hCOX-1 (IC50 = 18 nM in CHO cells); hCOX-2 (IC50 = 26 nM in CHO cells)

In vitro antitumor activity of indomethacin (Indometacin) (0-150 μM; 24 hours; 3LL-D122 cells) has been reported [2]. By activating PKR and phosphorylating eF2α, indomethacin (Indometacin) (0-1000 μM) inhibits viral replication (IC50=2 μM) and stops viral protein translation, protecting host cells from viral harm [3]. M1 type RAW 264.7 cells undergo M2 type differentiation when exposed to 8 μM of indomethacin for 26 hours [4]. Human adipose-derived stem cells undergo transdifferentiation into neurogenic-like cells when exposed to indomethacin (200 μM) for five days [5].

Using indomethacin (IND), gastric ulcer model can be generated in animals as detailed below:
Generation of Gastric Ulcer Model: all animals fasted 24 h before drug administration. Except for the control group, ulcers were induced by administering IND to the three experimental study groups, namely IND, IND+ ESP and IND + CA. The same volume of physiological saline was administered to the experimental animals as to the control group. 50 mg/kg ketamine and 5 mg/kg xylazine were administered to rats 6 h after IND administration. Anesthetized rats were euthanized by cervical dislocation, after which tissue samples were collected. Specifically, the stomach was opened along the greater curvature and washed with physiological saline at 4 °C. Washed stomach tissues were stored in tubes containing 10% formalin for histological procedures and at −800 °C for biochemical determination until analyses. Hematoxylin-eosin staining of the taken tissues was evaluated histopathologically and immunohistochemically.[6]

Determination of Ki and k2 values for the time-dependent inhibition of COX-2[1]
Purified COX-2 (2.3 μg) was preincubated with inhibitor for 0–15 min in 180 μl of the reaction buffer described above, before the initiation of the reaction with a mixture of arachidonic acid and TMPD. The cyclo-oxygenase activity was determined by the spectrophotometric method as described above. For experiments performed without preincubation of the inhibitor, the reaction was initiated by addition of the assay mixture containing the enzyme to the inhibitor and arachidonic acid/TMPD ethanolic solution. The rate constants (kobs) for the time-dependent loss of activity at each inhibitor concentration were calculated by fitting of the data to a first order equation of the form y=a + b.exp(–kobst) by use of Sigmaplot software. Data were analysed in terms of the model developed by Rome and Lands (1975) for the time-dependent inhibition of ovine COX-1. In this model (Scheme 1), an initial reversible binding of enzyme and inhibitor (characterized by the dissociation constant Ki) is followed by a first order inactivation process (characterized by a first order rate constant k2). The rate of reversal of this process (k–2) is considered to be negligible.

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Determination of the stoichiometry of inhibitor binding[1]
Aliquots of purified COX-2 (0.25 mg ml-1, concentration of subunit of 3.4 μm) were incubated in buffer (100 mm Tris-HCl, pH 8.0, 5 mm EDTA, 1 mm phenol) in the presence of varying concentrations of inhibitors (0–8 μm) for 15 or 30 min. An aliquot (20 μl) was then removed for determination of the remaining cyclo-oxygenase activity by oxygen uptake as described above. Enzyme concentration was determined by amino acid concentration following acid hydrolysis (Percival et al., 1994).

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Competition of time-dependent inhibition of COX-2 by arachidonic acid[1]
Purified COX-2 (3.6 μg) was diluted into preincubation buffer (0.03 ml, 100 mm Tris-HCl, pH 8.0, 5 mm EDTA, 2 mm phenol) containing 60 mm diethyldithiocarbamic acid to prevent substrate oxygenation (Lands et al., 1974) and either 10 μm inhibitor, or 10 μm inhibitor plus 5 μm arachidonic acid, or 10 μm inhibitor plus 30 μm arachidonic acid. After a preincubation period of 0–4 min, the total enzyme was assayed for enzymatic activity by oxygen consumption at 30°C as described above.

Assay of cellular COX activity[2]
Cultured cells were treated with indomethacin (0.1–50 μM) for 30 min, after which arachidonic acid was added (15 μM final concentration) and the cells incubated for 15 min. The media were analyzed by radioimmunoassay using anti-PGE2 (prostaglandin E2) antisera from Sigma. Assay of platelet COX-1 activity was performed by withdrawing blood from the mice by orbital eye bleeding and allowing it to clot at 37° for 15 min. The resulting serum was assayed for thromboxane B2 (TXB2) by radioimmunoassay using anti-TXB2 antisera.

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Indomethacin added to cultured Lewis lung carcinoma cells exerted a potent antiproliferative effect ((3)H thymidine assay) and reduced cell viability (MTT[3-(4,5-dimethyl(thiazol-2-yl)-2,5 diphenyl tetrazolium bromide] assay) at low doses (10-20 μM/microM) in parallel with its inhibitory effect on cellular cyclooxygenase. These effects of indomethacin appeared to arise from a clear antiproliferative shift in the profile of the cell cycle parameters towards a reduced percentage of cells at the S and G(2)/M phases, together with an increased percentage of cells at the G(1) phase.[2]

Animal/Disease Models: Male SD (Sprague-Dawley) rats[1]
Doses: 0.01-10 mg/kg
Route of Administration: Oral administration; for 3 hrs (hours)
Experimental Results: Inhibited the carrageenan-induced rat paw oedema (ED50=2.0 mg/kg) and hyperalgesia (ED50= 1.5 mg/kg) in a dose-dependent manner.

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Animal/Disease Models: Male C57BL/6J mice[2]
Doses: 10 mg/mL
Route of Administration: Oral administration; daily, for 29 days
Experimental Results: Delayed the onset of tumor growth and the initial growth rate of the footpad tumors.

Absorption, Distribution and Excretion
Indometacin displays a linear pharmacokinetics profile where the plasma concentrations and area under the curve (AUC) are dose-proportional, whereas half-life (T1/2) and plasma and renal clearance are dose-dependent. Indometacin is readily and rapidly absorbed from the gastrointestinal tract. The bioavailability is virtually 100% following oral administration and about 90% of the dose is absorbed within 4 hours. The bioavailability is about 80-90% following rectal administration. The peak plasma concentrations following a single oral dose were achieved between 0.9 ± 0.4 and 1.5 ± 0.8 hours in a fasting state. Despite large intersubject variation as well using the same preparation, peak plasma concentrations are dose-proportional and averaged 1.54 ± 0.76 μg/mL, 2.65 ± 1.03 μg/mL, and 4.92 ± 1.88 μg/mL following 25 mg, 50 mg, and 75 mg single doses in fasting subjects, respectively. With a typical therapeutic regimen of 25 or 50 mg t.i.d., the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose.
Indometacin is eliminated via renal excretion, metabolism, and biliary excretion. It is also subject to enter the enterohepatic circulation through excretion of its glucuronide metabolites into bile followed by resorption of indometacin after hydrolysis. The extent of involvement in the enterohepatic circulation ranges from 27 to 115%. About 60 percent of an oral dosage is recovered in urine as drug and metabolites (26 percent as indomethacin and its glucuronide), and 33 percent in the feces (1.5 percent as indomethacin).
The volume of distribution ranged from 0.34 to 1.57 L/kg following oral, intravenous, or rectal administration of single and multiple doses of indometacin in healthy individuals. Indometacin is distributed into the synovial fluid and is extensively bound to tissues. It has been detected in human breast milk and placenta. Although indometacin has been shown to cross the blood-brain barrier (BBB), its extensive plasma protein binding allows only the small fraction of free or unbound indometacin to diffuse across the BBB.
In a clinical pharmacokinetic study, the plasma clearance of indometacin was reported to range from 1 to 2.5 mL/kg/min following oral administration.
Patent ductus arteriosus (PDA) is a frequent complication in premature infants. Intravenous indomethacin is the standard mode of medical therapy and has been shown to be efficacious in closing the ductus. In our setup, oral indomethacin is being regularly used for medical treatment of suspected or clinically diagnosed PDA. Non-availability of the parenteral preparation and lack of information regarding the pharmacokinetic disposition of indomethacin in the premature infants in north Indian population led us to conduct this pharmacokinetic study with oral indomethacin. Twenty premature infants with gestational age 30.3 +/- 0.3 wk and birth weight, 1209.8 +/- 39.5 g; admitted to the neonatal unit of the Nehru Hospital, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh were enrolled in the study. Indomethacin was administered in a single oral dose of 0.2 mg/kg and blood samples were collected through an indwelling vascular catheter at 0 and 1, 2, 4, 8 and 12 hr after administration of indomethacin. Plasma indomethacin concentrations were assayed by spectrofluorometric technique. Large interindividual variability was observed for peak plasma concentrations (Cmax; 137.9 +/- 14.0 ng/mL), elimination half-life (t1/2 el; 21.4 +/- 1.7 hr) and area under the plasma concentrations time curve (AUC0-infinity;4172 +/- 303 ng.hr/mL) in these infants. Variables like birth weight, and sex did not have any sigiificant effect on indomethacin pharmacokinetics. However, the plasma t1/2 el of indomethacin was significantly (P < 0.01) larger in older infants (gestational age > 30 wk) in comparison to younger ones (gestational age < or = 30 wk). There was a negative correlation between gestational age and elimination t1/2 (r = -0.77). In conclusion, indomethacin pharmacokinetics showed a wide variability in premature infants. In view of these findings it can be suggested that infants of smaller gestational age are at greater risk of cumulative toxicity if more than one dose of indomethacin is given. With advancing age, metabolism as well as elimination of drug is faster that may require modification in indomethacin dose to achieve therapeutic response. These preliminary results may be of use in designing future pharmacokinetic studies of oral indomethacin in preterm neonates on a larger sample.
Approximately 33% or more of a 25-mg oral dose of indomethacin is excreted in feces principally as demethylated metabolites in their unconjugated forms; 1.5% of fecal drug excretion occurs as indomethacin. Indomethacin and its conjugates undergo enterohepatic circulation.
In one study in healthy fasting adults, peak plasma concentrations of indomethacin occurred in 0.5-2 hours and were about 0.8-2.5 ug/mL following a 25-mg oral dose, and 2.5-4 ug/mL following a 50-mg oral dose. When indomethacin was administered orally to healthy fasting individuals in 25-mg doses 3 times daily, mean steady-state plasma drug concentrations ranged from 0.39-0.63 ug/mL.
In premature neonates, absorption of oral indomethacin appears to be poor and incomplete; bioavailability is reportedly only about 20%. It has been suggested that poor oral absorption of the drug in premature neonates may result from abnormal pH-dependent diffusion and gastric motility and from lower gastric acid secretion. In neonates, gastric emptying time and motility are increased and peristalsis is irregular and unpredictable. In addition, the lack of solubility of the capsule form of indomethacin in aqueous media may present problems in drug delivery and absorption from extemporaneous preparations.
For more Absorption, Distribution and Excretion (Complete) data for INDOMETHACIN (20 total), please visit the HSDB record page.

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Metabolism / Metabolites
Indometacin undergoes hepatic metabolism involving glucuronidation, O-desmethylation, and N-deacylation. O-desmethyl-indomethacin, N-deschlorobenzoyl-indomethacin, and O-desmethyl-N-deschlorobenzoyl-indomethacin metabolites and their glucuronides are primarily inactive and have no pharmacological activity. Unconjugated metabolites are also detected in the plasma. Its high bioavailability indicates that indometacin is unlikely to be subject to the first-pass metabolism.
Indomethacin is metabolized in the liver to its glucuronide conjugate and to desmethyl, desbenzoyl, and desmethyl-desbenzoyl metabolites and their glucuronides. These metabolites do not appear to possess anti-inflammatory activity. A portion of the drug is also N-deacylated by a nonmicrosomal system.
Indomethacin has known human metabolites that include (2S,3S,4S,5R)-6-[2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetyl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid and O-Desmethylindomethacin.
Hepatic.
Route of Elimination: Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion.
Half Life: 4.5 hours

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Biological Half-Life
Indometacin disposition from the plasma is reported to be biphasic, with a half-life of 1 hour during the initial phase and 2.6–11.2 hours during the second phase. Interindividual and intraindividual variations are possible due to the extensive and sporadic nature of the enterohepatic recycling and biliary discharge of the drug. The mean half-life of oral indomethacin is estimated to be about 4.5 hours. The disposition of intravenous indometacin in preterm neonates was shown to vary across premature infants. In neonates older than 7 days, the mean plasma half-life of intravenous indometacin was approximately 20 hours, ranging from 15 hours in infants weighing more than 1000 g and 21 hours in infants weighing less than 1000 g.
Plasma concentrations of indomethacin have been studied in 5 healthy volunteers after single and multiple doses (25 mg intravenously [iv], 25, 50, and 100 mg orally, 100 mg rectally, and 25 mg three times daily [tid]. In 8 other normal subjects and in 5 patients a 50-mg oral dose of indomethacin was given and the indomethacin concentration was followed from 8 to 32 hr after dosing. ... The half-life of the beta-phase varied between 2.6 and 11.2 hr.
In premature neonates, the serum or plasma elimination half-life of indomethacin is inversely related to postnatal age. In a limited number of neonates, the mean plasma half-life of indomethacin has been reported to be about 20-28 hours in those receiving the drug during the first week of life, compared to about 12-19 hours in those receiving the drug after the first week. The elimination half-life in neonates may also be inversely related to body weight. In one study, the plasma indomethacin half-life showed considerable interindividual variation but averaged 21 hours in neonates weighing less than 1 kg and 15 hours in those weighing more than 1 kg. Total body clearance of indomethacin increases with increasing postnatal age. It was suggested that extensive enterohepatic circulation may commonly occur in premature neonates and may contribute to the relatively long half-life of elimination.
In studies in healthy adults or patients with rheumatoid arthritis, the disappearance of indomethacin from plasma appears to be biphasic with a half-life of approximately 1 hour during the initial phase and 2.6-11.2 hours during the second phase; variations in terminal plasma half-life may be due to individual differences in enterohepatic circulation of the drug. There appears to be no difference between plasma half-life in healthy adults and in rheumatoid arthritis patients.
In one study in healthy adults and patients with arthritis, the half-life for disappearance of indomethacin from synovial fluid was 9 hours.
... Twenty premature infants with gestational age 30.3 +/- 0.3 wk and birth weight, 1209.8 +/- 39.5 g; admitted to the neonatal unit of the Nehru Hospital, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh were enrolled in the study. Indomethacin was administered in a single oral dose of 0.2 mg/kg and blood samples were collected through an indwelling vascular catheter at 0 and 1, 2, 4, 8 and 12 hr after administration of indomethacin. Plasma indomethacin concentrations were assayed by spectrofluorometric technique. Large interindividual variability was observed for peak plasma concentrations (Cmax; 137.9 +/- 14.0 ng/mL), elimination half-life (t1/2 el; 21.4 +/- 1.7 hr) and area under the plasma concentrations time curve (AUC0-infinity;4172 +/- 303 ng.hr/mL) in these infants. Variables like birth weight, and sex did not have any sigiificant effect on indomethacin pharmacokinetics. However, the plasma t1/2 el of indomethacin was significantly (P < 0.01) larger in older infants (gestational age > 30 wk) in comparison to younger ones (gestational age

Toxicity Summary
IDENTIFICATION AND USE: Indomethacin is a pale-yellow to yellow-tan, crystalline powder. It is an anti-inflammatory drug. It is also indicated to close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1,750 g when 48 hours usual medical management is ineffective. HUMAN EXPOSURE AND TOXICITY: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. Elderly patients are at greater risk for serious gastrointestinal events. NSAIDs may also cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke. Severe reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have been reported in patients receiving NSAIDs. Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving indomethacin. Drowsiness, lethargy, mental confusion, nausea, vomiting, paresthesia, numbness, aggressive behavior, disorientation, and seizures have been reported following acute overdosage of the drug. Exposure of the fetus to indomethacin by administration of the drug to the mother may cause many side effects, including premature closure of the ductus arteriosus. Short-term indomethacin administered within 4 days prior to delivery resulted in a transient, yet significant renal dysfunction. ANIMAL STUDIES: Acute oral administration of indomethacin to rats induced macroscopic and microscopic damage to the small intestine, increased translocation of enterobacteria from lumen into the mucosa, myeloperoxidase activity and lipid peroxidation. After subchronic exposure to indomethacin for six to 12 weeks, rats displayed microcytic anemia, hypoalbuminemia, small intestinal ulceration, cecal ulceration and inconspicuous raised mucosal lesions in the cecum that histologically showed submucosal fibrosis with disruption and thickening of the apical muscularis mucosa. Indomethacin had no effect on fertility in rats or mice at dosages up to 0.5 mg/kg daily. In rats and mice, 4 mg/kg/day given during the last three days of gestation caused a decrease in maternal weight gain and some maternal and fetal deaths. An increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses was observed. Teratogenic studies were conducted in mice and rats at dosages of 0.5, 1, 2, and 4 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Indomethacin did not have any mutagenic effect in in vitro bacterial tests (Ames test and E. coli with or without metabolic activation) and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethal mutations in Drosophila, and the micronucleus test in mice. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day.
Antiinflammatory effects of Indomethacin are believed to be due to inhibition of cylooxygenase in platelets which leads to the blockage of prostaglandin synthesis. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Indomethacin is a prostaglandin G/H synthase (also known as cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2 (COX-1 and -2). Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to a number of prostaglandins involved in fever, pain, swelling, inflammation, and platelet aggregation. Indomethacin antagonizes COX by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Indomethacin, unlike other NSAIDs, also inhibits phospholipase A2, the enzyme responsible for releasing arachidonic acid from phospholipids. Indomethacin is more selective for COX-1 than COX-2, which accounts for its increased adverse gastric effects relative to other NSAIDs. COX-1 is required for maintaining the protective gastric mucosal layer. The analgesic, antipyretic and anti-inflammatory effects of indomethacin occur as a result of decreased prostaglandin synthesis. Its antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation.

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Hepatotoxicity
Mild and transient elevations in serum aminotransferase levels are found in up to 15% of patients taking indomethacin chronically. Moderate ALT elevations (>3 times ULN) occur in less than 1% of patients. Frank liver injury with jaundice from indomethacin is rare (estimated at 1.1 per 100,000 prescriptions), and fewer than a dozen cases have been reported in the literature. The latency to onset of symptoms or jaundice is variable, but is usually within 1 to 8 weeks of starting, although instances of latency of 4 to 6 months have been reported. Patients present with anorexia, nausea and vomiting followed by jaundice. Hepatocellular patterns of enzyme elevations are most common, but cholestatic and mixed patterns have been reported. Allergic manifestations and autoimmune features are not common. The injury is usually self-limited, resolving in 1 to 3 months, but several fatal cases have been reported (Case 1), particularly after use of high doses in patients with juvenile rheumatoid arthritis or Still disease. Many of the reported cases of severe indomethacin associated hepatotoxicity have occurred in patients with a pre-existing, underlying chronic liver disease.
Likelihood score: C (probable rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because of the low levels of indomethacin in breastmilk and therapeutic administration directly to infants, it is acceptable to use in nursing mothers. However, other agents with more published information on use during lactation may be preferable, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
In one case report, a breastfeeding mother had been taking daily doses of indomethacin that increased to 200 mg (3 mg/kg) from the fourth to the sixth day postpartum. On the same day that indomethacin was stopped, the infant had a generalized seizure, followed by another on the next day. No metabolic findings could account for the convulsions and no indomethacin levels were measured in the mother or infant. This case was rated as indomethacin possibly causing the seizure; however, later studies and the established therapeutic use of indomethacin in newborns make this causality seem unlikely.
In one study, 7 women breastfed their neonates while taking indomethacin. No adverse effects were noted in any of the infants.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Indometacin is a weak organic acid that is 90-99% bound to protein in plasma over the expected range of therapeutic plasma concentrations. Like other NSAIDs, indometacin is bound to plasma albumin but it does not bind to red blood cells.

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Toxicity Data
LD50: 50 mg/kg (oral, mice) (based on 14 day mortality response)
LD50: 12 mg/kg (oral, rat) (based on 14 day mortality response)

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Interactions
Severe, sometimes fatal, toxicity has occurred following administration of a NSAIA (e.g., indomethacin, ketoprofen) concomitantly with methotrexate (principally high-dose therapy) in patients with various malignant neoplasms or rheumatoid arthritis. The toxicity was associated with elevated and prolonged blood concentrations of methotrexate. The exact mechanism of the interaction remains to be established, but it has been suggested that NSAIAs may inhibit renal elimination of methotrexate, possibly by decreasing renal perfusion via inhibition of renal prostaglandin synthesis or by competing for renal elimination. Further studies are needed to evaluate the interaction between NSAIAs and methotrexate. Caution is advised if methotrexate and a NSAIA are administered concomitantly.
A patient experienced a transient deterioration of renal function induced by indomethacin during recovery from idiosyncratic phenylbutazone-associated renal failure. Since both drugs inhibit prostaglandin synthesis, this patient may illustrate a unique enhancement of the more common and clinically unimportant effect of altered glomerular filtration rate induced by such drugs. The renal insufficiency per se associated with the idiosyncratic reaction to phenylbutazone may have also enhanced this patient's reaction to indomethacin. Careful observation of patients during administration of such drugs in this and other settings of acute renal failure appears warranted.
The effects of warfarin and NSAIAs on GI bleeding are synergistic.420 Concomitant use of indomethacin and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone. It appears that indomethacin has little, if any, direct influence on the hypoprothrombinemic effect of warfarin or other oral anticoagulants when these drugs are administered concurrently. Because indomethacin may cause GI bleeding and may inhibit platelet aggregation, the drug should be used with caution in patients receiving any anticoagulant or thrombolytic agent (e.g., streptokinase).
Severe systemic hypertension developed in a patient who took indomethacin shortly after ingesting an appetite suppressant ('Trimolets') containing phenylpropanolamine. The hypertension was attributed to a drug interaction whereby the inhibition of prostaglandin synthesis by indomethacin exacerbated the sympathomimetic effects of phenylpropanolamine. ...
For more Interactions (Complete) data for INDOMETHACIN (40 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 12 mg/kg
LD50 Mouse oral 50 mg/kg

[1]. Riendeau D, et, al. Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor. Br J Pharmacol. 1997 May;121(1):105-17.
[2]. Eli Y, et, al. Comparative effects of indomethacin on cell proliferation and cell cycle progression in tumor cells grown in vitro and in vivo. Biochem Pharmacol. 2001 Mar 1;61(5):565-71.
[3]. Amici C, et, al. Inhibition of viral protein translation by indomethacin in vesicular stomatitis virus infection: role of eIF2α kinase PKR. Cell Microbiol. 2015 Sep;17(9):1391-404.
[4]. Luo X, Xiong H, Jiang Y, et al. Macrophage Reprogramming via Targeted ROS Scavenging and COX-2 Downregulation for Alleviating Inflammation. Bioconjug Chem. 2023;34(7):1316-1326.
[5]. Kompisch KM, Lange C, Steinemann D, et al. Neurogenic transdifferentiation of human adipose-derived stem cells? A critical protocol reevaluation with special emphasis on cell proliferation and cell cycle alterations. Histochem Cell Biol. 2010;134(5):453-468.

Therapeutic Uses
Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Agents; Cyclooxygenase Inhibitors; Gout Suppressants; Tocolytic Agents
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Indomethacin is included in the database.
Carefully consider the potential benefits and risks of indomethacin capsules and other treatment options before deciding to use indomethacin. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. Indomethacin has been found effective in active stages of the following: Moderate to severe rheumatoid arthritis including acute flares of chronic disease. Moderate to severe ankylosing spondylitis. Moderate to severe osteoarthritis. Acute painful shoulder (bursitis and/or tendinitis). Acute gouty arthritis. /Included in US product labeling/
Indomethacin for Injection is indicated to close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1,750 g when 48 hours usual medical management (e.g., fluid restriction, diuretics, digitalis, respiratory support, etc.) is ineffective. Clear-cut clinical evidence of a hemodynamically significant patent ductus arteriosus should be present, such as respiratory distress, a continuous murmur, a hyperactive precordium, cardiomegaly, or pulmonary plethora on chest x-ray. /Included in US product label/
For more Therapeutic Uses (Complete) data for INDOMETHACIN (19 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ Cardiovascular Risk. Nonsteroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. Indomethacin is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.
/BOXED WARNING/ Gastrointestinal Risk. Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.
Indomethacin should be used with extreme caution and under close supervision in patients with a history of GI bleeding or peptic ulcer disease, and such patients should receive an appropriate ulcer preventive regimen. All patients considered at increased risk of potentially serious adverse GI effects (e.g., geriatric patients, those receiving high therapeutic dosages of NSAIAs, those with a history of peptic ulcer disease, those receiving anticoagulants or corticosteroids concomitantly) should be monitored closely for signs of ulcer perforation or GI bleeding. To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed. For patients who are at high risk, therapy other than an NSAIA should be considered.
Adverse dermatologic effects of indomethacin occur in less than 1% of patients and include pruritus, urticaria, rash, macular and morbilliform eruptions, erythema nodosum, petechiae or ecchymosis, exfoliative dermatitis, loss of hair, Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis.
For more Drug Warnings (Complete) data for INDOMETHACIN (43 total), please visit the HSDB record page.

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Pharmacodynamics
Indometacin is an NSAID with analgesic and antipyretic properties that exerts its pharmacological effects by inhibiting the synthesis of factors involved in pain, fever, and inflammation. Its therapeutic action does not involve pituitary-adrenal stimulation. Indometacin primarily works by suppressing inflammation in rheumatoid arthritis by providing relief of pain as well as reducing fever, swelling, and tenderness. This effectiveness has been demonstrated by a reduction in the extent of joint swelling, the average number of joints displaying symptoms of inflammation, and the severity of morning stiffness. Increased mobility was demonstrated by a decrease in total walking time and by improved functional capability seen as an increase in grip strength. In clinical trials, indometacin was shown to be effective in relieving the pain, reducing the fever, swelling, redness, and tenderness of acute gouty arthritis. Due to its pharmacological actions, the use of indometacin is associated with the risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, as well as gastrointestinal effects such as bleeding, ulceration, and perforation of the stomach or intestines. In a study of healthy individuals, acute oral and intravenous indometacin therapy resulted in a transiently diminished basal and CO2 stimulated cerebral blood flow; this effect disappeared in one study after one week of oral treatment. The clinical significance of this effect has not been established. Compared to other NSAIDs, it is suggested that indometacin is a more potent vasoconstrictor that is more consistent in decreasing cerebral blood flow and inhibiting CO2 reactivity. There have been studies that show indometacin directly inhibiting neuronal activity to some extent in the trigeminocervical complex after either superior salivatory nucleus or dural stimulation.

C19H16CLNO4

357.79

357.077

C, 63.78; H, 4.51; Cl, 9.91; N, 3.91; O, 17.89

53-86-1

Indomethacin;53-86-1;Indomethacin sodium hydrate;74252-25-8; 7681-54-1 (sodium); 87377-08-0

3715

White to off-white solid powder

1.32g/cm3

499.4ºC at 760 mmHg

155-162 °C

255.8ºC

3.927

1

4

4

25

506

0

CGIGDMFJXJATDK-UHFFFAOYSA-N

InChI=1S/C19H16ClNO4/c1-11-15(10-18(22)23)16-9-14(25-2)7-8-17(16)21(11)19(24)12-3-5-13(20)6-4-12/h3-9H,10H2,1-2H3,(H,22,23)

2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.81 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.81 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (5.81 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: ≥ 1.25 mg/mL (3.49 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 5: ≥ 1.25 mg/mL (3.49 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 6: ≥ 1.25 mg/mL (3.49 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)