Laropiprant

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Niacin/laropiprant
Combination of
Niacin Hypolipidemic agent
Laropiprant Prostaglandin receptor antagonist
Clinical data
Trade names Cordaptive, Tredaptive
AHFS/Drugs.com UK Drug Information
Licence data EMA:Link
Legal status
  • Withdrawn
Routes Oral
Identifiers
CAS number  N
ATC code C10AD52
PubChem CID 11948701
 N (what is this?)  (verify)
Laropiprant
Laropiprant.png
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
Legal status
  • Withdrawn
Identifiers
CAS number 571170-77-9 YesY
ATC code None
PubChem CID 9867642
ChemSpider 8043333
UNII G7N11T8O78 N
KEGG D08940 YesY
ChEMBL CHEMBL426559 N
Synonyms MK-0524A
Chemical data
Formula C21H19ClFNO4S 
Molecular mass 435.90 g/mol
 N (what is this?)  (verify)

Laropiprant (INN) is a drug used in combination with niacin to reduce blood cholesterol (LDL and VLDL). Merck & Co. planned to market this combination under the trade names Cordaptive in the US and Tredaptive in Europe. Both brands contain 1000 mg of niacin and 20 mg of laropiprant in each tablet.[1] Laropiprant itself has no cholesterol lowering effect, but it reduces facial flushes induced by niacin.

Mechanism of action[edit]

Niacin in cholesterol lowering doses (500–2000 mg per day) causes facial flushes by stimulating biosynthesis of prostaglandin D2 (PGD2), especially in the skin. PGD2 dilates the blood vessels via activation of prostaglandin D2 receptors (DP1), increasing blood flow and thus leading to flushes.[1][2] Laropiprant acts as a DP1 antagonist, reducing the vasodilation.[1]

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,[3] but this medication also increases the risk of gastrointestinal bleeding,[4] though the increased risk is less than 1 percent.[5]

History[edit]

In the mid-2000s, in a trial with 1613 patients, 10.2% patients stopped taking the medication in the combination drug group versus 22.2% under niacin monotherapy.[6]

On April 28, 2008, the U.S. Food and Drug Administration (FDA) issued a "not approved" letter for Cordaptive.[7] Tredaptive was approved by the European Medicines Agency (EMA) on July 3, 2008.[8]

On January 11, 2013, Merck & Co Inc. announced they were withdrawing the drug worldwide as a result of European regulators recommendations.[9]

The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) involved more than 25,000 adults. The treatment group received 2 g of extended-release niacin and 40 mg of laropiprant daily. Study results, reported in July 2014, showed that the combination of niacin and laropiprant did not have any beneficial effects when compared with a placebo treatment and had an increase in adverse effects. [10]

References[edit]

  1. ^ a b c "Tredaptive Prescribing Information" (PDF). Merck & Co. Retrieved 2009-11-14. 
  2. ^ Sood, A.; Arora, R. (2009). "Mechanisms of Flushing Due to Niacin and Abolition of These Effects". The Journal of Clinical Hypertension 11 (11): 685–9. doi:10.1111/j.1559-4572.2008.00050.x. PMID 19878384.  edit
  3. ^ 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. Retrieved 2009-11-14. 
  4. ^ 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. 
  5. ^ "For Healthy People Daily Aspirin May Do More Harm Than Good". Medical News Today. 31 August 2009. 
  6. ^ 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. 
  7. ^ Carey, John (April 29, 2008). "FDA Rejects Merck's Cordaptive". BusinessWeek. Retrieved 2009-11-13. 
  8. ^ "Tredaptive European Public Assessment Report". European Medicines Agency. Retrieved November 13, 2009. 
  9. ^ "Merck withdraws cholesterol drug Tredaptive globally". Reuters. January 11, 2013. Retrieved 11 January 2013. 
  10. ^ The HPS2-THRIVE Collaborative Group (July 17, 2014). "Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients". New England Journal of Medicine 371: 203–212. doi:10.1056/NEJMoa1300955. Retrieved 2014-10-27.