Sitaxentan

drugbox |
IUPAC_name = "N"-(4-chloro-3-methyl-oxazol-5-yl)-2- [2-(6-methylbenzo
[1,3] dioxol-5-yl)acetyl] thiophene-3-sulfonamide

---

CAS_number = 210421-64-0
ATC_prefix = C02
ATC_suffix = KX03
PubChem = 216235
DrugBank =
smiles = Cc1cc2OCOc2cc1CC(=O)c3sccc3S(=O)(=O)Nc4onc(C)c4Cl
C = 18 | H = 15 | Cl = 1 | N = 2 | O = 6 | S = 2
molecular_weight = 454.906 g/mol
bioavailability = 70 to 100%
protein_bound = >99%
metabolism = Hepatic (CYP2C9- and CYP3A4-mediated)
elimination_half-life = 10 hours
excretion = Renal (50 to 60%)
Fecal (40 to 50%)
licence_EU = Thelin
pregnancy_AU =
pregnancy_US =
pregnancy_category =
legal_AU = S4
legal_CA =
legal_UK = POM
legal_US =
legal_status =
routes_of_administration = Oral

Sitaxentan sodium, sometimes spelled "Sitaxsentan sodium", (marketed as Thelin by Encysive Pharmaceuticals) is a small molecule that blocks the action of endothelin (ET) on the endothelin-A (ET_A) receptor selectively (by a factor of 6000 compared to the ET_B). It is a sulfonamide class endothelin receptor antagonist (ERA) and is undergoing Food and Drug Administration (FDA) review for treating pulmonary hypertension. The rationale for benefit compared to bosentan, 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. However, in clinical trials, the efficacy of sitaxsentan has been much the same as bosentan, but the liver toxicity has been better. Therefore sitaxsentan is expected to be marketed as a safer drug than bosentan, but not necessarily more effective.

Regulatory status

Thelin has been approved for marketing in both the European Union (on 10 August 2006), in Canadacite web |date=30 May 2007 |url=http://www.reuters.com/article/governmentFilingsNews/idUSBNG28335020070530 |title=UPDATE 1-Encysive gets Canadian approval for hypertension drug |publisher=Reuters |accessdate = 2007-07-08] and in Australia (on 7 March 2007). By February 2008 it had been launched commercially in Germany, Austria, The Netherlands, the United Kingdom, Ireland, France, Spain and Italy.

On the Prescription Drug User Fee Act (PDUFA) target action date of 24 March 2006 the United States' FDA recommended an approvable status to Thelin but said it would not yet approve the product. On 24 July 2006 Thelin 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. However, in September 2007 the company announced that it was making preparations for another phase III clinical trial (STRIDE-5) to overcome the FDA's deficiency claims concerning the New Drug Application, and that it would not pursue the dispute resolution processcite web |date=29 September 2007 |url=http://ir.encysive.com/ireye/ir_site.zhtml?ticker=ency&script=410&layout=-6&item_id=1054488|title=Encysive Pharmaceuticals to Conduct Phase III Study With Thelin (Sitaxsentan Sodium) in Pulmonary Arterial Hypertension | publisher=PrimeNewswire via COMTEX News Network | accessdate = 2007-12-12] .

Adverse effects

Adverse effects observed with Thelin are class effects of endothelin receptor antagonists, and include :
* liver enzyme abnormalities (increased ALT and AST)
* headache
* oedema
* constipation
* nasal congestion
* upper respiratory tract infection
* dizziness
* insomnia
* flushing.

Because Thelin inhibits metabolism of warfarin, a decreased dose of warfarin is needed when co-administered with thelin. This is because warfarin acts to prevent blood from clotting, and if it remains unmetabolized, it can continue to thin the blood.

External links

* http://www.drugs.com/nda/thelin_050714.html

References

* Girgis RE, Frost AE, Hill NS, Horn EM, Langleben D, Mc Laughlin VV, Oudiz RJ, Robbins IM, Seibold JR, Shapiro S, Tapson VF, Barst RJ. 'Selective endothelinA receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease' ARD 2007 [0: ard.2007.069609v2]
* ATS 2005. The International Conference of the American Thoracic Society. 20 May - 25 May 2005. San Diego, CA.
* American Heart Association. [http://www.americanheart.org/presenter.jhtml?identifier=4752 Primary or Unexplained Pulmonary Hypertension]
* Barst RJ, Langleben D, Frost A et al. "Sitaxsentan therapy for pulmonary arterial hypertension." American Journal of Respiratory Critical Care Medicine 2004 15 February 2004 ;169(4):441-7. Electronic publication 20 November 2003.
* Robyn J. Barst, MD; Stuart Rich, MD, FCCP; Allison Widlitz, MS, PA; Evelyn M. Horn, MD; Vallerie McLaughlin, MD and Joyce McFarlin, RN : [http://www.chestjournal.org/cgi/content/abstract/121/6/1860 Clinical Efficacy of Sitaxsentan, an Endothelin-A Receptor Antagonist, in Patients With Pulmonary Arterial Hypertension] Chest. 2002;121:1860-1868.