Effect of antacid on imatinib absorption.

PURPOSE: Imatinib often causes gastric upset resulting in frequent co-administration of an antacid. Elevated gastric pH, delayed gastric emptying, or introduction of Mg(2+)/Al(3+) could potentially change imatinib absorption, thereby affecting the therapeutic effectiveness of imatinib. Indeed, antacid co-administration with dasatinib does result in a twofold decrease in dasatinib absorption. We aimed to define the effect of antacid on the pharmacokinetics of imatinib. METHODS: Twelve healthy subjects were enrolled in a 2-period, open-label, randomized cross-over, fixed-sequence study. In one period, each subject received 400 mg imatinib p.o., and in the other, the same dose of imatinib preceded by 20 mL antacid, containing 1.6 g Al(OH)(3) + 1.6 g Mg(OH)(2), 15 min before imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were determined by LC-MS, and data were analyzed non-compartmentally. RESULTS: Antacid administration did not significantly affect the area under the plasma imatinib concentration versus time curve (AUC) [31.7 microg/(mL h) alone versus 32.6 microg/(mL h) with antacid, P = 0.37; 80% power]. CONCLUSIONS: Our results indicate that the use of Mg(2+)-Al(3+)-based antacid does not significantly affect imatinib absorption.

Fluorescent sensors for specific RNA: a general paradigm using chemistry and combinatorial biology.

Here, we describe a new paradigm for the development of small molecule-based RNA sensors. We prepared a series of potential PET (photoinduced electron transfer) sensors on the basis of 2',7'-dichlorofluorescein (DCF) fluorophore conjugated with two aniline derivatives as electron donors (quenchers). NMR and fluorescent spectroscopic analyses of these DCF derivatives revealed the correlation between the conformations, the PET, and the fluorescent intensities of these DCF derivatives, enabling us to select a sensor candidate. RNA aptamers were raised against the aniline-based quencher via in vitro selection (SELEX). One of these aptamers enhanced the fluorescence intensity of the DCF-aniline conjugate in a concentration-dependent manner. To demonstrate the power and generality of this approach, additional in vitro selection was performed and aptamers from this selection were found to have similar activities. These results show that one can develop fluorescence-inducing reporter RNA and morph it into remotely related sequences without prior structural insight into RNA-ligand binding.

A strategy for the development of small-molecule-based sensors that strongly fluoresce when bound to a specific RNA.

We report a broadly applicable approach for the development of small-molecule-based RNA sensors. Our photoinduced electron transfer (PET) sensor consists of a fluorescein derivative as the fluorophore and two aniline derivatives as electron donors (quenchers). The isolation of electron-donor-binding RNA by in vitro selection (also known as SELEX) yielded an RNA aptamer that could increase the fluorescence intensity of the sensor by 13-fold. This result shows that RNA-electron-donor interactions can be used to develop modular RNA chemosensors.

Effect of binding and conformation on fluorescence quenching in new 2',7'-dichlorofluorescein derivatives.

[structure: see text] Symmetrical and unsymmetrical 2',7'-dichlorofluorescein (DCF) derivatives have been synthesized by means of Mannich reactions and an aromatic Claisen rearrangement. NMR and fluorescence spectroscopic studies reveal the correlation between the conformations, the photoinduced electron transfer mechanism, and fluorescent intensities of these DCF derivatives. Two quenching nitrogen atoms cooperatively and reversibly suppress the fluorescence of the chromophore.