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National Institute on Drug Abuse -  NIDA NOTES
Research Findings
Volume 14, Number 2 (August, 1999)

Blood-borne Medications Could Intercept Drugs Before They Reach the Brain

By Patrick Zickler, NIDA NOTES Staff Writer

The damage done by cocaine and other drugs of abuse takes place among neurons deep in the brain, but the drugs are transported to these nerve cells by the blood. A number of researchers are investigating possible medications that could intercept and neutralize cocaine and other drugs in the bloodstream, preventing them from initiating the neurochemical reactions that lead to abuse and addiction.

"This represents a different approach to therapeutic research, which has most often focused on interfering with a drug's activity in the brain. This strategy is aimed at preventing the drug from reaching the brain," says Dr. Steven Sparenborg of NIDA's Medications Development Division.

Blood-borne medications, referred to as peripheral blockers, would offer several advantages over other pharmacological approaches to addictions, notes Dr. David Gorelick of NIDA's Intramural Research Program. They do not require knowledge of how or where the abused drug acts in the brain, they would be effective against drugs with multiple sites of action in the brain, and they could protect against a drug's actions- such as cardiovascular toxicity- at sites outside the central nervous system.

Peripheral blockers are modeled after the enzymes and antibodies of the body's natural defense system, according to Dr. Sparenborg. One peripheral blocker approach would bind drugs like cocaine, phencyclidine (PCP), or nicotine to antibodies, creating a drug-antibody complex that is too large to move through blood vessel walls into the brain. This would trap the drug within the bloodstream until it could be eliminated from the body through normal kidney activity. Another approach would enhance the rate at which naturally occurring enzymes break down drug molecules into inactive byproducts. A third method under investigation employs an engineered antibody that both binds to and breaks down drugs. Although individuals might overcome the action of these peripheral blockades by taking more of the drug and overwhelming the antibody or enzyme, effective blood-borne medications would serve as valuable components of treatment programs that protect against relapse or counteract acute toxic effects from drugs of abuse.

"There is still a long way to go with this research, but the validity of the approach has been demonstrated in animal tests. First-phase clinical trials of an active cocaine vaccine are under way now, and we're encouraged by the progress," says Dr. Sparenborg.


Molecules as small as cocaine typically do not trigger the body's immune system to create antibodies. However, Dr. Barbara Fox and her colleagues at ImmuLogic Pharmaceutical Corporation in Waltham, Massachusetts, have developed a technique that links cocaine derivatives to a larger protein molecule, or carrier, to stimulate an immune reaction. Animals vaccinated with the cocaine-carrier combination develop cocaine-specific antibodies that bind with cocaine in the blood, preventing most of the drug from reaching the brain.
These results suggest that catalytic antibodies have the unique potential both to treat the acute effects of cocaine overdose and to block some of the chronic reinforcing effects of abuse.

"In mice, the vaccine induced an antibody response that kept cocaine from reaching its targets in the central nervous system," says Dr. Fox, now with Addiction Therapies, Inc., in Wayland, Massachusetts. "And it appears to be long-lasting. Periodic boosters maintained the response for more than a year, which is a significant portion of a mouse's life."

The vaccine, which is currently being studied in first-phase human trials by researchers with Cantab Pharmaceuticals, uses a protein that generates a strong antibody response as a carrier. More than two dozen fragments of the cocaine molecule are bound to the carrier. When injected into animals, the large protein molecules stimulate the production of antibodies that recognize the cocaine fragments. Moreover, the antibodies also bind to norcocaine, one of cocaine's minor but pharmacologically active metabolites, or byproducts, but do not bind to the more abundant but inactive ones. "This means that the antibodies don't become saturated with inactive metabolites and lose the capacity to bind with cocaine," Dr. Fox says.

Dr. Fox and her colleagues found that injecting cocaine into rats immunized with the compound resulted in significantly higher levels of cocaine in the blood, and correspondingly lower levels in the brain, than did injecting the same amount of cocaine into nonimmunized animals. As much as 63 percent of administered cocaine was bound in the blood as soon as 30 seconds after administration. In addition, immunized rats were much less likely to self-administer cocaine than were nonimmunized rats. This finding, Dr. Fox notes, suggests that the vaccine could help prevent relapse in patients in drug treatment programs. "This is not a 'magic bullet' treatment. Patients could overcome it by taking more drug. But for motivated patients it could be a very valuable part of a comprehensive treatment program," Dr. Fox says.


Naturally occurring enzymes can break down cocaine and other drugs before they reach the brain, but they cannot rapidly neutralize the amounts of drugs that are typically ingested by drug abuse patients. Studies involving cocaine abusers suffering acute toxic reactions show a significant relationship between activity levels in the blood of butyrylcholinesterase (BChE), an enzyme produced in the liver, and the severity of cocaine toxicity. Patients with severe reactions to cocaine tend to have lower levels of BChE. NIDA-supported research has demonstrated that enhancing BChE activity can lead to improved treatment of cocaine overdose.

Gilberto Carmona, a doctoral student in NIDA's Intramural Research Program, has shown that the metabolism of cocaine in the blood can be dramatically increased and the drug's effects decreased by raising BChE activity. Mr. Carmona and his colleagues demonstrated that cocaine half-life- the time needed for half the drug to be cleared from the blood- dropped from more than 5 hours to less than 5 minutes in rats pretreated with purified BChE that raised the enzyme's blood activity 400-fold. The increase in BChE activity significantly decreased the increased motor activity caused by a cocaine injection and changed the pattern of cocaine metabolism, resulting in production of predominantly nontoxic byproducts rather than pharmacologically active ones.

NIDA-supported researcher Dr. Oksana Lockridge at the University of Nebraska in Omaha has found that naturally-occurring variations in human BChE have different capacities for cocaine metabolism. "People who don't have the typical variant may react to a 'standard' dose of cocaine as though it were an overdose," Dr. Lockridge says. "Other variants exist at levels as low as one-third of normal levels, and people with these variants are probably at very high risk for cocaine toxicity."

Building on this knowledge of BChE variants, Dr. Lockridge and her colleagues engineered a mutant form of BChE- designated A328Y- that demonstrated four times the catalytic activity of normal BChE when tested in the laboratory. Dr. Kenneth Dretchen at Georgetown University in Washington, D.C., is conducting animal trials of A328Y to determine if the more active variant can be used as a treatment for cocaine overdose. "We know that the butyrylcholinesterase can reduce cocaine-induced convulsions, hyperactivity, and hypertension, and we know that A328Y will act much more aggressively to break cocaine down into inactive metabolites. A328Y could prove to be a valuable 'crash cart' tool for treating acute cocaine toxicity in emergency room situations," he says.

Catalytic Antibodies

Dr. Donald Landry, a researcher at Columbia University College of Physicians and Surgeons in New York City, has developed a cocaine-specific catalytic antibody- a compound that combines features of antibodies that bind to cocaine molecules with features of enzymes that break the drug down into inactive fragments.

The catalytic antibody developed by Dr. Landry and his colleagues uses a molecule that mimics the structure of a cocaine molecule in its transition state- the shape of a cocaine molecule undergoing a chemical reaction. When the catalytic antibody binds to cocaine, the drug molecule takes on the configuration of the transition state. "This accelerates the rate of cocaine hydrolysis to inactive fragments. The antibody then releases the fragments and is free to bind to another cocaine molecule and initiate another cycle," Dr. Landry explains.

"Each molecule of the most potent antibody we have developed breaks down more than 2 cocaine molecules per minute and retains more than 95 percent of its activity through at least 200 turnovers," Dr. Landry says.

Animal tests of the antibody- designated mAB 15A10- demonstrate that it can reduce the toxic effects of cocaine overdose. Other tests show that pretreatment with the compound will prevent rats from self-administering cocaine.

"These results suggest that catalytic antibodies have the unique potential both to treat the acute effects of cocaine overdose and to block some of the chronic reinforcing effects of abuse," Dr. Landry says. "A humanized version of the antibody mAB 15A10 could be useful either as an emergency treatment for overdose or as part of a broader treatment program for addiction."


Carmona, G.N., et al. Attenuation of cocaine-induced locomotor activity by butyrylcholinesterase. Experimental and Clinical Psychopharmacology 6(3):274-279, 1998.

Fox, B.S., et al. Efficacy of a therapeutic cocaine vaccine in rodent models. Nature Medicine 2(10):1129-1132, 1996.

Fox, B.S. Development of a therapeutic vaccine for the treatment of cocaine addiction. Drug and Alcohol Dependence 48:153-158, 1997.

Gorelick, D.A. Enhancing cocaine metabolism with butyrylcholinesterase as a treatment strategy. Drug and Alcohol Dependence 48:159-165, 1997.

Landry, D.W. Immunotherapy for cocaine addiction. Scientific American 276(2):42-45, 1997.

Mattes, C.E.; Belendiuk, G.W.; Lynch, T.J.; Brady, R.O.; and Dretchen, K.L. Butyrylcholinesterase: An enzyme antidote for cocaine intoxication. Addiction Biology 3:171-188, 1998.

Mets, B.; Winger, G.; Cabrera, C.; Seo, S.; Jamdar, S.; Yang, G.; Zhao, K.; Briscoe, R.J.; Almonte, R.; Woods, J.H.; and Landry, D.W. A catalytic antibody against cocaine prevents cocaine's reinforcing and toxic effects in rats. Proceedings of the National Academy of Sciences 95:10176-10181, 1998.

Sparenborg, S.; Vocci, F.; and Zukin, S. Peripheral cocaine-blocking agents: New medications for cocaine dependence. Drug and Alcohol Dependence 48:149-151, 1997.

Xie, W.; Altimirano, C.V.; Bartels, C.F.; Speirs, R.J.; Cashman, J.R.; and Lockridge, O. An improved cocaine hydrolase: The A328Y mutant of human butyrylcholinesterase is 4-fold more efficient. Molecular Pharmacology 55(1):83-91, 1999.


NIDA NOTES - Volume 14, Number 2

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