A 'biorelevant' system to investigate in vitro drug released from a naltrexone implant.

This research is based on the recognized need for an in vitro release method for drug implants that better simulate physiological conditions at the site of implantation ('biorelevance'). In this paper, we describe the evaluation of a 'biorelevant' approach for in vitro drug release testing of a biodegradable implant of naltrexone in a pre-clinical stage of development. A miniature, capillary cell culture device was modified and tested as a biorelevant alternative for a standard commercially available flow-through cell. The real-time data generated through 90 days indicated a 48% lower rate of release for the capillary system. The profiles using both systems followed zero-order kinetics after an initial period of burst release. In vitro release data from the capillary device resulted in a 1-to-1 correlation with dog plasma pharmacokinetic data, and furthermore, the capillary device potentially simulated the lag-time in absorption more effectively than the flow-through cell. Scanning electron micrographs revealed that the sheath was continuous with no signs of cracks at the end of in vitro and in vivo studies. However, at the interface of the sheath and the core, intercalating, "finger-like" projections were observed consistent with penetration of the medium. No macroscopic or clinical toxicity signs were observed during the in vivo implantation study.

Evaluation of the reinforcing effects of the cannabinoid CB1 receptor antagonist, SR141716, in rhesus monkeys.

The abuse liability of a selective cannabinoid CB1 receptor antagonist, SR141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide hydrochloride), was evaluated in rhesus monkeys. Four rhesus monkeys with chronically indwelling venous catheters were initially trained to self-administer cocaine (30 microg/kg/injection) during daily 1-h sessions under a fixed ratio 50 (FR50) schedule of reinforcement. SR141716 was subsequently substituted for cocaine, and SR141716 dose was varied from 1 to 100 microg/kg/injection. Each dose of SR141716 was tested for four consecutive sessions and each unit dose was separated by at least three sessions of cocaine self-administration. Substitution of SR141716 for cocaine resulted in rapid extinction of lever pressing and none of the doses of SR141716 tested was self-administered above the vehicle levels. When the highest dose of SR141716 (100 microg/kg/injection) was evaluated, self-administration behavior was suppressed below vehicle levels suggesting that behaviorally active doses were evaluated. Since positive results in self-administration tests are generally predictive of abuse potential, the negative results with SR141716 suggest that this drug would likely have low abuse liability.

Animal models of substance abuse and addiction: implications for science, animal welfare, and society.

Substance abuse and addiction are well recognized public health concerns, with 2 NIH institutes (the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism) specifically targeting this societal problem. As such, this is an important area of research for which animal experiments play a critical role. This overview presents the importance of substance abuse and addiction in society; reviews the development and refinement of animal models that address crucial areas of biology, pathophysiology, clinical treatments, and drug screening for abuse liability; and discusses some of the unique veterinary, husbandry, and IACUC challenges associated with these models.