Laropiprant (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway. Before the advent of motorized transportation, they also provided accomm ...

) was a drug used in combination with

nicotinic acid Nicotinic acid, or niacin, is an organic compound and a vitamer of vitamin B3, an essential human nutrient. It is produced by plants and animals from the amino acid tryptophan. Nicotinic acid is also a prescription medication. Amounts f ...

to reduce blood cholesterol (

LDL Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...

and

VLDL Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, LDL, low-density ...

) 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.

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. Laropiprant acts as a selective DP₁

receptor antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...

to inhibit the vasodilation of prostaglandin D₂-induced activation of DP₁. Taking 325 mg of

aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...

20–30 minutes prior to taking nicotinic acid has also been proven to prevent flushing in 90% of patients, presumably by suppressing prostaglandin synthesis, but this medication also increases the risk of

gastrointestinal bleeding Gastrointestinal bleeding (GI bleed), also called gastrointestinal hemorrhage (GIB), is all forms of bleeding in the gastrointestinal tract, from the mouth to the rectum. When there is significant blood loss over a short time, symptoms may includ ...

, though the increased risk is less than 1 percent.

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. On April 28, 2008, the

U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) issued a "not approved" letter for Cordaptive. Tredaptive was approved by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

(EMA) on July 3, 2008. On January 11, 2013, Merck & Co Inc. announced they were withdrawing the drug worldwide as a result of European regulators recommendations. 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 A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

treatment and had an increase in adverse effects.

References

{{Prostanoidergics Combination lipid-lowering drugs Drugs developed by Merck & Co. Indoles 4-Chlorophenyl compounds Fluoroarenes Benzosulfones Acetic acids