Laropiprant
{{Short description|Chemical compound}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 408651073
| drug_name = nicotinic acid / laropiprant
| type = combo
| component1 = Nicotinic acid
| class1 = Hypolipidemic agent
| component2 = Laropiprant
| class2 = Prostaglandin receptor antagonist
| tradename = Cordaptive, Tredaptive, Trevaclyn, Pelzont{{Cite news |date=2013-12-02 |title=Tredaptive, Pelzont and Trevaclyn - referral | publisher=European Medicines Agency (EMA) |url=https://www.ema.europa.eu/en/medicines/human/referrals/tredaptive-pelzont-trevaclyn |access-date=2024-12-25 |language=en}}
| USAN = niacin/laropiprant
| Drugs.com = {{drugs.com|UK|tredaptive-1000-mg-20-mg-modified-release-tablets-1360}}
| MedlinePlus =
| licence_EU = yes
| INN_EMA = laropiprant
| pregnancy_AU =
| pregnancy_US =
| pregnancy_category =
| legal_AU =
| legal_CA =
| legal_UK =
| legal_US =
| legal_status = Withdrawn
| routes_of_administration = Oral
| index2_label = + niacin
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number2 = 1046050-73-0
| CAS_number = 571170-77-9
| ATC_prefix = C10
| ATC_suffix = AD52
| PubChem = 9867642
| PubChem2 = 11948701
| ChemSpiderID = 8392225
| UNII = G7N11T8O78
| ChEBI = 135942
| ChEMBL = 426559
| DrugBank = DB11629
| KEGG = D08940
| StdInChI=1S/C21H19ClFNO4S/c1-29(27,28)18-10-15(23)9-17-16-7-4-13(8-19(25)26)20(16)24(21(17)18)11-12-2-5-14(22)6-3-12/h2-3,5-6,9-10,13H,4,7-8,11H2,1H3,(H,25,26)/t13-/m1/s1
| StdInChIKey = NXFFJDQHYLNEJK-CYBMUJFWSA-N
| SMILES = CS(=O)(=O)C1=CC(=CC2=C1N(C3=C2CC[C@@H]3CC(=O)O)CC4=CC=C(C=C4)Cl)F
}}
{{Drugbox
| drug_name =
| Verifiedfields = changed
| verifiedrevid = 408651073
| IUPAC_name = (−)-[(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetic acid
| image = Laropiprant.svg
| Drugs.com = {{drugs.com|international|laropiprant}}
| legal_status = Withdrawn
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion =
| IUPHAR_ligand = 3356
| ATC_prefix = none
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 571170-77-9
| PubChem = 9867642
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = G7N11T8O78
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08940
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 426559
| ChemSpiderID = 8043333
| synonyms = MK-0524A
| chemical_formula =
| C=21 | H=19 | Cl=1 | F=1 | N=1 | O=4 | S=1
| smiles = O=S(=O)(c1cc(F)cc2c1n(c3c2CC[C@@H]3CC(=O)O)Cc4ccc(Cl)cc4)C
| StdInChI = 1S/C21H19ClFNO4S/c1-29(27,28)18-10-15(23)9-17-16-7-4-13(8-19(25)26)20(16)24(21(17)18)11-12-2-5-14(22)6-3-12/h2-3,5-6,9-10,13H,4,7-8,11H2,1H3,(H,25,26)/t13-/m1/s1
| StdInChIKey = NXFFJDQHYLNEJK-CYBMUJFWSA-N
}}
Laropiprant (INN) was a drug used in combination with nicotinic acid to reduce blood cholesterol (LDL and VLDL) that is no longer sold, due to increases in side-effects with no cardiovascular benefit. Laropiprant itself has no cholesterol lowering effect, but it reduces facial flushes induced by nicotinic acid.
Merck & Co. planned to market this combination under the trade names Cordaptive in the US and Tredaptive in Europe. Both brands contained 1000 mg of nicotinic acid (niacin) and 20 mg of laropiprant in each tablet.{{cite web | url = http://www.merck.com/newsroom/pdf/Tredaptive_pi.pdf | title = Tredaptive Prescribing Information | publisher = Merck & Co. | access-date = 2009-11-14 }}
Mechanism of action
Nicotinic acid 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 the prostaglandin D2 receptor subtype DP1, increasing blood flow and thus leading to flushes.{{cite journal | vauthors = Sood A, Arora R | title = Mechanisms of flushing due to niacin and abolition of these effects | journal = Journal of Clinical Hypertension | volume = 11 | issue = 11 | pages = 685–689 | date = November 2009 | pmid = 19878384 | pmc = 8673406 | doi = 10.1111/j.1559-4572.2008.00050.x | s2cid = 32102745 | doi-access = free }} Laropiprant acts as a selective DP1 receptor antagonist to inhibit the vasodilation of prostaglandin D2-induced activation of DP1.
Taking 325 mg of aspirin 20–30 minutes prior to taking nicotinic acid has also been proven to prevent flushing in 90% of patients, presumably by suppressing prostaglandin synthesis,{{cite journal | vauthors = Kunin RA | url = http://www.orthomolecular.org/library/jom/1976/pdf/1976-v05n02-p089.pdf | title = The Action of Aspirin in Preventing the Niacin Flush and its Relevance to the Antischizophrenic Action of Megadose Niacin | journal = Orthomolecular Psychiatry | volume = 5 | issue = 2 | year = 1976 | pages = 89–100 | access-date = 2009-11-14 }} but this medication also increases the risk of gastrointestinal bleeding,{{cite journal | vauthors = Sørensen HT, Mellemkjaer L, Blot WJ, Nielsen GL, Steffensen FH, McLaughlin JK, Olsen JH | title = Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin | journal = The American Journal of Gastroenterology | volume = 95 | issue = 9 | pages = 2218–2224 | date = September 2000 | pmid = 11007221 | doi = 10.1111/j.1572-0241.2000.02248.x | s2cid = 33742424 }} though the increased risk is less than 1 percent.{{cite news | vauthors = Paddock C |title=For Healthy People Daily Aspirin May Do More Harm Than Good| url=http://www.medicalnewstoday.com/articles/162385.php|publisher=Medical News Today|date=31 August 2009}}
History
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 nicotinic acid monotherapy.{{cite journal | vauthors = Lai E, De Lepeleire I, Crumley TM, Liu F, Wenning LA, Michiels N, Vets E, O'Neill G, Wagner JA, Gottesdiener K | display-authors = 6 | title = Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1 | journal = Clinical Pharmacology and Therapeutics | volume = 81 | issue = 6 | pages = 849–857 | date = June 2007 | pmid = 17392721 | doi = 10.1038/sj.clpt.6100180 | s2cid = 2126240 }}
On April 28, 2008, the U.S. Food and Drug Administration (FDA) issued a "not approved" letter for Cordaptive.{{cite news | title = FDA Rejects Merck's Cordaptive | url = http://www.businessweek.com/bwdaily/dnflash/content/apr2008/db20080429_182260.htm | archive-url = https://web.archive.org/web/20080502170658/http://www.businessweek.com/bwdaily/dnflash/content/apr2008/db20080429_182260.htm | url-status = dead | archive-date = May 2, 2008 | date = April 29, 2008 | access-date= 2009-11-13 | work = BusinessWeek | vauthors = Carey J
}} Tredaptive was approved by the European Medicines Agency (EMA) on July 3, 2008.{{cite web | url= http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000889/WC500042219.pdf | title= Tredaptive European Public Assessment Report | publisher=European Medicines Agency | access-date=November 13, 2009 }}
On January 11, 2013, Merck & Co Inc. announced they were withdrawing the drug worldwide as a result of European regulators recommendations.{{cite web|title=Merck withdraws cholesterol drug Tredaptive globally|url=https://www.reuters.com/article/2013/01/11/us-merck-cholesteroldrug-withdrawal-idUSBRE90A0MB20130111?feedType=RSS&feedName=healthNews|archive-url=https://web.archive.org/web/20231127043428/https://www.reuters.com/article/2013/01/11/us-merck-cholesteroldrug-withdrawal-idUSBRE90A0MB20130111/?feedType=RSS&feedName=healthNews|url-status=dead|archive-date=November 27, 2023|publisher=Reuters|access-date=11 January 2013|date=January 11, 2013}}
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 nicotinic acid and 40 mg of laropiprant daily. Study results, reported in July 2014, showed that the combination of nicotinic acid and laropiprant did not have any beneficial effects when compared with a placebo treatment and had an increase in adverse effects.{{cite journal | vauthors = Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, Armitage J | display-authors = 6 | title = Effects of extended-release niacin with laropiprant in high-risk patients | journal = The New England Journal of Medicine | volume = 371 | issue = 3 | pages = 203–212 | date = July 2014 | pmid = 25014686 | doi = 10.1056/NEJMoa1300955 | s2cid = 23548060 | doi-access = free }}
References
{{Reflist|2}}
{{Lipid modifying agents}}
{{Prostanoidergics}}
Category:Combination lipid-lowering drugs
Category:Drugs developed by Merck & Co.