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TSRI Researcher Develops New Vaccine to Treat Cocaine AddictsA group at TSRI has designed a new vaccine against cocaine that could become a valuable tool in treating addiction. Principal investigator Kim Janda and his colleagues in the chemistry and neuropharmacology departments have synthesized this molecule and tested its efficacy against cocaine. Structurally similar to cocaine, this vaccine was successful in laboratory models—data that is presented in the February 13th issue of the Proceedings of the National Academy of Sciences. In the mid-1990s, Janda’s group discovered a previous and similarly potent vaccine. “[These vaccines] suppress the reinforcing aspects of the drug,” says Janda. What is most interesting is, unlike other types of treatment, these vaccines do not interfere with the neurological targets of the drug, but instead help the body keep cocaine from ever reaching the brain in the first place. The vaccines do this by inducing an active immune response that creates antibodies against cocaine in the bloodstream. If an addict later takes a hit, the antibodies will clear the cocaine from the system. Clinically, this sort of therapy could be given to people in treatment programs to aid in their recovery. And, like most other types of treatment, it will only be useful for those who want the help. “This is for people who are who are interested in getting off the drug,” says Janda. This may be a large market. Though the epidemic of cocaine addiction has waned somewhat since its peak in the mid-1980s, the numbers are still alarming. There are nearly 2 million regular cocaine users in the United States today, according to the National Institute on Drug Abuse (NIDA), and cocaine is the leading cause of heart attacks and strokes for people under 35. The DrugCocaine, which is derived from the leaf of the Erythroxylaceae coca plant, is a highly potent drug that, as a salt, is either snorted or dissolved in water and injected directly into the bloodstream. The salt is also often neutralized to make an insoluble “free-base” form that is smoked. Once it is ingested in the bloodstream, the drug crosses the blood–brain barrier and accumulates rapidly in the brain. “The brain levels rise very rapidly once cocaine is taken into the system,” says Janda. Moreover, the cocaine builds up in the ventral tegmental area. This area is connected by nerve cells to the nucleus accumbens, the so-called pleasure center of the brain. There, the cocaine molecules interfere with the normal regulation of dopamine by binding to dopamine transporters and blocking them from recycling the neurotransmitter. This leads to the build-up of dopamine in the brain’s pleasure center, which produces a euphoric feeling in the user—a quick rush that hits seconds after taking the drug that lasts several minutes. The psychological effect of this immediate reward is the basis of the addiction that many cocaine users suffer from. Compulsive users—addicts—will keep a perceived need for the effect that will many times confound a recovering addict’s best efforts to stay clean. There’s an old truism among intravenous drug addicts that their first boost—that first snort of coke, shot of heroin, or puff of crack—was the greatest feeling they had ever experienced. Many of them will also tell you that they too often spent their money, their health, their family, their friends, and their lives to get that feeling back. “Many crack addicts will say the same thing,” says David Smith, founder and medical director of the Haight Ashbury Free Clinics in San Francisco. “They will tell you, ‘I took 10,000 hits, one hit at a time,’ always thinking of the next.” Smith has run outpatient and residential drug detoxification, counseling, and substance abuse treatment programs in his Bay area clinics since 1967. Cocaine abuse is especially problematic in urban settings like the Bay area, where high numbers of addicts create large markets—nearly $5 billion a year nationwide—which only increase the drug’s availability. Not surprisingly, the high availability of cocaine in those areas where the biggest addicts live is perhaps the worst possible complication for those users who are seeking treatment. After all, says Smith, “cocaine addiction is a chronic brain disease characterized by compulsion and lack of control.” Smith believes the best recovery programs are those that combine traditional psychosocial behavioral therapy with pharmacological treatment, because this is the best way to treat addiction in general. Many heroin addicts, for instance, are able to stay clean through a combination of counseling and daily doses of methadone, a treatment that has been available for several decades. The Treatment“Unfortunately,” says Janda, “there is no methadone for cocaine.” In fact, says Janda, there currently are no suitable medications at all for treating cocaine addiction. Some compounds do exist, but these act by interfering with cocaine in the brain, leading to unwanted neurological side effects. Janda’s new potential medication, called GND, is similar in structure to another cocaine vaccine, called GNC, which the group designed several years ago. Both vaccines are structurally similar to cocaine. Although they have not yet undergone clinical trials, the vaccines have shown great promise in Janda’s studies. GND and GNC act by stimulating an active immune response in the bloodstream. After taking the vaccine, a patient’s immune system would, in theory, create an antibody against the vaccine, and this antibody would also target cocaine because of its similar molecular shape. Janda also looked at boosting passive immunity by administering the antibody and not the vaccine, another way of achieving the same effect. The studies show that the vaccine and antibody treatments given alone both suppress the psychomotor effects of cocaine for up to twelve days following vaccine inoculation. The studies also showed that the effect increased dramatically through concurrent passive immunization—administering the antibody the immune system creates at the same time as the vaccine. In practice, the vaccine would be an integral part of certain rehabilitation processes and would be administered by health professionals in a treatment setting. Addicts would probably receive boosters of both the vaccine and the antibody, as this combination has proven to have the longest lasting effect in the study. Then if these recovering addicts later try to get high, their immune systems will keep most of the cocaine molecules from entering the brain. The drug would then, in theory, have a minimal effect on dopamine regulation in their brains’ pleasure centers. They wouldn’t feel high, and they wouldn’t experience psychological reinforcement. Hopefully, this would help prevent relapse, the bane of all treatment programs. “You have to prevent relapse early,” says Smith. “The vaccine will be good for keeping people on the path of recovery.” An Uncertain FutureThough the GNC and GND molecules are very similar—both structurally and in terms of how they stimulate the immune system—the antibodies they produce are not the same. In the laboratory, model systems using GND, the new vaccine, showed a slightly greater efficacy than previous models that used GNC. However, this greater laboratory efficacy may not mean that the newer compound will replace the older one before either eventually finds use in treatment. Both are years away, and GND is in a much earlier stage of development than GNC. GNC, the original vaccine, has already gone through a lengthy testing process and is coming close to human trials. The vaccine had to be made non-toxic to humans. Plus details of its synthesis had to be worked out so that it can be manufactured easily and on a massive scale. These issues necessitated an investment of basic science capital long before GNC was even close to reaching patients. Janda’s work has been funded through NIDA, with a big boost coming from the generous private contributions of the Joseph Drown Foundation and Mr. Robert E. Martini. Such support allowed Janda to extend his work on GNC and make the second-generation vaccine, GND. Whether or not GND makes it to the clinic or even as far as human trials, though, depends a lot on whether there is any interest in developing the compound clinically. “It works like gangbusters,” says Janda, “But it’s not as synthetically accessible as the original.” Not yet.
For more information, see M. Rocio A. Carrera, Jon A. Ashley, Peter Wirsching, George F. Koob, and Kim D. Janda, "A second-generation vaccine protects against the psychoactive effects of cocaine," Proceedings of the National Academy of Sciences, USA, Vol. 98, Issue 4 (Feb. 13, 2001), 1988-1992.
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