Pharmacokinetic and Pharmacodynamic Evaluation of Cocaine Hydrolases for the Treatment of Cocaine Overdose and Cocaine Addiction Using Rodent Models

Overdose and addiction are two medical complications of cocaine abuse. To date, there is no FDA approved pharmacotherapy specific for cocaine abuse. Cocaine hydrolases (CocHs) have been extensively investigated for its potential in anti-cocaine therapy. Previous studies have demonstrated that CocHs efficiently hydrolyze cocaine to generate biologically inactive metabolites both in vivo and in vitro. However, it has not been studied whether there is gender difference in the therapy using CocHs. In addition, the effectiveness of CocHs is unknown for treating cocaine toxicity when alcohol is co-administered. The main purpose of this dissertation is to characterize and evaluate efficient CocHs for cocaine overdose and cocaine addiction treatment. In the first set of studies, the effectiveness of human serum albumin-fused CocH1 were studied in male and female rats. The pharmacokinetic profiles, as well as the pharmacodynamic effects of CocH1-HSA were compared in male and female rats. The obtained data clearly demonstrated that CocH1-HSA was equally effective in both genders. The second set of studies investigated the efficiency of Fc-fused CocH5 in reversing cocaine toxicity in rats receiving simultaneous administration of cocaine and alcohol. Results showed that CocH5-Fc rapidly hydrolyzed cocaine and cocaine’s toxic metabolites in rats, and demonstrated that CocH5-Fc was efficient in treating cocaine toxicity when alcohol was simultaneously administered. In later studies to investigate the effects of CocH5-Fc for the treatment of cocaine addiction, a mathematical model was developed and validated to predict the effects of CocH5-Fc on the disposition of cocaine in rat blood and brain. This model adequately described the effects of CocH5-Fc in accelerating the elimination of cocaine and its toxic metabolites in both rat blood and brain. In conclusion, the studies within the current dissertation demonstrate the clinical potential of CocHs for the treatment of both cocaine overdose and cocaine addiction

The crossing number of locally twisted cubes

The {\it crossing number} of a graph $G$ is the minimum number of pairwise intersections of edges in a drawing of $G$. Motivated by the recent work [Faria, L., Figueiredo, C.M.H. de, Sykora, O., Vrt'o, I.: An improved upper bound on the crossing number of the hypercube. J. Graph Theory {\bf 59}, 145--161 (2008)] which solves the upper bound conjecture on the crossing number of $n$-dimensional hypercube proposed by Erd\H{o}s and Guy, we give upper and lower bounds of the crossing number of locally twisted cube, which is one of variants of hypercube.Comment: 17 pages, 12 figure

Blocking Drug Activation as a Therapeutic Strategy to Attenuate Acute Toxicity and Physiological Effects of Heroin

Heroin is a growing national crisis in America. There is an increasing frequency of heroin overdoses. All of the currently used therapeutic approaches to treatment of heroin abuse and other opioid drugs of abuse focus on antagonizing a brain receptor (particularly µ-opiate receptors). However, it has been known that the therapeutic use of certain µ-opiate receptor antagonist may actually increase heroin overdose. Once overdosed, heroin addicts may continue to get overdosed again and again until fatal. Here we report our design and validation of a novel therapeutic strategy targeting heroin activation based on our analysis of the chemical transformation and functional change of heroin in the body. An effective blocker of heroin activation, such as ethopropazine tested in this study, may be used as a standalone therapy or in combination with a currently available, traditional medications targeting µ-opiate receptors (e.g. naltrexone or its extended-release formulation Vivitrol). The combination therapy would be ideal for heroin abuse treatment as the effects of two therapeutic agents targeting two independent mechanisms are cooperative