Furthermore, we wanted to understand how to generate high affinity antibodies for METH, (+)-amphetamine and (+)-3,4-methylenedioxymethamphetamine (the positive isomer in the racemic mixture commonly known as ecstasy) with the use of one or more haptens. stage of preclinical development. Both of these vaccines could play an essential role in a well planned recovery program from human METH addiction by providing long-lasting protection from the rewarding and reinforcing effect of METH. Keywords: Dependency, amphetamines, drug abuse, methamphetamine, monoclonal antibody, vaccines INTRODUCTION Stimulant abuse, especially methamphetamine (METH) abuse, continues to be a major problem in the USA and world-wide. The number of patients in the USA admitted to treatment for METH or amphetamine as their primary substance of abuse increased over 400% from 1993-2003.1 In addition, 58% of law enforcement agencies in 45 says indicated that METH is the greatest drug problem.2 METH use results in a complex constellation of acute and chronic effects that involve many organ systems in the body (Table 1). The profound central nervous system (CNS) effects of METH include a sense of increased energy, self-confidence, and well-being; as well as heightened awareness, appetite suppression, euphoria, and increased sexual performance. These effects are significantly reinforcing, and undoubtedly play a role in establishing addiction to METH. The adverse biological effects of METH may be sudden, resulting in acute organ system dysfunction, or they may be longer lasting, resulting in dependency or permanent tissue damage. Effects around the cardiovascular system (CVS), CNS and toxic metabolic effects, such as hypertension, tachycardia, myocardial infarction, strokes, seizures and acute renal failure, pose the most serious acute medical problems.3-6 However, chronic effects such as increased vulnerability to infectious diseases and long-term neurotoxicity play an important role in the societal impact form abuse-related problems.6, 7 Table 1 Complications of Methamphetamine Use METH effects in the brain, BEFORE anti-METH antibody treatment. After taking METH (circles), the drug is delivered to the brain through the blood stream (left barrel) where the drug rapidly penetrates the blood brain barrier (, Mouse monoclonal to TGF beta1 dashed line). In the brain, METH interacts with the dopamine transporter, monoamine oxidase, and vesicular transport mechanisms (), causing CNS-related effects of METH (). Because of the concentration Lapaquistat acetate gradient of METH across the blood brain barrier, more METH initially enters the brain (in arrow) than is removed (out arrow). METH effects in the brain, AFTER anti-METH antibody treatment. In the presence of anti-METH antibodies (Y-shaped objects), METH is no longer able to freely move Lapaquistat acetate across the blood brain barrier, due to high affinity binding to the antibody. Thus, a much smaller amount of METH is able to penetrate the blood brain barrier (, dashed line). Due to this altered drug concentration gradient, METH leaves the brain (out arrow) at a relatively higher rate than it enters. This results Lapaquistat acetate in a cascade of significantly reduced amounts, and rates of association, of METH at the sites of action within CNS nerve terminals (, compare Kon and Koff arrows at nerve terminals before and after antibody treatment). Antibody binding of METH leads to significantly attenuated CNS () and peripheral effects, symbolized by the smaller arrows for CNS and peripheral effects in the lower panel. Hapten design is critical to the development of both active and passive immunization approaches. This is in part because METH is an extremely small molecule with a molecular weight of only 151. Thus, it is near the lower limit of the antigenic size for generation of antibodies. We have conducted extensive structure activity studies of the molecular features of haptens that would stimulate high affinity immune responses to METH because high affinity for METH is our most important goal. Furthermore, we wanted to understand how to generate high affinity antibodies for METH, (+)-amphetamine and (+)-3,4-methylenedioxymethamphetamine (the positive isomer in the racemic mixture commonly known as ecstasy) with the use of one or more haptens. All three of these structurally related drugs have significant abuse potential. It is established that the (+) or specificity of the anti-METH mAb against the other drugs of abuse. When the anti-METH mAb was tested against PCP, cocaine and amphetamine, there were no drug discrimination effects observed on the dose-response curve for those drugs, indicating a high degree of specificity for anti-METH mAbs.45, 47 In contrast, when the anti-METH and anti-PCP mAbs were co-administered to pigeons in behavioral drug discrimination studies, there was a simultaneous, yet drug selective protective effect against each of these drugs. 47 This is the first study to use a mAb cocktail to provide protection against the effects of two drugs at once. HUMAN APPLICATIONS Lapaquistat acetate FOR IMMUNOTHERAPIES There are two primary indications for the use of immunotherapies in the treatment of human METH abuse. The first is treatment of overdose. This indication will necessarily.
