Bilastine vs. hydroxyzine : occupation of brain histamine H-receptors evaluated by positron emission tomography in healthy volunteers

A close correlation exists between positron emission tomography (PET)-determined histamine H-receptor occupancy (HRO) and the incidence of sedation. Antihistamines with HRO <20% are classified as non-sedating. The objective was to compare the HRO of bilastine, a second generation antihistamine, with that of hydroxyzine. This randomized, double-blind, crossover study used PET imaging with [ 11 C]-doxepin to evaluate HRO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and HROs were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs), were also evaluated. The mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P < 0.01; mean difference and 95% CI −0.130 [−0.155, 0.105]). There was no significant difference between bilastine and placebo. Overall HRO by bilastine was significantly lower than that by hydroxyzine (mean value −3.92% vs. 53.95%, P < 0.01; mean difference and 95% CI 57.870% [42.664%, 73.075%]). There was no significant linear relationship between individual bilastine plasma concentrations and total binding potential values. No significant between-treatment differences were observed for sedation and psychomotor performance. Twenty-six non-serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine. A single oral dose of bilastine 20 mg had minimal HRO, was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment-related sedative AEs, thus satisfying relevant subjective, objective and PET criteria as a non-sedating antihistamine

Oncolytic Adenoviruses Armed with Thymidine Kinase Can Be Traced by PET Imaging and Show Potent Antitumoural Effects by Ganciclovir Dosing

Replication-competent adenoviruses armed with thymidine kinase (TK) combine the concepts of virotherapy and suicide gene therapy. Moreover TK-activity can be detected by noninvasive positron emission-computed tomography (PET) imaging, what could potentially facilitate virus monitoring in vivo. Here, we report the generation of a novel oncolytic adenovirus that incorporates the Tat8-TK gene under the control of the Major Late Promoter in a highly selective backbone thus providing selectivity by targeting the retinoblastoma pathway. The selective oncolytic TK virus, termed ICOVIR5-TK-L, showed reduced potency compared to a non-selective counterpart. However the combination of ICOVIR5-TK-L with ganciclovir (GCV) induced a potent antitumoural effect similar to that of wild type adenovirus in a preclinical model of pancreatic cancer. Although the treatment with GCV provoked a reduction in the viral yield, both in vitro and in vivo, a two-cycle treatment of virus and GCV resulted in an enhanced antitumoral response that correlated with high TK-activity, based on microPET measurements. Thus, TK-expressing oncolytic adenoviruses can be traced by PET imaging providing real time information on the activity of the virus and its antitumoral potency can be optimized by GCV dosing

Comparison of the Performance Evaluation of the MicroPET R4 Scanner According to NEMA Standards NU 4-2008 and NU 2-2001

The purpose of this work was to evaluate the performance of the microPET R4 system for rodents according to the NU 4-2008 standards of the National Electrical Manufacturers Association (NEMA) for small-animal positron emission tomography (PET) systems and to compare it against its previous evaluation according the adapted clinical NEMA NU 2-2001. The performance parameters evaluated here were spatial resolution, sensitivity, scatter fraction, counting rates for rat- and mouse-sized phantoms, and image quality. Spatial resolution and sensitivity were measured with a 22Na point source, while scatter fraction and count rate performance were determined using a mouse and rat phantoms with an 18F line source. The image quality of the system was assessed using the NEMA image quality phantom. Assessment of attenuation correction was performed using γ-ray transmission and computed tomography (CT)-based attenuation correction methods. At the center of the field of view, a spatial resolution of 2.12 mm at full width at half maximum (FWHM) (radial), 2.66 mm FWHM (tangential), and 2.23 mm FWHM (axial) was measured. The absolute sensitivity was found to be 1.9% at the center of the scanner. Scatter fraction for mouse-sized phantoms was 8.5 %, and the peak count rate was 311 kcps at 153.5 MBq. The rat scatter fraction was 22%, and the peak count rate was 117 kcps at 123.24 MBq. Image uniformity showed better results with 2-D filtered back projection (FBP), while an overestimation of the recovery coefficients was observed when using 2-D and 3-D OSEM MAP reconstruction algorithm. All measurements were made for an energy window of 350-650 keV and a coincidence window of 6 ns. Histogramming and reconstruction parameters were used according to the manufacturer's recommendations. The microPET R4 scanner was fully characterized according to the NEMA NU 4-2008 standards. Our results diverge considerably from those previously reported with an adapted version- of the NEMA NU 2-2001 clinical standards. These discrepancies can be attributed to the modifications in NEMA methodology, thereby highlighting the relevance of specific small-animal standards for the performance evaluation of PET systems.This work was supported in part by the Fondo de Investigación Sanitaria (FIS) of the Instituto de Salud Carlos III under Grants PS09/02620 and PS09/02217, the CDTI as part of the CENIT Program (AMIT Project), the Ministerio de Ciencia e Innovación under Project No. SAF2009-08076, and the Spanish Ministry of Economy and Competitivenes

Positron Emission Tomographic Imaging of the Cannabinoid Type 1 Receptor System with [C]OMAR ([C]JHU75528): Improvements in Image Quantification Using Wild-Type and Knockout Mice

In this study, we assessed the feasibility of using positron emission tomography (PET) and the tracer [ 11 C]OMAR ([ 11 C]JHU75528), an analogue of rimonabant, to study the brain cannabinoid type 1 (CB1) receptor system. Wild-type (WT) andCB1 knockout (KO) animals were imaged at baseline and after pretreatment with blocking doses of rimonabant. Brain uptake in WT animals was higher (50%) than in KO animals in baseline conditions. After pretreatment with rimonabant, WT uptake lowered to the level of KO animals. The results of this study support the feasibility of using PET with the radiotracer [ 11 C]JHU75528 to image the brain CB1 receptor system in mice. In addition, this methodology can be used to assess the effect of new drugs in preclinical studies using genetically manipulated animals

Metabolic footprint of aging and obesity in red blood cells

Aging is a physiological process whose underlying mechanisms are still largely unknown. The study of the biochemical transformations associated with aging is crucial for understanding this process and could translate into an improvement of the quality of life of the aging population. Red blood cells (RBCs) are the most abundant cells in humans and are involved in essential functions that could undergo different alterations with age. The present study analyzed the metabolic alterations experienced by RBCs during aging, as well as the influence of obesity and gender in this process. To this end, the metabolic profile of 83 samples from healthy and obese patients was obtained by Nuclear Magnetic Resonance spectroscopy. Multivariate statistical analysis revealed differences between Age-1 (= 30) subgroups, while no differences were associated with gender. A general decrease in the levels of amino acids was detected with age, in addition to metabolic alterations of glycolysis, the pentose phosphate pathway, nucleotide metabolism, glutathione metabolism and the Luebering-Rapoport shunt. Obesity also had an impact on the metabolomics profile of RBCs; sometimes mimicking the alterations induced by aging, while, in other cases, its influence was the opposite, suggesting these changes could counteract the adaptation of the organism to senescence

Comparison of the Performance Evaluation of the MicroPET R4 Scanner According to NEMA Standards NU 4-2008 and NU 2-2001

The purpose of this work was to evaluate the performance of the microPET R4 system for rodents according to the NU 4-2008 standards of the National Electrical Manufacturers Association (NEMA) for small-animal positron emission tomography (PET) systems and to compare it against its previous evaluation according the adapted clinical NEMA NU 2-2001. The performance parameters evaluated here were spatial resolution, sensitivity, scatter fraction, counting rates for rat- and mouse-sized phantoms, and image quality. Spatial resolution and sensitivity were measured with a 22Na point source, while scatter fraction and count rate performance were determined using a mouse and rat phantoms with an 18F line source. The image quality of the system was assessed using the NEMA image quality phantom. Assessment of attenuation correction was performed using γ-ray transmission and computed tomography (CT)-based attenuation correction methods. At the center of the field of view, a spatial resolution of 2.12 mm at full width at half maximum (FWHM) (radial), 2.66 mm FWHM (tangential), and 2.23 mm FWHM (axial) was measured. The absolute sensitivity was found to be 1.9% at the center of the scanner. Scatter fraction for mouse-sized phantoms was 8.5 %, and the peak count rate was 311 kcps at 153.5 MBq. The rat scatter fraction was 22%, and the peak count rate was 117 kcps at 123.24 MBq. Image uniformity showed better results with 2-D filtered back projection (FBP), while an overestimation of the recovery coefficients was observed when using 2-D and 3-D OSEM MAP reconstruction algorithm. All measurements were made for an energy window of 350-650 keV and a coincidence window of 6 ns. Histogramming and reconstruction parameters were used according to the manufacturer's recommendations. The microPET R4 scanner was fully characterized according to the NEMA NU 4-2008 standards. Our results diverge considerably from those previously reported with an adapted version- of the NEMA NU 2-2001 clinical standards. These discrepancies can be attributed to the modifications in NEMA methodology, thereby highlighting the relevance of specific small-animal standards for the performance evaluation of PET systems.This work was supported in part by the Fondo de Investigación Sanitaria (FIS) of the Instituto de Salud Carlos III under Grants PS09/02620 and PS09/02217, the CDTI as part of the CENIT Program (AMIT Project), the Ministerio de Ciencia e Innovación under Project No. SAF2009-08076, and the Spanish Ministry of Economy and Competitivenes

Metabolic footprint of aging and obesity in red blood cells

Aging is a physiological process whose underlying mechanisms are still largely unknown. The study of the biochemical transformations associated with aging is crucial for understanding this process and could translate into an improvement of the quality of life of the aging population. Red blood cells (RBCs) are the most abundant cells in humans and are involved in essential functions that could undergo different alterations with age. The present study analyzed the metabolic alterations experienced by RBCs during aging, as well as the influence of obesity and gender in this process. To this end, the metabolic profile of 83 samples from healthy and obese patients was obtained by Nuclear Magnetic Resonance spectroscopy. Multivariate statistical analysis revealed differences between Age-1 (= 30) subgroups, while no differences were associated with gender. A general decrease in the levels of amino acids was detected with age, in addition to metabolic alterations of glycolysis, the pentose phosphate pathway, nucleotide metabolism, glutathione metabolism and the Luebering-Rapoport shunt. Obesity also had an impact on the metabolomics profile of RBCs; sometimes mimicking the alterations induced by aging, while, in other cases, its influence was the opposite, suggesting these changes could counteract the adaptation of the organism to senescence

Positron Emission Tomographic Imaging of the Cannabinoid Type 1 Receptor System with [ 11

In this study, we assessed the feasibility of using positron emission tomography (PET) and the tracer [ 11 C]OMAR ([ 11 C]JHU75528), an analogue of rimonabant, to study the brain cannabinoid type 1 (CB1) receptor system. Wild-type (WT) andCB1 knockout (KO) animals were imaged at baseline and after pretreatment with blocking doses of rimonabant. Brain uptake in WT animals was higher (50%) than in KO animals in baseline conditions. After pretreatment with rimonabant, WT uptake lowered to the level of KO animals. The results of this study support the feasibility of using PET with the radiotracer [ 11 C]JHU75528 to image the brain CB1 receptor system in mice. In addition, this methodology can be used to assess the effect of new drugs in preclinical studies using genetically manipulated animals