Search

Bosentan (Tracleer) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, and SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and DILI. After adjusting for body mass index, CYP2C9*2 was the only polymorphism associated with ALT, AST, and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; odds ratio 95% CI = 2.29-∞, P = 0.003, respectively). Bosentan metabolism by CYP2C9*2 in vitro was significantly reduced compared with CYP2C9*1 and was comparable to that by CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment. more...

Despite the possible risk of stroke, over-the-counter (OTC) nasal decongestants are widely used but there are little published data on pharmacodynamic effects. We studied the cardiovascular (CV) pharmacodynamics of the Vicks™ Vapor Inhaler™, an OTC decongestant that has 1-methamphetamine (1-MA; nominally a DEA schedule II drug) as its active ingredient. Twelve normotensive nondrug using subjects were enrolled in an ascending dose, open-label, 3 treatment, 3 period study and dosed with the Vicks inhaler at the manufacturer's maximum recommended dose, and 2 and 4 times that dose over 8 hours. In a separate session, a 200 μg iv dose of phenylephrine was given as a comparator for alpha-adrenergic response. Cardiovascular effects were non-invasively assessed with impedance and 2D stress echocardiography; data were analyzed by ANOVA. Results show that inhaled 1-MA had no acute effects on CV measures; measures were sensitive enough to detect circadian variation and the effects of exercise on multiple CV parameters, but there were no effects of 1-MA. Plasma 1-MA levels were always below detection limits; urine 1-MA concentration increased in a dose proportional manner. Visual analog measures of 'any drug', 'good drug', and 'dizziness' significantly increased from baseline (p more...