A pharmacokinetic model of the intracellular dosimetry of inhaled nickel

The potential associations between exposure to nickel compounds and cancer have been evaluated in both animal and epidemiological studies of occupationally exposed workers. The results of the epidemiological studies suggest that not all nickel compounds are equally carcinogenic, an observation supported by the animal bioassay results. Given the complexity and the differences in the modes of uptake of different forms of nickel by cells and the subsequent delivery of nickel to the nucleus, it would be expected that some forms of nickel would be more potent than others. A physiologically based pharmacokinetic (PBPK) model would be useful in estimating the cellular exposure to nickel resulting from inhalation of the different forms of nickel. To this end, a preliminary model of a tracheobronchial epithelial cell was developed to describe the differences in the extracellular and intracellular kinetics of the different classes of nickel compounds. Data available in the published literature were used to define the initial model parameters. The resulting cellular dosimetry model was able to describe kinetic data on three forms of nickel (soluble chloride and insoluble sulfide and subsulfide). This preliminary model development effort has identified critical data gaps that could be filled by additional research. The ultimate goal will be to integrate a refined cellular dosimetry model with published lung deposition/clearance and systemic distribution/clearance models for nickel. The use of such an integrated PBPK model would allow for more biologically based risk estimates for the inhalation of the different nickel compounds, as well as mixtures of these compounds.     

Food deprivation-like effects of neuropeptide Y on heroin self-administration and reinstatement of heroin seeking in rats

Numerous findings suggest that drug seeking and ingestive behaviors share common neurobiological mechanisms, but the relevant pathways are unknown. Dietary manipulations result in changes in endocrine the and/or neuropeptide signals, such as the hormones leptin and ghrelin, which are dynamically linked to energy balance and the regulation of feeding behavior. We have recently demonstrated that food deprivation-induced reinstatement of heroin seeking can be blocked with leptin, and others have suggested a role for ghrelin in drug-related behaviors. The feeding-relevant effects of leptin and ghrelin involve the inhibition or activation, respectively, of neuropeptide Y/agouti-related peptide (NPY/AGRP) neurons in the hypothalamus. However, the effects of NPY, a highly potent orexigenic peptide, on drug-related behaviors have not been thoroughly studied. Here we examined the effect of acute NPY administration on the rate of heroin self-administration and the reinstatement of extinguished heroin-seeking behavior. Heroin intake (0.05mg/kg/infusion) was tested using a self-administration procedure (FR-1), 10-min post-NPY injections (0.0, 4.0, and 10mug/rat, ICV). In a different group of rats, NPY-induced reinstatement (0.0, 4.0, and 10mug/rat, ICV) of extinguished heroin seeking was assessed. NPY injections increased on-going heroin self-administration, and induced a reinstatement of extinguished heroin-seeking behavior. These findings suggest that NPY can modulate the rewarding and conditioned reinforcing effects of drugs of abuse.     

In vitro structure-activity relationship and in vivo characterization of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 antagonists

The synthesis and structure-activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.