快樂小藥師 Im pharmacist nichts glücklich

肺高壓的藥品最近開始有比較多的廠商在做了

目前市面上的除了小劑量的sildenafil（Revatio）

以外，還有bayer的ventavis及另外一個作用在soluble guanylate cyclase (sGC)，可以同時治療chronic thromboembolic pulmonary hypertension (CTEPH) 和 pulmonary arterial hypertension (PAH)的新藥，再來就是今天要介紹的這個藥物了。

Sitaxsentan(Thelin)

Sitaxsentan is an orally administered endothelin receptor blocker that offers the effective and safe treatment of patients with mild to moderate PAH.

不過個藥品的製造公司Encysive目前出現財務困難，可能會被輝瑞收購

2b-Clinical Review_Benedict.indd

Pharmacology

Multiple factors are involved in contributing to the vasoconstric­tion and vascular hypertrophy seen in PAH. Genetic predisposition, reduced synthesis of natural pulmo­nary vasodilators, and overexpression of vasoconstrictors are thought to be the major factors. Endothelin-1, a potent endogenous vasoconstrictor and smooth-muscle mitogen, has been shown to be overexpressed in the plasma and lung tissue of pa­tients with PAH. Thus, the reduc­tion or blockade of endothelin-1 may aid in disease symptomatology and progression.

The endothelin effect is medi­ated through two receptor isoforms, ETA and ETB. Activation of ETA leads to vasoconstriction and vascular smooth-muscle cell prolif­eration, while ETB receptor activation leads to the clearance of endothelin and a compensatory vasodilatory response.10 Therefore, in theory, an ideal endothelin antagonist would selectively antagonize the ETA recep­tor without ETB blockade. Bosentan exerts its vasodilatory effect through nonselective antagonism of ETA and ETB receptors.

Sitaxsentan (Thelin, Encysive Pharmaeuticals) is an orally ac­tive, organic nonpeptide that binds competitively to the human ETA receptor.11 It is currently undergoing Phase III trials, and unlike bosentan, it has a high affinity for the ETA re­ceptor. Sitaxsentan has been reported to be at least 6000-fold more selec­tive for ETA than ETB receptors.12,13 It is anticipated that ETA-selective antagonists will be more effective vasodilators in treating PAH than dual endothelin receptor antagonists. However, it is unclear whether this selectivity is clinically superior in patient outcomes.

Dosing and administration

In a preliminary randomized trial, sitaxsentan 100 and 300 mg/day improved exercise capacity, WHO FC, and cardiopulmonary hemo­dynamics compared with placebo.1However, the frequency of elevated hepatic transaminases greater than three times the upper limit of nor­mal, serious adverse events, and drug discontinuation rates were higher in the 300-mg group. STRIDE-2 compared sitaxsentan 50- and 100-mg daily doses.2Results proved the 50-mg dose to be subtherapeutic, while the 100-mg dose demonstrated significant improvements in exercise capacity and WHO FC. Therefore, on the basis of the findings of these randomized trials, 100 mg/day PO is the optimal dose of sitaxsentan.

There are no recommendations for sitaxsentan dosing in renal im­pairment or in the elderly. Caution should be exercised in patients with hepatic dysfunction, chronic liver disease, chronic renal insufficiency, portal hypertension, significant pa­renchymal lung disease, or human immunodeficiency virus because these patients were excluded from randomized trials.