clinical experience with mesalazine overdosage. Mesalazine is an aminosalicylate, and symptoms of salicylate toxicity may be possible, such as tinnitus, vertigo, headache, confusion, drowsiness, sweating, hyperventilation, vomiting, and diarrhea. Severe intoxication with salicylates can lead to disruption of electrolyte balance and blood-pH, hyperthermia, and dehydration.

In large registration trials of various forms of mesalamine, serum enzyme elevations were no more common with the products than with placebo therapy and were less common than with sulfasalazine. In these large studies, there were no reported instances of clinically apparent liver injury. Since approval and wide scale usage, however, there have been isolated reports of acute and chronic liver injury with jaundice attributed to mesalamine therapy. Clinically apparent liver injury is estimated to occur at an incidence of 3.2 cases per million prescriptions. Several patterns of injury have been reported, including asymptomatic and mild elevations in serum ALT levels, mild hepatitis accompanying a hypersensitivity reaction within a few days or weeks of starting (sometimes following a similar reaction to sulfasalazine), drug fever with accompanying serum enzyme elevations or mild hepatitis, and more typically, idiosyncratic cholestatic or hepatocellular liver injury (Cases 1 and 2), which typically arises after 1 to 6 months of treatment and is not accompanied by signs of hypersensitivity (rash, fever, eosinophilia). Most cases of liver injury with jaundice have been mild-to-moderate in severity and resolve rapidly upon stopping. In cases with hypersensitivity reactions, corticosteroid therapy is often used and appears to speed recovery. There have been no convincing reports of fatal acute liver injury, chronic hepatitis or vanishing bile duct syndrome attributable to mesalamine.

Omeprazole may increase gastrointestinal pH; concurrent use may result in an increase in the absorption of mesalamine.|Acidification of the colonic lumen by lactulose may impair release of mesalamine from delayed- or extended-release formulations.

Mesalamine is substantially eliminated by the kidneys, and the risk of toxic reactions may be greater in patients with impaired renal function. Because of the greater frequency of decreased renal function observed in geriatric individuals, mesalamine should be used with caution in these patients and renal function monitored prior initiation of and during administration of oral mesalamine delayed-release tablets.|Clinical studies of oral mesalamine delayed-release tablets and rectal suppositories of the drug did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. While other clinical experience has not revealed differences in response, drug dosage should be selected cautiously in geriatric patients. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered. Reports from uncontrolled studies suggest that a higher incidence of blood dyscrasias (i.e., agranulocytosis, neutropenia, pancytopenia) may occur in patients 65 years of age or older receiving oral mesalamine delayed-release tablets; complete blood cell counts (CBCs) should be monitored closely in these patients during therapy with these oral preparations.

Mesalazine is approximately 43% bound to plasma proteins,.

Mesalamine's production and use in the manufacture of light-sensitive paper, azo and sulfur dyes and as a gastrointestinal medication(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that mesalamine is expected to have very high mobility in soil(SRC). Volatilization of mesalamine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.0X10-12 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Mesalamine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.1X10-8 mm Hg(SRC), determined from a fragment constant method(4). Mesalamine is considered completely biodegradable under anaerobic conditions, as was indicated by 95.6% methane production following acclimation(5).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that mesalamine is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 5.0X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from an estimated log Kow of 0.98(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Mesalamine is considered completely biodegradable under anaerobic conditions, as was indicated by 95.6% methane production following acclimation(8).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), mesalamine, which has an estimated vapor pressure of 6.1X10-8 mm Hg at tt °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase mesalamine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 18 hrs(SRC), calculated from its rate constant of 2.1X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Mesalamine does contain chromophores that absorb at wavelengths >290 nm and therefore may be susceptible to direct photolysis by sunlight(4).

The rate constant for the vapor-phase reaction of mesalamine with photochemically-produced hydroxyl radicals has been estimated as 2.1X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 18 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Reaction with hydroxyl radical has been shown to yield a phenoxyl radical in alkaline solutions with only a weak spectrum of the semiquinone radical at pH 12 being observed(2). Mesalamine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). Mesalamine does contains chromophores that absorb at wavelengths >290 nm and therefore may be susceptible to direct photolysis by sunlight(3).

An estimated BCF of 3 was calculated in fish for mesalamine(SRC), using an estimated log Kow of 0.98(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of mesalamine can be estimated to be 10(SRC). According to a classification scheme(2), this estimated Koc value suggests that mesalamine is expected to have very high mobility in soil. A predicted Kd value of 1.37 calculated for sludge samples in the UK, suggests that adsorption to sludge is low(3). Estimated pKa values of 2.09, 5.26 and 13.64(4) indicate that this compound will dissociate to the zwitterion form in the environment(SRC).

The Henry's Law constant for mesalamine is estimated as 5.0X10-12 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that mesalamine is expected to be essentially nonvolatile from water surfaces(2). Estimated pKa values of 2.09, 5.26 and 13.64(4) indicate that this compound will dissociate to the zwitterion form in the environment(SRC). Mesalamine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.1X10-8 mm Hg(SRC), determined from a fragment constant method(3).

The literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through subsoils into aquifers(

Following oral administration, low concentrations of mesalamine and higher concentrations of its metabolite, N-acetyl-5-aminosalicylic acid, have been detected in human breast milk. It is not known whether mesalamine or its metabolites are distributed into milk in humans following rectal administration.

Occupational exposure to mesalamine may occur through inhalation and dermal contact with this compound at workplaces where mesalamine is produced or used. Use data indicate that the general population may be exposed to mesalamine via dermal contact with products containing this compound as well as via ingestion following administration of drugs containing mesalamine, a gastrointestinal anti-inflammatory. (SRC)

Mesalazine is indicated for the induction of remission in patients with active or mild to moderate acute exacerbations of ulcerative colitis and for the maintenance of remission of ulcerative colitis,. Prescribing information for mesalazine in the UK also indicates the medication for the maintenance of remission of Crohn's ileo-colitis.|FDA Label|Treatment of ulcerative colitis

Mesalamine, also known as mesalazine and 5-aminosalicylate, is an orally available, antiinflammatory agent used for the treatment of ulcerative colitis to both induce and maintain remissions in disease. Mesalamine therapy has been associated with a low rate of serum enzyme elevations during therapy and with rare instances of clinically apparent acute liver injury.

Gastrointestinal Agents

Mesalamine rectal suspension is indicated for the treatment of mild to moderate distal ulcerative colitis, proctosigmoiditis, and proctitis. /Included in US product labeling/|Mesalamine rectal suspension is indicated to help maintain remission of distal ulcerative colitis. /NOT included in US product labeling/|Mesalamine suppositories are indicated for the treatment of active ulcerative proctitis. /Included in US product labeling/|Mesalamine is indicated to treat and to maintain remission of mild to moderate ulcerative colitis or (Crohn's disease). /Included in US product labeling/|Lialda /the first oral once daily mesalamine tablet/ is indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis.

Oral and rectal mesalamine preparations usually are well tolerated. The most common adverse effects of oral or rectal mesalamine are GI effects and headache. In clinical studies, most adverse effects associated with oral or rectal preparations were mild in severity and were transient or reversible. However, adverse effects have been severe enough to require discontinuance of the drug in less than 1% or in up to about 4-5% of patients receiving rectal or oral mesalamine, respectively, although in some studies, the rate of discontinuance of the drug was similar to or less than in those receiving placebo. Most of the adverse effects reported with the use of oral mesalamine delayed-release tablets were similar in short- and long-term studies.|Exacerbation of colitis symptoms was reported in 3% of patients receiving oral mesalamine delayed-release tablets. Other adverse GI effects associated with oral mesalamine extended-release capsules and occurring in less than 1% of patients, include abdominal distention, constipation, duodenal ulcer, dysphagia, eructation, esophageal or mouth ulcer, fecal incontinence, GI bleeding (e.g., rectal bleeding), stool abnormalities (e.g., change in color or texture), oral moniliasis, and thirst, although a causal relationship to the drug of many of these adverse effects has not been established.|In controlled clinical trials in patients receiving oral mesalamine delayed-release tablets, abdominal pain, eructation, nausea, diarrhea, dyspepsia, vomiting, constipation, flatulence, exacerbation of colitis, abdominal enlargement, gastroenteritis, GI hemorrhage, rectal disorder (e.g., hemorrhage, tenesmus), and stool abnormalities, were the most common adverse GI effects, occurring in about 2-18% of patients; dry mouth, indigestion, stomatitis, and cramping were reported rarely. Frequency of these GI effects did not seem to increase with increased dosages, although in uncontrolled studies, the incidence of abdominal pain, flatulence, and GI bleeding were dose related. The most common adverse GI effects of oral mesalamine extended-released capsules were diarrhea (including melena), nausea, abdominal pain, dyspepsia, vomiting, anorexia, worsening of ulcerative colitis, and rectal urgency, occurring in greater than 0.4-3% of patients.|An acute intolerance syndrome (sensitivity reaction), characterized by cramping, abdominal pain, bloody diarrhea, and, occasionally, fever, headache, malaise, conjunctivitis, pruritus, and rash, has occurred in a few patients receiving mesalamine and required prompt discontinuance of the drug. In patients manifesting such intolerance, a history of sulfasalazine intolerance, if any, should be reevaluated.|For more Drug Warnings (Complete) data for MESALAMINE (26 total), please visit the HSDB record page.

Mesalazine is one of the two components of sulphasalazine, the other being sulphapyridine. It is the latter which is responsible for the majority of the side effects associated with sulphasalazine therapy whilst mesalazine is known to be the active moiety in the treatment of ulcerative colitis. The pharmacodynamic actions of mesalazine occur in the colonic/rectal mucosae local to the delivery of drug from mesalazine tablets into the lumen. There is information suggesting that the severity of colonic inflammation in ulcerative colitis patients treated with mesalazine is inversely correlated with mucosal concentrations of mesalazine. Plasma concentrations representing systemically absorbed mesalazine are not believed to contribute extensively to efficacy.

Anti-inflammatory agents that are non-steroidal in nature. In addition to anti-inflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions.They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects. (See all compounds classified as Anti-Inflammatory Agents, Non-Steroidal.)

Depending on the formulation administered, prescribing information for orally administered delayed-released tablets of 2.4g or 4.8g of mesalazine given once daily for 14 days to healthy volunteers was to found to be about 21% to 22% of the administered dose while prescribing information for an orally administered controlled-release capsule formulation suggests 20% to 30% of the mesalazine in the formulation is absorbed. In contrast, when mesalamine is administered orally as an unformulated 1-g aqueous suspension, mesalazine is approximately 80% absorbed.|Elimination of mesalazine is mainly via the renal route following metabolism to N-acetyl-5-aminosalicylic acid (acetylation). However, there is also limited excretion of the parent mesalazine drug in the urine. After the oral administration of the extended-release formulation of mesalazine, of the approximately 21% to 22% of the drug absorbed, less than 8% of the dose was excreted unchanged in the urine after 24 hours, compared with greater than 13% for N-acetyl-5-aminosalicylic acid. When given the controlled-release formulation, about 130 mg free mesalazine was recovered in the feces following a single 1-g dose, which was comparable to the 140 mg of mesalazine recovered from the molar equivalent sulfasalazine tablet dose of 2.5 g F3001]. Elimination of free mesalazine and salicylates in feces increased proportionately with the dose given. N-acetylmesalazine was the primary compound excreted in the urine (19% to 30%) following the controlled-release dosing.|The apparent volume of distribution (Vd) of the drug in adults is approximately 0.2 L/kg.|The mean (SD) renal clearance in L/h for mesalazine following the single dose administration of mesalazine delayed-release tablets 4.8g under fasting conditions to young and elderly subjects was documented as 2.05 (1.33) in young subjects aged 18 to 35 years old, 2.04 (1.16) in elderly subjects aged 65 to 75 years old, and 2.13 (1.20) in elderly subjects older than 75 years.|Following oral administration, low concentrations of mesalamine and higher concentrations of its metabolite, N-acetyl-5-aminosalicylic acid, have been detected in human breast milk. It is not known whether mesalamine or its metabolites are distributed into milk in humans following rectal administration.|Mesalamine and N-acetyl-5-aminosalicylic acid cross the placenta following oral administration; however, serum concentrations of mesalamine in umbilical cord and amniotic fluid are very low. It is not known whether mesalamine crosses the placenta following rectal administration.|In vitro, mesalamine and N-acetyl-5-aminosalicylic acid are approximately 44-55 and 80% bound, respectively, to plasma proteins. Protein binding of N-acetyl-5-aminosalicylic acid does not appear to be concentration dependent at concentrations ranging from 1-10 ug/mL.|It is generally accepted that 5-aminosalicylate (5-ASA; mesalamine), widely used in inflammatory bowel disease therapy, exerts its action from the intraluminal site of the intestine. In addition to local metabolism of 5-ASA, it has been assumed that therapeutic mucosal concentrations of 5-ASA depend on transporter-mediated secretion back to the lumen. ... The hypothesis that 5-ASA represents a substrate of P-glycoprotein (P-gp) and/or multidrug resistance-associated protein 2 (MRP2), thereby possibly contributing to variable therapeutic effects /was tested/. Polarized, basal-to-apical transport of [(3)H]5-ASA was studied in monolayers of Caco-2 and L-MDR cells, both of which express P-gp in their apical membrane, as well as in MDCK cells transfected with human MRP2. Moreover, we investigated the influence of 5-ASA on transport of digoxin in Caco-2 cells. In Caco-2 cells a P-gp-mediated efflux of 5-ASA (5-500 muM) could be excluded. Likewise, in L-MDR1 and MRP2 cells no transport differences in either the basal-to-apical or apical-to-basal direction were measurable. 5-ASA (50 muM to 5 mM) had no effect on the transport of digoxin. ...|For more Absorption, Distribution and Excretion (Complete) data for MESALAMINE (15 total), please visit the HSDB record page.

The primary metabolite of mesalazine (5-aminosalicylic acid) is predominantly N-acetyl-5-aminosalicylic acid (Ac-5-ASA). This metabolite is generated via N-acetyltransferase (NAT) activity in the liver and intestinal mucosa cells, largely by NAT-1, in particular.|Mesalazine (5-aminosalicylic acid, 5-ASA), an anti-inflammatory agent for the treatment of inflammatory bowel diseases, is metabolized in organism to the principal biotransformation product, N-acetyl-5-ASA. Some other phase II metabolites (N-formyl-5-ASA, N-butyryl-5-ASA, N-beta-d-glucopyranosyl-5-ASA) have also been described. 5-ASA is a polar compound and besides it exhibits amphoteric properties. ...|The exact metabolic fate of mesalamine has not been clearly established. The drug undergoes rapid N-acetylation, probably in the liver, to form N-acetyl-5-aminosalicylic acid; mesalamine and N-acetyl-5-aminosalicylic acid also may undergo conjugation with glucuronic acid. Several other, unidentified metabolites also may be formed. It has been suggested that N-acetylation also may occur (to a limited extent) in the intestinal wall and/or the lumen. The intestinal flora probably are involved in this acetylation, and extensive floral acetylation may adversely affect clinical efficacy of the drug. Correlation between acetylator phenotype of patients receiving mesalamine and the degree of N-acetylation does not appear to exist. Although it has been suggested that N-acetyl-5-aminosalicylic acid may be pharmacologically active, therapeutic response has been poor in some patients treated rectally with this metabolite, and the relative contribution of this metabolite to the therapeutic effect of mesalamine remains questionable. N-Acetyl-5-aminosalicylic acid did not inhibit lipoxygenase in vitro.|Mesalazine has known human metabolites that include mesalazine, N-acetyl.

The apparent elimination half-life documented for oral delayed-release mesalazine tablets is 7 to 12 hours. The elimination half-life recorded for the active N-acetyl-5-aminosalicylic acid metabolite generated from the administration of oral delayed-release mesalazine tablets is 12 to 23 hours.|Elimination of metabolite: 5 to 10 hr /N-acetyl-5-aminosalicylci acid/|Elimination: 0.5-1.5 hours

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 (NKkB) and consequently the production of key of 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. There is evidence that mesalazine produces pharmacodynamic effects through direct activation of PPAR gamma receptors in the colonic/rectal epithelium as well. 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, epidermal growth factor, or ceramide in the presence or absence of mesalamine. Proliferation was studied by hemocytometry. Mitogen-activated protein (MAP) kinase activation and IkappaBalpha expression were determined by Western blot analysis. Nuclear transcription factor kappaB (NF-kappaB) nuclear translocation was determined by confocal laser immunofluorescent microscopy. The antiproliferative effects of TNF-alpha were blocked by mesalamine. TNF-alpha and ceramide activation of MAP kinase were inhibited by mesalamine, whereas epidermal growth factor activation of MAP kinase was unaffected. TNF-alpha-stimulated NF-kappaB activation and nuclear translocation and the degradation of Ikappa-Balpha were blocked by mesalamine. Mesalamine inhibits TNF-alpha-mediated effects on intestinal epithelial cell proliferation and activation of MAP kinase and NF-kappaB. Therefore, it may function as a therapeutic agent based on its ability to disrupt critical signal transduction events in the intestinal cell necessary for perpetuation of the chronic inflammatory state.

SYMPTOMS: Symptoms of exposure to this compound include acute intolerance syndrome characterized by cramping, acute abdominal pain and discomfort, and bloody diarrhea. It may also cause headache, rash, gas (flatulence), nausea, flu, tiredness, weakness, malaise, fatigue, cold, sore throat, leg pain, joint pain, dizziness, bloating, back pain, hemorrhoids, itching, rectal pain, constipation, hair loss, peripheral edema, urinary burning, rectal soreness and burning, asthenia and insomnia. Other symptoms include fever, gastrointestinal problems, anorexia, epigastric pain, skin eruptions of various types, agranulocytosis, leukopenia, eosinophilia, lymphocytosis, atypical mononucleosis syndrome, thrombocytopenia and acute hemolytic anemia. Symptoms of exposure to a related compound include pruritus, erythematous macular or bullous eruptions, acidosis, hypokalemia, crystalluria, vomiting, hepatic necrosis, leukocytosis, laryngeal edema, methemoglobinemia and thyroid suppression. Other symptoms include allergic reactions, gastrointestinal irritation and prolonged prothrombin times. ACUTE/CHRONIC HAZARDS: This compound may be harmful by inhalation, ingestion or skin absorption. It may cause irritation. When heated to decomposition it emits toxic fumes of carbon monoxide, carbon dioxide and nitrogen oxides. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

To decrease absorption: ... Activated charcoal may also be administered. Supportive care: Fluid and electrolyte imbalance should be corrected by the administration of appropriate intravenous therapy. Vital functions should be monitored and supported.

/SIGNS AND SYMPTOMS/ Peripheral or generalized edema has been reported in about 1% of patients receiving the drug rectally. Pericarditis, manifested as chest pain, fever, and/or dyspnea, has occurred rarely in patients receiving rectal mesalamine. Evidence of pericarditis occurred within several days to weeks after initiation of rectal mesalamine therapy and resolved following discontinuance of the drug. In most patients, pericarditis recurred with mesalamine or olsalazine rechallenge. However, the risk of cross-sensitivity with sulfasalazine or other 5-aminosalicylic acid (mesalamine) prodrugs (e.g., olsalazine) currently is not known. Other evidence of pericarditis included pericardial friction rub, radiographic evidence of pleural effusion and/or cardiac enlargement with possible tamponade, echocardiographic evidence of pericardial effusion, and/or ECG abnormalities (e.g., ST- and T-wave changes and inferior Q waves suggestive of myocardial infarction, ST-segment depression). Although there appears to be an association between mesalamine use and the development of pericarditis in these patients, the mechanism is unknown and pericarditis also has been reported in patients with inflammatory bowel disease who were not receiving mesalamine. In some of these latter patients, pericarditis developed during sulfasalazine therapy and therefore, may have been secondary to the drug rather than to the underlying condition. The possibility of pericarditis should be considered in any patient who develops chest pain or dyspnea during mesalamine therapy. Discontinuance of therapy with the drug may be warranted in some such patients, while mesalamine rechallenge may be performed under careful clinical observation if there is a continued therapeutic need for the drug.|/SIGNS AND SYMPTOMS/ Ecchymosis, thrombocythemia, and thrombocytopenia have been reported in less than 1% of patients receiving oral mesalamine extended-release capsules; however, a causal relationship to the drug of these adverse effects has not been established. Adverse hematologic effects associated with preparations containing or being metabolized to mesalamine and reported in clinical studies, medical literature, or postmarketing reports include agranulocytosis, aplastic anemia, eosinophilia, leukopenia, anemia, and lymphadenopathy. In at least one patient receiving mesalamine rectal suppositories (500 mg every evening) for 7 months, leukopenia and thrombocytopenia occurred.|/CASE REPORTS/ We describe a case of a 25-yr-old woman with ulcerative colitis who developed marked thrombocytopenia during treatment and upon rechallenge with oral mesalamine. In contrast to its parent drug, sulfasalazine, which has often been reported to cause serious blood disorders, particularly agranulocytosis, mesalamine has rately been implicated as a cause of serious blood disorders. Although previous cases of hematological toxicity have been described in patients taking mesalamine, none of these patients were rechallenged in an effort to prove causality between 5-aminosalicyclic acid and the hematological abnormality as well as outrule the possible "autoimmune" contribution of inflammatory bowel disease to the hematological toxicity of these agents. This report demonstrates that mesalamine has the potential, like sulphasalazine, to cause marked thrombocytopenia in an idiosyncratic fashion. ...|/CASE REPORTS/ ... Two cases of biopsy-confirmed interstitial nephritis in patients being treated with 5-aminosalicylic acid /are reported/. Both had a trial of steroid therapy. One patient had partial recovery of renal function but the other patient was in chronic renal failure and likely was approaching the need for dialysis. Interstitial nephritis is an under-recognized complication of 5-aminosalicylic acid therapy. Early identification and withdrawal of this drug can lead to a partial or complete reversal of renal dysfunction.|For more Human Toxicity Excerpts (Complete) data for MESALAMINE (18 total), please visit the HSDB record page.

5 Aminosalicylate

(2000, England) 40,421.72 kg/yr

... The pharmaceutical industry has been developing different delivery systems for Multi-Matrix System (MMX) mesalamine for the treatment of Crohn's disease and ulcerative colitis. The new oral mesalamine formulation is a once-daily MMX tablet that delivers the mesalamine to the colon, making it most useful in the treatment of ulcerative colitis. The MMX coating matrix and coating system begin dissolution in the final portion of the ileum. ...|Oral: Capsules, extended-release: 250 mg Pentasa, (Shire); 500 mg Pentasa, (Shire). Tablets, delayed-release: 400 mg Asacol, (Procter & Gamble). Rectal: Suppositories: 500 mg Canasa, (Axcan Scandipharm); 1 g Canasa, (Axcan Scandipharm). Suspension: 4 g/60 mL Mesalamine Suspension Enema, (Clay-Park), Mesalamine Suspension Enema, (Teva), Rowasa Suspension Enema (with potassium metabisulfite), (Solvay).|Oral: Tablet Delayed Release: 1.2 g Lialda (Shire).

Benzoic acid, 5-amino-2-hydroxy-: ACTIVE|One of the top 25 English prescription pharmaceuticals in 2000.

Analyte: mesalamine; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: mesalamine; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards|Analyte: mesalamine; matrix: chemical purity; procedure: liquid chromatography with detection at 254 nm and comparison to standards|Analyte: mesalamine; matrix: pharmaceutical preparation (delayed-release tablet; extended-release capsule); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification)|For more Analytic Laboratory Methods (Complete) data for MESALAMINE (7 total), please visit the HSDB record page.

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