A Summary of Peripheral Blockers as Treatments for Substance Abuse and Dependence
This scientific review meeting was held at the National Institute on Drug Abuse, Rockville, MD on April 27 and 28, 1998. Peripheral blockers are proteins or chemicals that will slow, or block, the entry of an abused substance into the brain by either binding to the substance or metabolizing it. These actions reduce the effectiveness of abused substances by reducing their concentration in the brain. Thus, from a treatment perspective, peripheral blockers favorably alter the pharmacokinetics of abused substances. The purpose of the meeting was to review progress on technical aspects of developing vaccines, catalytic antibodies and enzymes that will metabolize or bind drugs of abuse. A secondary purpose was to bring scientists in this field together to share ideas and stimulate further thinking about the issues and problems yet to be solved. A strong sense of having achieved much progress was evident at the meeting, and many came away with a new realization that these medications are both feasible and potentially useful as treatments.
Sixteen scientists made oral presentations in four scientific sessions at the meeting and an additional five scientists made poster presentations. The abstracts of these presentations and a brief biographical sketch of their authors are found on this web site under Program Books. Discussants for the meeting were: Dr. B. P. Doctor of the Walter Reed Army Institute of Research, Dr. Roy Wise of the National Institute on Drug Abuse, Dr. Marjorie Shapiro and Dr. Carol Trapnell of the Center for Biologics Evaluation and Research, FDA.
Dr. Charles R. Schuster, former Director of NIDA and now at Wayne State University School of Medicine, delivered an introductory lecture in which he reviewed his work in developing an efficacious vaccine against heroin in the 1970's. He explained that this vaccine was not used clinically because it was specific to heroin and would not have worked against any other opiate, limiting its usefulness among most addicts. Furthermore, the new opiate antagonist naltrexone had just been developed that blocked all opiates and it was assumed at the time that it would supercede the use of a vaccine. Another serious drawback to the usefulness of the heroin vaccine was that vaccinated monkeys would continue to self-administer heroin if sufficient quantities of heroin were available to overcome the vaccine blockade. Dr. Schuster then discussed how the current generation of immunological approaches to drug dependence could benefit by addressing the need to control for drug substitution when the medication targeted a specific drug of abuse and by the use of voucher-based systems of compliance motivation.
Dr. Michael Owens of the University of Arkansas for Medical Sciences gave the keynote address. He stressed the need for a rational plan for medication development of these new biological modifiers. Consequently, there is a need to fully understand the pharmacokinetic and pharmacodynamic relationships involved in each type of medication and a need to match the capability of that treatment approach to the different types of abuse and dependence problems confronted in the clinic. He described how recent advances in the biological sciences and in the area of large-scale production of biological reagents could be used to benefit the treatment of abuse/dependence with immunological and enzymatic methods.
Progress in the biotechnology of these new approaches to treatments was reported and discussed. Many of the projects have progressed beyond the in vitro stage and have started preclinical pharmacology and behavioral studies in rodents. The data suggest that the pharmacological effects of cocaine, nicotine and phencyclidine can be blocked, shortened or rapidly reversed with the use of antibodies or enzymes.
Catalytic antibodies are designed to bind to a target molecule, such as cocaine, and bend it to a point that makes it easy to cleave into inactive entities, just as butyrylcholinesterase, the naturally occurring enzyme degrades cocaine. The energy of the binding reaction between the antibody and cocaine is used to change the shape of the cocaine molecule, leading to its catalysis. Gail Winger and colleagues tested Donald Landry's monoclonal antibody, which has catalytic actions, and found that it reduced cocaine-induced blood pressure increases and blocked cocaine self-administration. These are very promising results even though the reaction rate of this artificial enzyme is slower than that of human BChE in metabolizing cocaine. They stated that this antibody would be humanized to allow repeated injections in humans without causing an unwanted immune reaction. Its efficacy in humans will only be known after adequate trials in cocaine users.
John Cashman and Kim Janda are attempting to develop faster catalytic antibodies using multiple approaches. Janda proposed two recent technological advancements developed by he and his colleagues that could be applied to cocaine catalytic antibody production. First, direct selection is a method of screening an antibody library for catalytic activity in one step, without having to first screen for binding activity and then screen for catalysis. Second, reactive immunization is another process that augments energy in the binding reaction of antigen and antibody and should be useful in producing more efficient antibodies. Cashman's work has centered on developing better haptens through the synthesis of phosphonate monoesters as transition state analogs. Neither Cashman nor Janda reported on specific catalytic antibodies that were ready to test in animals.
Active immunization is the process of stimulating the immune system of an animal to produce antibodies with proteins coupled to haptens, such as cocaine or nicotine. Barbara Fox of the ImmuLogic Pharmaceutical Co. reported that clinical trials of their active cocaine vaccine in humans began in mid-April, 1998. The first opportunity to determine how effective this vaccine will be is expected to occur in 1999. Small molecules like cocaine normally do not stimulate the production of antibodies, but Fox and her colleagues stimulated an immune response by binding cocaine to a large carrier protein for use as an antigen. Kathleen Kantak tested the vaccine from ImmuLogic in rats trained to press a lever to self-administer cocaine. Some vaccinated rats extinguished lever-pressing as though they were receiving saline, even when primed with up to 10 mg/kg (i.v.) cocaine. Janda and M.R.A. Carrera, of the Scripps Research Institute, reported that their vaccine reduced the entry of cocaine into the brains of rats and subsequently reduced cocaine-stimulated locomotor activity. Rats immunized with the Scripps vaccine reduced their self-administration of cocaine under normal testing conditions. However, when Carrera allowed the rats unlimited access to cocaine, the rats apparently overcame the antibody blockade and self-administered cocaine as though there had been no vaccination. Finally, Mariangela Segre reported her progress in developing an anti-idiotypic anti-cocaine vaccine that is expected to become as efficacious in rodent studies as other vaccines developed thus far.
Two groups reported success in developing vaccines for nicotine. Paul Pentel of the University of Minnesota and Marion Kasaian of ImmuLogic each described the effectiveness of their nicotine vaccines in rat and mouse models, respectively. Each group bound nicotine to a protein carrier, which, when injected in rodents, stimulated the production of nicotine antibodies. These antibodies kept a greater proportion of administered nicotine in the bloodstream of immunized rodents than in controls.
Michael Owens and colleagues have developed an antibody fragment that rapidly pulls PCP out of the brain and eventually carries it out of the body through the kidneys. This approach is well-suited to treatment of PCP overdoses. Andrew Norman has produced a monoclonal antibody that abolished cocaine self-administration at low unit doses and dose-dependently increased the unit-dose of cocaine required to initiate self-administration. He intends to develop a human, passively-administered monoclonal antibody against cocaine that will be ready to start clinical trials within a few years.
David Gorelick reviewed the advantages and disadvantages of using enzymes to treat cocaine dependent persons. Gilbert Carmona presented his work with horse-derived butyrylcholinesterase (BChE) that he administered intravenously to rats. When these rats were subsequently given cocaine (i.p.), the increased level of locomotor activity that normally develops was significantly reduced. Similarly, Kazuo Matsubara found that pretreatment with the experimental drug JTP-4819 reduced cocaine-stimulated locomotor activity in mice, presumably because BChE levels had been elevated to more than twice normal by the test drug. Dr. Clarence Broomfield introduced the topic of site-directed mutagenesis of the BChE molecule to optimize the reaction rate for cocaine. Wei Hua Xie, representing Dr. Oksana Lockridge, reported that they had achieved a 4-fold increase in the reaction rate of human BChE for cocaine through site-directed mutagenesis. John Cashman reviewed his efforts at altering the acetylcholinesterase molecule in a manner that would direct future efforts toward improving the activity of BChE. Site-directed mutagenesis is likely to provide powerful forms of enzymatic activity against cocaine.
Discussions in the meeting included considerations of the roles of the various treatment approaches. It was felt that these new therapies could be matched to the appropriate drug abuse-related medical problems, but that the therapies will not replace more conventional psychosocial treatment techniques. It is important to point out that they would also not interfere with the use of possible receptor-based pharmacological treatments that may be developed in the future. Peripheral blockade medications could become part of a comprehensive medical plan that would increase the therapeutic options for physicians and drug abuse counselors. For example, many combinations of active immunizations, catalytic antibodies, and passive administration of a human monoclonal anti-cocaine or anti-nicotine IgG could be used to blunt or block the reinforcing effects of cocaine or nicotine during attempts to quit using drugs. High-affinity Fab fragments could be used for acute PCP overdose crises. Those therapies with higher binding affinities were expected to be more successful with acute treatment efforts, such as overdoses. Lower binding affinities were expected to be more successful with relapse prevention efforts where rapid dissociation of the antibody/drug complex would allow the antibody to quickly act on another target molecule.
There would be a risk of repeated drug use after a blocker had been given in a relapse prevention effort. For example, a patient may try to overcome the blockade provided by the antibody or enzyme by taking greater than normal amounts of cocaine or nicotine. The potential for any of the blockers presented at this meeting to be overcome by the administration of large quantities of abused drugs was vigorously discussed. Dr. Roy Wise, of the NIDA Intramural Research Program spurred on discussion of this issue. He challenged the interpretation of some of the behavioral results from investigations of cocaine vaccines. The rats with essentially no constraints on their lever-pressing, as reported by M. Rocio. A. Carrerra and as mentioned above, overcame the blockade resulting from the vaccine and spent all their energy to obtain more and more cocaine. However, Kathleen Kantak reported that rats with some constraints did not continue to lever-press for cocaine and apparently did not overcome the blockade. It is more likely that the different outcomes of testing these two vaccines are based on the contingencies placed on the rats by the experimenters rather than their comparative effectiveness. Since neither of these behavioral models perfectly addresses the contingencies facing human cocaine users, satisfying answers to these questions may not come until late-stage clinical trials. Fortunately, pre-clinical data presented here showed that the lethality of cocaine is based on the free concentration in plasma, not on the bound fraction. The reinforcing properties of cocaine are also based on the free concentration. Since the concentration for reinforcement is lower than that for lethality, a recovering cocaine user who tried to overcome a peripheral block by using greater than normal amounts of cocaine could get "high" and then discontinue use to avoid the risk of overdose.
Overall, there was a stirring realization that these new medications can provide powerful new tools for treating the problems of addiction and drug abuse. Another summary of this meeting has been published as "New Generation of Medications for Drug Abuse," in Pharmaceutical News, December, 1998, in press, written by S. Michael Owens, Andrew Norman and Steven Sparenborg.
[Scientific Meeting Dates and Summaries][Peripheral Blockers Program Book]