| Revision as of 20:30, 18 January 2011 editNono64 (talk | contribs)Autopatrolled, Pending changes reviewers, Rollbackers96,246 editsm Low-density lipoprotein← Previous edit |
Latest revision as of 20:03, 25 December 2024 edit undoArthurfragoso (talk | contribs)Extended confirmed users2,080 edits Niacin -> Nicotinic acid, as it is the international nonproprietary name, as per MEDMOS. Also included european brand namesTag: ProveIt edit |
| (69 intermediate revisions by 45 users not shown) |
| Line 1: |
Line 1: |
|
|
{{Short description|Chemical compound}} |
|
{{Drugbox |
|
{{Drugbox |
|
|
| Verifiedfields = changed |
|
| image = laropiprant.png |
|
|
|
| Watchedfields = changed |
|
| IUPAC_name = (-)-indol-3-yl]acetic acid |
|
|
|
| verifiedrevid = 408651073 |
|
| CAS_number = 571170-77-9 |
|
|
|
| drug_name = nicotinic acid / laropiprant |
|
| CAS_supplemental = |
|
|
|
| type = combo |
|
| ATC_prefix = C10 |
|
|
|
| component1 = Nicotinic acid |
|
| ATC_suffix = AD52 |
|
|
|
| class1 = ] |
|
| ATC_supplemental = <br />(combination with ]) |
|
|
|
| component2 = Laropiprant |
|
| PubChem = |
|
|
|
| class2 = ] ] |
|
| DrugBank = |
|
|
|
|
|
| KEGG = D08940 |
|
|
|
<!-- Clinical data --> |
|
| chemical_formula = |
|
|
|
| tradename = Cordaptive, Tredaptive, Trevaclyn, Pelzont<ref name="EMA-Suspend">{{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}}</ref> |
|
| C=21 | H=19 | Cl=1 | F=1 | N=1 | O=4 | S=1 |
|
|
|
| USAN = niacin/laropiprant |
|
| molecular_weight = 435.90 g/mol |
|
|
|
| Drugs.com = {{drugs.com|UK|tredaptive-1000-mg-20-mg-modified-release-tablets-1360}} |
|
| synonyms = MK-0524A |
|
|
| bioavailability = |
|
| MedlinePlus = |
|
|
| licence_EU = yes |
|
| protein_bound = |
|
|
|
| INN_EMA = laropiprant |
|
| metabolism = |
|
|
|
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
|
| elimination_half-life = |
|
|
| excretion = |
|
| pregnancy_US = <!-- A / B / C / D / X --> |
|
|
| pregnancy_category = |
|
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> |
|
|
| pregnancy_US = <!-- A / B / C / D / X --> |
|
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> |
|
|
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> |
|
| pregnancy_category= |
|
|
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> |
|
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> |
|
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> |
|
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
|
|
| legal_status = Withdrawn |
|
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> |
|
|
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> |
|
|
| legal_status = |
|
|
| routes_of_administration = Oral |
|
| routes_of_administration = Oral |
|
|
|
|
| licence_EU = Tredaptive |
|
|
|
<!-- Identifiers --> |
|
|
| 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=C2CC3CC(=O)O)CC4=CC=C(C=C4)Cl)F |
|
}} |
|
}} |
|
|
|
|
|
|
{{Drugbox |
|
'''Laropiprant''' (]) is used in combination with ] to reduce blood cholesterol (] and ]). ] planned to market this combination under the trade names '''Cordaptive''' and '''Tredaptive'''. On April 28, 2008, the ] (FDA) issued a "not approved" letter for Cordaptive.<ref> |
|
|
|
| drug_name = |
|
{{cite news |
|
|
|
| Verifiedfields = changed |
|
| title = FDA Rejects Merck's Cordaptive |
|
|
|
| verifiedrevid = 408651073 |
|
| url = http://www.businessweek.com/bwdaily/dnflash/content/apr2008/db20080429_182260.htm |
|
|
|
| IUPAC_name = (−)-indol-3-yl]acetic acid |
|
| date = April 29, 2008 |
|
|
|
| image = Laropiprant.svg |
|
| accessdate= 2009-11-13 |
|
|
| work = ] |
|
|
| last = Carey |
|
|
| first= John |
|
|
}}</ref> Tredaptive was approved by the ] (EMA) on July 3, 2008.<ref> |
|
|
{{cite web |
|
|
| url= http://www.emea.europa.eu/humandocs/Humans/EPAR/tredaptive/tredaptive.htm |
|
|
| title= Tredaptive European Public Assessment Report |
|
|
| publisher=] |
|
|
| accessdate=November 13, 2009 |
|
|
}}</ref> |
|
|
|
|
|
|
|
<!-- Clinical data --> |
|
Laropiprant itself has no cholesterol lowering effect, but it reduces facial ] 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.<ref> |
|
|
|
| Drugs.com = {{drugs.com|international|laropiprant}} |
|
{{cite journal |
|
|
|
| legal_status = Withdrawn |
|
| author = Lai E, De Lepeleire I, Crumley TM, ''et al.'' |
|
|
| title = Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1 |
|
|
| journal = Clin. Pharmacol. Ther. |
|
|
| volume = 81 |
|
|
| issue = 6 |
|
|
| pages = 849–57 |
|
|
| year = 2007 |
|
|
| month = June |
|
|
| pmid = 17392721 |
|
|
| doi = 10.1038/sj.clpt.6100180 |
|
|
| accessdate = 2009-11-14 |
|
|
}}</ref> |
|
|
|
|
|
|
|
<!--Pharmacokinetic data--> |
|
Tredaptive contains 1000 mg of niacin and 20 mg of laropiprant in each tablet.<ref name="Tredaptive_pi"> |
|
|
|
| bioavailability = |
|
{{cite web |
|
|
|
| protein_bound = |
|
| url = http://www.merck.com/newsroom/pdf/Tredaptive_pi.pdf |
|
|
| format = PDF |
|
| metabolism = |
|
|
| elimination_half-life = |
|
| title = Tredaptive Prescribing Information |
|
|
|
| excretion = |
|
| publisher = ] |
|
|
|
|
|
| accessdate = 2009-11-14 |
|
|
|
<!--Identifiers--> |
|
}}</ref> |
|
|
|
| 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 data--> |
|
|
| chemical_formula = |
|
|
| C=21 | H=19 | Cl=1 | F=1 | N=1 | O=4 | S=1 |
|
|
| smiles = O=S(=O)(c1cc(F)cc2c1n(c3c2CC3CC(=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''' (]) was a drug used in combination with ] to reduce blood cholesterol (] and ]) 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 ] induced by nicotinic acid. |
|
|
|
|
|
] 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.<ref name="Tredaptive_pi">{{cite web | url = http://www.merck.com/newsroom/pdf/Tredaptive_pi.pdf | title = Tredaptive Prescribing Information | publisher = ] | access-date = 2009-11-14 }}</ref> |
|
|
|
|
|
==Mechanism of action== |
|
==Mechanism of action== |
|
Niacin in cholesterol lowering doses (500–2000 mg per day) causes facial flushes by stimulating biosynthesis of ] D<sub>2</sub>, especially in the skin. PG D<sub>2</sub> acts as a ] via ], increasing blood flow and thus leading to flushes.<ref name="Tredaptive_pi" /><ref>{{pmid|19878384}}</ref> |
|
Nicotinic acid in cholesterol lowering doses (500–2000 mg per day) causes facial flushes by stimulating biosynthesis of ] (PGD<sub>2</sub>), especially in the skin. PGD<sub>2</sub> ] via activation of the ] subtype ], increasing blood flow and thus leading to flushes.<ref name="Tredaptive_pi" /><ref>{{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 }}</ref> Laropiprant acts as a selective DP<sub>1</sub> ] to inhibit the vasodilation of prostaglandin D<sub>2</sub>-induced activation of DP<sub>1</sub>.<ref name="Tredaptive_pi" /> |
|
|
|
|
|
|
Taking 325 mg of ] 20–30 minutes prior to taking nicotinic acid has also been proven to prevent flushing in 90% of patients, presumably by suppressing prostaglandin synthesis,<ref>{{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 }}</ref> but this medication also increases the risk of ],<ref>{{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 }}</ref> though the increased risk is less than 1 percent.<ref>{{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}}</ref> |
|
Laropiprant acts as a DP<sub>1</sub> antagonist, reducing the vasodilation.<ref name="Tredaptive_pi" /> |
|
|
|
|
|
|
|
==History== |
|
Taking 650 mg of ] 20–30 minutes prior to taking niacin has also been proven to prevent flushing in 90% of patients, presumably by suppressing prostaglandin synthesis,<ref> |
|
|
|
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.<ref>{{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 }}</ref> |
|
{{cite journal |
|
|
| author = Richard A. Kunin |
|
|
| 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 |
|
|
| format = PDF |
|
|
| accessdate = 2009-11-14 |
|
|
}}</ref> but this medication also increases the risk of ],<ref> |
|
|
{{cite journal |
|
|
| author = Sørensen HT, Mellemkjaer L, Blot WJ, ''et al.'' |
|
|
| title = Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin |
|
|
| journal = Am. J. Gastroenterol. |
|
|
| volume = 95 |
|
|
| issue = 9 |
|
|
| pages = 2218–24 |
|
|
| year = 2000 |
|
|
| month = September |
|
|
| pmid = 11007221 |
|
|
| doi = 10.1111/j.1572-0241.2000.02248.x |
|
|
| accessdate = 2009-11-14 |
|
|
}}</ref> though the increased risk is less than 1 percent.<ref>{{Dead link|date=November 2009}}</ref> |
|
|
|
|
|
|
|
On April 28, 2008, the ] (FDA) issued a "not approved" letter for Cordaptive.<ref>{{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 = ] | vauthors = Carey J |
|
==References== |
|
|
|
}}</ref> Tredaptive was approved by the ] (EMA) on July 3, 2008.<ref>{{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=] | access-date=November 13, 2009 }}</ref> |
|
{{reflist}} |
|
|
|
|
|
|
On January 11, 2013, Merck & Co Inc. announced they were withdrawing the drug worldwide as a result of European regulators recommendations.<ref>{{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|publisher=Reuters|access-date=11 January 2013|date=January 11, 2013}}{{dead link|date=July 2021|bot=medic}}{{cbignore|bot=medic}}</ref> |
|
|
|
|
|
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 ] treatment and had an increase in adverse effects.<ref>{{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 }}</ref> |
|
|
|
|
|
== References == |
|
|
{{Reflist|2}} |
|
|
|
|
|
{{Lipid modifying agents}} |
|
{{Lipid modifying agents}} |
|
|
{{Prostanoidergics}} |
|
|
|
|
|
] |
|
] |
|
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
] |
|
|
] |
|
|
|
|
] |
|