Evaluation of Antihistamine Drugs by Human 11{sup left}Cdoxepin Dynamic PET Studies with a Parametric Image Approach

摘要

The side effects of sedation induced by antihistamine drugs are considered due to their occupation on cerebral HI receptor. To evaluate the pharmacological effects of antihistamines on central nervous system quantitatively, PET scans on twelve healthy adults were performed on a GE Advance scanner after intravenous bolus injection of high specific activity [11{sup left}C]doxepin. Three representative antihistamine drugs used for the treatment of allergy-based diseases, diphenhydramine, cetirizine, and fexofenadine, were selected in this study for evaluation. Each subject received at least two PET studies in one day, a baseline scan followed by a scan with a single oral therapeutic dose of a tested drug. A linear regression with spatial constraint (LRSC) algorithm derived from a 2-compartmental 3-parameter model was used to estimate the transport rate constant KX and distribution volume (DV). The images of binding potential (BP) were calculated as BP = DV(pixeI)/DV(cerebellum)-l. Both PET-to-PET intra-subject image registration and spatial normalization using PET template were based on K{sub}1 images by using SPM99. The paired T mapping from parametric images were calculated for statistical analysis. Results showed that the model used in this study fits well to the brain tissue [11{sup left}C]doxepin kinetics measured by PET. The linear operational equations yield a reliable, computationally efficient, and robust LRSC algorithm to generate KI and DV images. There is no significant effects on K{sub}1 for the 3 tested drugs. The percent occupancy of diphenhydramine on HI receptors is 30 to 80% in most cortex regions, and its blocking on HI receptor in caudate, putamen and thalamus is not significant. Cetirizine is of marginal occupation of HI receptor in cortex regions in a range of 5 to 20%. Fexofenadine does not have any blockade effects on HI receptor in brain tissue, and it should be classified as a third generation antihistamine drug.