[18F]-FMISO PET/MRI Imaging Shows Ischemic Tissue around Hematoma in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH), being the most severe cerebrovascular disease, accounts for 10-15% of all strokes. Hematoma expansion is one of the most important factors associated with poor outcome in intracerebral hemorrhage (ICH). Several studies have suggested that an "ischemic penumbra" might arise when the hematoma has a large expansion, but clinical studies are inconclusive. We performed a preclinical study to demonstrate the presence of hypoxic-ischemic tissue around the hematoma by means of longitudinal [18F]-fluoromisonidazole ([18F]-FMISO) PET/MRI studies over time in an experimental ICH model. Our results showed that all [18F]-FMISO PET/MRI images exhibited hypoxic-ischemic tissue around the hematoma area. A significant increase of [18F]-FMISO uptake was found at 18-24 h post-ICH when the maximum of hematoma volume is achieved and this increase disappeared before 42 h. These results demonstrate the presence of hypoxic tissue around the hematoma and open the possibility of new therapies aimed to reduce ischemic damage associated with ICH.

Positron Emission Tomography for the Development and Characterization of Corneal Permanence of Ophthalmic Pharmaceutical Formulations.

Purpose: This work is aimed at describing the utility of positron emission tomography/computed tomography (PET/CT) as a noninvasive tool for pharmacokinetic studies of biopermanence of topical ocular formulations. Methods: The corneal biopermanence of a topical ophthalmic formulation containing gellan gum and kappa carragenan (0.82% wt/vol) labeled with 18Fluorine (18F) radiotracers (18F-FDG and 18F-NaF) was evaluated by using a dedicated small-animal PET/CT, and compared with the biopermanence of an aqueous solution labeled with the same compounds. Regions of interest (ROIs) were manually drawn on the reconstructed PET images for quantifying the radioactivity concentration in the eye. The biopermanence of the formulations was determined by measuring the radioactivity concentration at different times after topical application. Additionally, cellular and ex vivo safety assays were performed to assess the safety of the performed procedures. Results: Differences were observed in the ocular pharmacokinetics of the two formulations. After 1.5 hours of contact, 90% of the hydrogel remained in the ocular surface, while only 69% of the control solution remained. Furthermore, it was observed that flickering had a very important role in the approach of the trial. The application of 18F-FDG in the eye was neither irritating nor cytotoxic for human corneal epithelial cells. Conclusions: The use of small-animal PET and 18F radiotracers in ocular pharmacokinetics of ophthalmic formulations is feasible and could be a safe method for future ocular pharmacokinetic studies in humans.

The increase in rat ventricular automaticity induced by salbutamol is mediated through ß(1)- but not ß(2)-adrenoceptors: role of phosphodiesterases.

AIMS: While ß(2)-adrenoceptor (AR) agonists are useful bronchodilators, they also produce cardiac arrhythmias. These agents are not fully selective and also activate ß(1)-AR, but the involvement of ß(1)-AR and ß(2)-AR in the observed pro-arrhythmic effect has not been established. We studied the effect of ß(1)-AR and ß(2)-AR activation on ventricular automaticity and the role of phosphodiesterases (PDE) in regulating this effect. MAIN METHODS: Experiments were performed in the spontaneously beating isolated right ventricle of the rat heart. We also measured cAMP production in this tissue. KEY FINDINGS: The ß(2)-AR agonist salbutamol (1-100 µM) produced a concentration-dependent increase in ventricular automaticity that was not affected by 50nM of the ß(2)-AR antagonist ICI 118551. This effect was enhanced by the non-selective PDE inhibitor theophylline (100 µM) and by the selective PDE4 inhibitors rolipram (1 µM) and Ro 201724 (2 µM), but not modified by the selective PDE3 inhibitors cilostamide (0.3 µM) or milrinone (0.2 µM). The effects of salbutamol alone and in the presence of either theophylline or rolipram were virtually abolished by 0.1 µM ß(1)-AR antagonist CGP 20712A. Salbutamol (10 µM) increased the cAMP concentration, and this effect was abolished by CGP 20712A (0.1 µM) but enhanced by theophylline (100 µM) or rolipram (1 µM). Cilostamide (0.3 µM) failed to modify the effect of salbutamol on cAMP concentration. SIGNIFICANCE: These results indicate that the increase of ventricular automaticity elicited by salbutamol was exclusively mediated through ß(1)-AR and enhanced by non-selective PDE inhibition with theophylline or selective PDE4 inhibition. However, PDE3 did not appear to regulate this effect.