Sitaxsentan
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Sitaxsentan
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| Systematic (IUPAC) name | |
| N-(4-chloro-3-methyl-oxazol-5-yl)-2-[2-(6-methylbenzo [1,3]dioxol-5-yl)acetyl]thiophene-3-sulfonamide |
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| Identifiers | |
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| ATC code | ? |
| PubChem | |
| Chemical data | |
| Formula | C18H15ClN2O6S2 |
| Mol. mass | 454.906 g/mol |
| Pharmacokinetic data | |
| Bioavailability | 70 to 100% |
| Protein binding | >99% |
| Metabolism | Hepatic (CYP2C9- and CYP3A4-mediated) |
| Half life | 10 hours |
| Excretion | Renal (50 to 60%) Fecal (40 to 50%) |
| Therapeutic considerations | |
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| Pregnancy cat. |
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| Legal status | |
| Routes | Oral |
Sitaxsentan or sitaxsentan sodium (to be marketed as Thelin® by Encysive Pharmaceuticals) is a small molecule sodium salt that blocks the action of endothelin (ET) on the endothelin-A (ETA) receptor selectively (by a factor of 6000 compared to the ETB). 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 ETB 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.
The FDA on the Prescription Drug User Fee Act (PDUFA) target action date of 24 March 2006 recommended an approvable status to Thelin®.
An application in Europe was recommended for approval by the CHMP on June 2, 2006
On July 24, 2006 Thelin received a second approvable letter. One of the substantive items raised in the March 24 letter was still unresolved.
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[edit] Clinical trials
Clinical trials are at phase 3.
[edit] Adverse effects
Possible adverse effects include :
- liver dysfunction (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 due to the fact that warfarin acts to prevent blood from clotting, and if it remains unmetabolized, it can continue to thin the blood.
[edit] External links
[edit] References
- ATS 2005. The International Conference of the American Thoracic Society. 20 May - 25 May 2005. San Diego, CA.
- American Heart Association. 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 : Clinical Efficacy of Sitaxsentan, an Endothelin-A Receptor Antagonist, in Patients With Pulmonary Arterial Hypertension Chest. 2002;121:1860-1868.
