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Indomethacin

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General Features                  Clinical Study                  Chemical Intervention                 Pharmacological Aspects                 
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GENERAL FEATURES

-
Name: Indomethacin
Generic Names: 2-(1-(4-chlorobensoyl)-5-metoxi-2-methyl-3-indolyl-acetic acid[1]
1-(p-chlorobenzyl)-5-methoxy-2- methyl-3-indole acetic acid][2]
1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid[3],[4],[5],[6],[7]
MK 615[6]
Trade Names: Indocid®[8],[5],[7]
IUPAC name: (2-{1-[(4-chlorophenyl)- carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}acetic acid)[9]
Molecular Weight: 357.8 g/mol[10],[6]
Structure:
[3],[11],[5],[12],[13],[14],[9],[7]
Functional Group/
chemical
constitution:
The functional groups responsible for hydrogen radical scavenging in indomethacin are
N – C = O and [15].
Carbo- and heterocyclic acetic acids[14]
The indole, p-chlorophenyl, and carboxylic acid groups are each nearly planar[3]
Chemical Nature: Aryl-alkanoic derivative[16]
mentioned to be electron affinic and calcium antagonist[17]
It is relatively insoluble in water but soluble in the common organic solvents[6]
Actions
& Indications:
Pharmcological Action-
inhibitor of prostaglandin synthesis[18],[27] [19]
tocolytic drug[20]
non-steroidal anti-inflammatory drug(NSAID)[20], [6]
anti-tumor effect in mice[21], in human in vitro and in vivo[22]
immunomodulator[17]
analgesic[19]
antipyretic[19],[4],[6]
Therapeutic indications:
It is shown to be effective analgesic in patients with rheumatoid arthritis in clinical settings[23],[24]
It is proved to be effective in patients with gout, rheumatoid arthritis, ankylosing spondilitis, and osteoarthritis [6]
Preclinical study-
It inhibits cotton pellet granuloma formation in the rat[4]
Indomethacin is a potent inhibitor of edema induced in the rat's foot by carrageenin[4]
Notes: It is suggested that the eicosanoid profile of tumors could serve as a key to select patients likely to respond to indomethacin treatment[27]
Male germfree rats were found to be resistant to indomethacin-induced intestinal lesion and ulcers, while female germfree rats developed very mild lesions[25]
In a 72-hr study with rats, it was found that food deprivation only on the day of indomethacin administration prevented the intestinal perforations, while feeding the rats on the day of drug administration resulted in 100% ulcer incidence. The incidence of intestinal perforation could be altered by the duration of food deprivation and the amount of food consumed.[26]
it is fully active even in adrenalectomized animals.[6]
REFERENCES
1. Blomgren H et al, In vitro capacity of various cyclooxygenase inhibitors to revert immune suppression caused by radiation therapy for breast cancer. Radiother Oncol. 1990;19(4):329-35.
http://dx.doi.org/10.1016/0167-8140(90)90033-S
2. Pennington SN, Smith CP, Indomethacin stimulation of lipid peroxidation and chemiluminescense in rat liver microsomes. Lipids 1978;13(10):636-643.
http://dx.doi.org/10.1007/BF02533738
3. Kistenmacher TJ, Marsh RE, Crystal and molecular structure of an antiinflammatory agent, indomethacin, 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid. J. Am. Chem. Soc. 1972;94 (4):1340–1345.
http://dx.doi.org/10.1021/ja00759a047
4. Winter CA, Risley EA, Nuss GW, Anti-inflammatory and antipyretic activities of indomethacin(1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid). J Pharmacol Exp Ther. 1963 ;141:369-76.
http://www.ncbi.nlm.nih.gov/pubmed/14064201
5. Harman RE et al, The metabolites of indomethacin. A new anti-inflammatory drug. JPET 1964;143 (2):215-220.
http://jpet.aspetjournals.org/content/143/2/215.short
6. Hart FD, Boardman PL, Indomethacin: A new non-steroid anti-inflammatory agent. Br Med J. 1963;2(5363):965-70.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873102/
7. Hucker HB et al, Studies on the absorption, distribution and excretion of indomethacin in various species. JPET 1966 ;153(2): 237-249.
http://jpet.aspetjournals.org/content/153/2/237.abstract
8. Rainsford KD, An analysis of the gastro-intestinal side-effects of non-steroidal anti-inflammatory drugs, with particular reference to comparative studies in man and laboratory species. Rheumatol Int. 1982;2(1):1-10.
http://dx.doi.org/10.1007/BF00541263
9. Ukmar T et al, Structural and dynamical properties of indomethacin molecules embedded within the mesopores of SBA-15: A solid-state NMR view. J. Phys. Chem. C 2012;116 (4):2662–2671.
http://dx.doi.org/10.1021/jp2087016
10. Song CW, Drescher JJ, Tabachnick J, Effect of anti-inflammatory compounds on Beta-irradiation-induced increase in vascular permeability. Radiat. Res. 1968;34(3):616-625.
http://dx.doi.org/10.2307/3572506
11. Remmel RP et al, Studies on the metabolism of the novel, selective cyclooxygenase-2 inhibitor indomethacin phenethylamide in rat, mouse, and human liver microsomes: identification of active metabolites. Drug Metab Dispos. 2004;32(1):113-22.
http://dx.doi.org/10.1124/dmd.32.1.113
12. Burleigh ME et al, Inhibition of cyclooxygenase with indomethacin phenethylamide reduces atherosclerosis in apoE-null mice. Biochem Pharmacol. 2005;70(3):334-42.
http://dx.doi.org/10.1016/j.bcp.2005.04.044
13. Zhou SF et al, Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
http://dx.doi.org/10.2174/092986709789057635
14. Perrone MG et al, Selective COX-1 inhibition: A therapeutic target to be reconsidered. Curr Med Chem. 2010;17(32):3769-805.
http://dx.doi.org/10.2174/092986710793205408
15. Upadhyay SN, Chaudhury NK, Lahiri SS, A preliminary study on the survival pattern of mice with radioprotectors. IJNM 2004;19(2): 36-44.
http://medind.nic.in/iaw/t04/i2/iawt04i2p36.pdf
16. Famaey JP, Whitehouse MW, Interaction between nonsteroidal anti-inflammatory drugs and biological membranes-IV. Effects of nonsteroidal anti-inflammatory drugs and of various ions on the availability of sulfhydryl groups on lymphoid cells and mitochondrial membranes. Biochem Pharmacol. 1975;24(17):1609-15.
http://dx.doi.org/10.1016/0006-2952(75)90088-X
17. Shenoy MA, Singh BB, Studies on indomethacin as a potentiator for hyperthermic and radiation responses in a mouse fibrosarcoma. Cancer Letters 1989;45(3):227-232.
http://dx.doi.org/10.1016/0304-3835(89)90082-7
18. Furuta Y et al, Increase in radioresponse of murine tumors by treatment with indomethacin. Cancer Res. 1988;48(11):3008-13.
http://www.ncbi.nlm.nih.gov/pubmed/3365690
19. Vane JR, Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231(25):232-5.
http://dx.doi.org/10.1038/newbio231232a0
20. Loudon JA, Groom KM, Bennett PR, Prostaglandin inhibitors in preterm labour. Best Pract Res Clin Obstet Gynaecol. 2003;17(5):731-44.
http://www.ncbi.nlm.nih.gov/pubmed/12972011
21. Lynch NR et al, Mechanism of inhibition of tumour growth by aspirin and indomethacin. Br J Cancer. 1978;38(4):503-12.
http://www.ncbi.nlm.nih.gov/pubmed/365211
22. Wang HM, Zhang GY, Effect of indomethacin on human colorectal cancer cells HCT116 and SW480. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2004;29(1):28-31.
http://www.ncbi.nlm.nih.gov/pubmed/16136999
23. Wright V, Walker WC, McGuire RJ, Indomethacin in the treatment of rheumatoid arthritis. A controlled trial comparing indomethacin, phenylbutazone, and placebo. Ann Rheum Dis. 1969; 28(2): 157–162.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1031124/
24. Rothermich NO, An extended study of indomethacin. II. Clinical therapy. JAMA. 1966;195(13):1102-6.
http://dx.doi.org/10.1001/jama.1966.03100130076020
25. Robert A, Asano T, Resistance of germfree rats to indomethacin-induced intestinal lesions. Prostaglandins. 1977;14(2):333-41.
http://dx.doi.org/10.1016/0090-6980(77)90178-2
26. Brodie DA et al, Indomethacin-induced intestinal lesions in the rat. Toxicol Appl Pharmacol. 1970;17(3):615-24.
http://dx.doi.org/10.1016/0041-008X(70)90036-0
27. Furuta Y et al, Prostaglandin production by murine tumors as a predictor for therapeutic response to indomethacin. Cancer Res. 1988;48(11):3002-7.
http://www.ncbi.nlm.nih.gov/pubmed/3130182