Sitaxentan sodium (TBC-11251) is a medication for the treatment of pulmonary arterial hypertension (PAH). It was marketed as Thelin by Encysive Pharmaceuticals until

Pfizer Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...

purchased Encysive in February 2008. In 2010, Pfizer voluntarily removed sitaxentan from the market due to concerns about liver toxicity.Citing liver damage, Pfizer withdraws Thelin
Associated Press, December 12, 2010

Mechanism of action

Sitaxentan is a

small molecule Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ...

that blocks the action of

endothelin Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute ...

(ET) on the endothelin-A (ET_A) receptor selectively (by a factor of 6000 compared with the ET_B). It is a sulfonamide class

endothelin receptor antagonist An endothelin receptor antagonist (ERA) is a drug that blocks endothelin receptors. Three main kinds of ERAs exist: * selective ETA receptor antagonists ( sitaxentan, ambrisentan, atrasentan, BQ-123, zibotentan, edonentan), which affect e ...

(ERA) and is undergoing

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) review for treating pulmonary hypertension. The rationale for benefit compared with

bosentan Bosentan, sold under the brand name Tracleer and Safebo among others, is a dual endothelin receptor antagonist medication used in the treatment of pulmonary artery hypertension (PAH). Bosentan is available as film-coated tablets (62.5 mg o ...

, a nonselective ET blocker, is negligible inhibition of the beneficial effects of ET_B stimulation, such as nitric oxide production and clearance of ET from circulation. In clinical trials, the efficacy of sitaxentan has been much the same as bosentan, but the

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...

of sitaxentan outweighs its benefits. Dosing is once daily, as opposed to twice daily for bosentan.

Regulatory status

On December 10, 2010 Pfizer announced it would be withdrawing sitaxentan worldwide (both from marketing and from all clinical study use), citing that it is a cause of fatal liver damage. Sitaxentan was approved for marketing in the European Union in 2006, in Canada in 2006 and in Australia in 2007. By February 2008 it had been launched commercially in Germany, Austria, The Netherlands, the United Kingdom, Ireland, France, Spain and Italy. In March 2006, the FDA recommended an approvable status to sitaxentan but said it would not yet approve the product. In July 2006, sitaxentan received a second approvable letter stating that efficacy outcome issues raised in the context of the STRIDE-2 study were still unresolved. In July 2007, Encysive commenced a formal dispute resolution process in a preliminary meeting with the FDA. In September 2007 the company announced that it was making preparations for another phase III

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

(intended to be named STRIDE-5) to overcome the FDA's concerns. The takeover by Pfizer resulted in a reconfiguration and extension of these plans, to include combination therapy with sildenafil. The Sitaxentan Efficacy and Safety Trial With a Randomized Prospective Assessment of Adding Sildenafil (SR-PAAS) was an ongoing program of three clinical trials conducted in the United States (ClinicalTtrials.gov identifiers: NCT00795639, NCT00796666 and NCT00796510) with anticipated completion dates between June 2010 and January 2014.

Adverse effects

Adverse effects An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term complica ...

observed with sitaxentan are class effects of endothelin receptor antagonists, and include : *

liver enzyme Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin tim ...

abnormalities (increased ALT and AST) * headache * edema *

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

nasal congestion Nasal congestion is the blockage of nasal breathing usually due to membranes lining the nose becoming swollen from inflamed blood vessels. Background In about 85% of cases, nasal congestion leads to mouth breathing rather than nasal breathin ...

upper respiratory tract infection An upper respiratory tract infection (URTI) is an illness caused by an acute infection, which involves the upper respiratory tract, including the nose, sinuses, pharynx, larynx or trachea. This commonly includes nasal obstruction, sore thro ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

flushing Flushing may refer to: Places * Flushing, Cornwall, a village in the United Kingdom * Flushing, Queens, New York City ** Flushing Bay, a bay off the north shore of Queens ** Flushing Chinatown (法拉盛華埠), a community in Queens ** Flushin ...

Because sitaxentan inhibits

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...

warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...

, a decreased dose of warfarin is needed when co-administered with sitaxentan. This is because warfarin acts to prevent blood from

clotting Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...

, and if it remains unmetabolized, it can continue to thin the blood.

References

External links

* https://www.drugs.com/nda/thelin_050714.html * Mucke HAM
Sitaxsentan for the Oral Treatment of Pulmonary Arterial Hypertension: Benefits from Endothelin Receptor Subtype Selectivity?
Clinical Medicine: Therapeutics 2009:1 111–121. * ATS 2005. The International Conference of the American Thoracic Society. 20–25 May 2005. San Diego, CA. * Robyn J. Barst, MD; Stuart Rich, MD, FCCP; Allison Widlitz, MS, PA; Evelyn M. Horn, MD; Vallerie McLaughlin, MD and Joyce McFarlin, RN
Clinical Efficacy of Sitaxsentan, an Endothelin-A Receptor Antagonist, in Patients With Pulmonary Arterial Hypertension
Chest. 2002;121:1860-1868. * American Heart Association
Primary or Unexplained Pulmonary Hypertension
{{Antihypertensives and diuretics Benzodioxoles Chloroarenes Endothelin receptor antagonists Hepatotoxins Isoxazoles Sulfonamides Thiophenes Withdrawn drugs