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Liver sitaxsentan

Sitaxsentan is a potent and selective agent which inhibits ET-1 binding to ETA receptors (IC50 = 1.4 nM), while being essentially inactive at ETB receptors (IC50 = 9.8 pM).23 In the clinic, it was found to have excellent oral bioavailability (70-100%) and a terminal elimination half-life of 10 h, and is administered as a once daily 100 mg dose. It is highly protein bound in plasma (> 99%) and extensively metabolized in the liver to inactive metabolites, predominantly by CYPs 2C9 and 3A4. Excretion is 50 60% renal, with the balance in the feces.25 Sitaxsentan inhibits CYP 2C9, and was observed to increase exposure to warfarin by over twofold. The use of cyclosporine A is also contraindicated, but no interactions were observed with sildenafil.15 Sitaxsentan was well tolerated in trials, with only minor side effects reported. Reversible liver enzyme abnormalities were also observed, but less frequently than with bosentan.15 25... [Pg.214]

Liver Fulminant hepatic failure during treatment with sitaxsentan has been reported in a patient whose liver function tests had been normal less than a month before [86 ]. [Pg.329]

Liver The availability of ambrisentan in patients with pulmonary artery hypertension who have previously discontinued other endothelin receptor antagonists because of liver function abnormalities provides an important option for patients who have had adverse reactions to bosentan or sitaxsentan [76 ]. Ambrisentan is a... [Pg.421]

Liver In addition to the trial evidence, case studies of sitaxsentan and hepatic dysfunction have been reported. Liver damage associated with sitaxsentan progressed... [Pg.423]

Two other cases of severe liver dysfunction have been attributed to sitaxsentan within 12 weeks of treatment [89 ]. In both patients the aminotransferase activities peaked at up to 30 times the upper limit of normal and both had protracted periods of jaundice. Only the first was symptomatic at presentation, whereas the second was detected on routine liver function test monitoring. [Pg.423]

Therefore although there is direct comparative evidence from trial data of possible benefits of sitaxsentan compared with bosentan, it is possible that despite fewer cases of raised aminotransferases, there may be a greater potential for severe and possibly fatal liver toxicity from sitaxsentan. [Pg.423]

McGoon MD, Frost AE, Oudiz RJ, Badesch DB, Galie N, Olschewski H, McLaughlin W, Gerber MJ, Dufton C, Despain DJ, Rubin LJ. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest 2009 135(1) 122-9. [Pg.433]

Sitaxsentan was withdrawn from the worldwide market in December 2010 (SEDA-35) on accoxmt of hepatic damage that did not resolve on withdrawal of the drug but eventually proved fatal. A double-blind randomised controlled trial PO -] was conducted prior to the withdrawal to assess the efficacy and safety of lower dose range of sitaxsentan (50 or 100 mg) compared to placebo. Most adverse events documented by the authors including headaches, peripheral oedema, dizziness, nausea, extremity pain were said to be mild/moderate. Increased liver transaminases greater than three times of the upper limit was reported for one patient in each treatment arm, but reversed back to normal on discontinuation of the drug. [Pg.285]

Liver A case of a 61-year-old female who developed acute severe hepatitis following a 16-week therapy of sitaxsentan at 100 mg daily has been reported [31 ]. Despite withdrawal of therapy, her liver tests failed to improve after 6 weeks of follow-up. She however showed clinical and biochemical improvement when a high dose of corticosteroid was administered. The authors thus opined that an immxme-mediated mechanism as opposed to an inhibition of the bile salt transport is the pathway through which sitaxsentan causes hepatotoxicity. [Pg.285]


See also in sourсe #XX -- [ Pg.285 ]




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