Laropiprant

Laropiprant

Systematic (IUPAC) name
(-)-[(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetic acid
Clinical data
AHFS/Drugs.com	International Drug Names
Licence data	EMA:Link
Pregnancy cat.	?
Legal status	?
Routes	Oral
Identifiers
CAS number	571170-77-9 Y
ATC code	C10AD52 (combination with niacin)
UNII	G7N11T8O78 N
KEGG	D08940 Y
ChEMBL	CHEMBL426559 N
Synonyms	MK-0524A
Chemical data
Formula	C21H19ClFNO4S
Mol. mass	435.90 g/mol
N(what is this?)  (verify)

Laropiprant (INN) is used in combination with niacin to reduce blood cholesterol (LDL and VLDL). Merck & Co. planned to market this combination under the trade names Cordaptive and Tredaptive. On April 28, 2008, the U.S. Food and Drug Administration (FDA) issued a "not approved" letter for Cordaptive.^[1] Tredaptive was approved by the European Medicines Agency (EMA) on July 3, 2008.^[2]

Laropiprant itself has no cholesterol lowering effect, but it reduces facial flushes induced by niacin. In a trial with 1613 patients, 10.2% patients stopped taking the medication in the Cordaptive group versus 22.2% under niacin monotherapy.^[3]

Tredaptive contains 1000 mg of niacin and 20 mg of laropiprant in each tablet.^[4]

Mechanism of action

Niacin in cholesterol lowering doses (500–2000 mg per day) causes facial flushes by stimulating biosynthesis of prostaglandin D₂, especially in the skin. PG D₂ acts as a vasodilator via DP₁ receptors, increasing blood flow and thus leading to flushes.^[4][5]

Laropiprant acts as a DP₁ antagonist, reducing the vasodilation.^[4]

Taking 650 mg of aspirin 20–30 minutes prior to taking niacin has also been proven to prevent flushing in 90% of patients, presumably by suppressing prostaglandin synthesis,^[6] but this medication also increases the risk of gastrointestinal bleeding,^[7] though the increased risk is less than 1 percent.^[8]

References

1. ^ Carey, John (April 29, 2008). "FDA Rejects Merck's Cordaptive". BusinessWeek. http://www.businessweek.com/bwdaily/dnflash/content/apr2008/db20080429_182260.htm. Retrieved 2009-11-13. 
2. ^ "Tredaptive European Public Assessment Report". European Medicines Agency. http://www.emea.europa.eu/humandocs/Humans/EPAR/tredaptive/tredaptive.htm. Retrieved November 13, 2009. 
3. ^ Lai E, De Lepeleire I, Crumley TM, et al. (June 2007). "Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1". Clin. Pharmacol. Ther. 81 (6): 849–57. doi:10.1038/sj.clpt.6100180. PMID 17392721. 
4. ^ ^{a b c} "Tredaptive Prescribing Information" (PDF). Merck & Co.. http://www.merck.com/newsroom/pdf/Tredaptive_pi.pdf. Retrieved 2009-11-14. 
5. ^ Sood, A.; Arora, R. (2009). "Mechanisms of Flushing Due to Niacin and Abolition of These Effects". The Journal of Clinical Hypertension 11 (11): 685. doi:10.1111/j.1559-4572.2008.00050.x. PMID 19878384.  edit
6. ^ Richard A. Kunin (1976). "The Action of Aspirin in Preventing the Niacin Flush and its Relevance to the Antischizophrenic Action of Megadose Niacin" (PDF). Orthomolecular Psychiatry 5 (2): 89–100. http://www.orthomolecular.org/library/jom/1976/pdf/1976-v05n02-p089.pdf. Retrieved 2009-11-14. 
7. ^ Sørensen HT, Mellemkjaer L, Blot WJ, et al. (September 2000). "Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin". Am. J. Gastroenterol. 95 (9): 2218–24. doi:10.1111/j.1572-0241.2000.02248.x. PMID 11007221. 
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