This double-blind, randomized, placebo- and positive-controlled, four-way crossover thorough QTc study was designed to investigate the effects of therapeutic and supratherapeutic doses of macitentan on cardiac repolarization in healthy male and female subjects.
This conclusion is also supported by data from a single-dose study using supratherapeutic doses of indacaterol, salbutamol, and salmeterol, demonstrating a good overall safety profile of indacaterol.
A number of animal studies have found that the PCCs, Beriplex 28 30 and Octaplex, 29 result in haemostasis and reversal of blood loss after supratherapeutic doses of dabigatran.
Supratherapeutic doses of inhaled long-acting β2-agonists have the potential to produce systemic pharmacodynamic effects, including prolongation of the QT interval.
The SP864 study demonstrated dose-proportional pharmacokinetics of rotigotine at steady state in patients with advanced PD (n = 66) from 8 mg/24 h rotigotine to the maximum therapeutic dose of 16 mg/24 h, and supratherapeutic doses of 20 and 24 mg/24 h [ 33].
Conversely, the genetically epilepsy prone rat (GEPR) has been shown to be susceptible to the proconvulsant activity of antidepressants, as have cats and rabbits at supratherapeutic doses of these drugs (reviewed in Jobe and Browning [ 27]).
Our model used the SUCCESS trial results as the basis for the key celecoxib and nsNSAID ulcer probabilities, whereas Spiegel used those for a coxib hybrid with predominant weightings from rofecoxib trials and CLASS, with its supratherapeutic doses of celecoxib.
Concern about an association of tenofovir with fractures was initially raised by preclinical studies that showed a higher risk of spontaneous fractures and bone abnormalities in rhesus monkeys with simian immunodeficiency virus infection administered supratherapeutic doses of tenofovir (30 mg/kg/day) subcutaneously for one week to 24 months (mean, 14 months) compared with no treatment.
There was no observed hypoglycemia in normoglycemic rats and dogs treated over the long term with supratherapeutic doses of dapagliflozin (at exposure multiples >3000- and >5500-fold >5500-foldely), suggesting that counterespectively resuggestingre inthat and also suggesting a low potential for hypoglycemia with selective SGLT2 inhibition (Bristol-Myers Squibb and AstraZeneca, data on file).
Although the question of whether plasma GLP-1 can cross an intact blood-brain barrier is controversial [ 4], pre-treatment with supratherapeutic doses of linagliptin, a DPP-4 inhibitor, reduced neuronal loss in a mouse model of stroke [ 11], suggesting that GLP-1 may indeed have a central effect after injury.
