A monoclonal antibody being developed by NIDA-supported scientists may treat PCP (phencyclidine) overdose and abuse and also may block or reduce the fetal brain damage that can result from prenatal exposure to PCP (see "Ketamine, PCP, and Alcohol Trigger Widespread Cell Death in the Brains of Developing Rats,"). The antibody, which like other monoclonal antibodies is derived from a single cell and then produced in large quantities, reduces PCP's psychoactive and toxic effects by attaching itself to PCP in the bloodstream and blocking or reversing its chemical actions in the brain.
Researchers led by Dr. Michael Owens, who directs the Center for Alcohol and Drug Abuse Studies at the University of Arkansas Medical Center in Little Rock, have been testing the PCP antibody in an extensive series of studies aimed at increasing understanding of how such antibodies work in the body to counter the harmful effects of abused drugs. These studies have shown that a fragment of the PCP antibody, called "Fab," can rapidly remove PCP from the brains of rats. The full antibody, immunoglobulin G (IgG), can provide significant long-term reductions in PCP brain concentrations and reduce PCP's behavioral effects in rats given repeated doses of the drug.
Treating PCP Overdose
Every year, many PCP abusers are treated in hospital emergency rooms for psychotic symptoms, such as delusions and paranoia, or for overdose of the drug. PCP alone or in combination with other drugs prompted 2,287 visits to hospital emergency departments across the United States in the first 6 months of 1997, according to Drug Abuse Warning Network data compiled by the Substance Abuse and Mental Health Services Administration. People under the influence of PCP often become violent or suicidal. Thus, a treatment that could quickly detoxify PCP abusers with a single injection would be valuable in reducing the harm that PCP abusers can cause to themselves or others. It could also shorten hospital stays and reduce the long-term costs associated with their recovery.
Measurements of rats' movement showed that administering the PCP antibody, "Fab," dramatically reduced the distance PCP-treated rats traveled during the experiment. The antibody reduced PCP's behavioral effects almost immediately to levels of rats that were not given PCP.
In their studies, the researchers showed that a single large dose of "Fab" completely removed PCP within 15 minutes from the brains of living rats whose bodies had been saturated with PCP. The body processes "Fab" more quickly than it does the whole antibody and can eliminate it rapidly through the kidneys along with the PCP that is bound to it, Dr. Owens explains. "Fab's fast-in/fast-out action makes it perfect for treating the acute toxic effects of drug overdose in hospital emergency rooms," he says.
With NIDA's support, Dr. Owens plans to complete the necessary preclinical research and apply for approval from the Federal Food and Drug Administration (FDA) to begin clinical trials of "Fab" in humans.
Long-Term Treatment for PCP Abuse
The researchers found that, in contrast to the short-term effects of "Fab," a single, large dose of IgG, given 24 hours after they started infusing rats with PCP, significantly reduced PCP brain concentrations during 27 days of continuous high-dose PCP infusion. In other studies, a single injection of IgG greatly reduced such PCP-induced effects as hyperactivity and distance traveled by rats given escalating doses of PCP every 90 minutes, on every third day, over 2 weeks. Measurements of these behavioral effects during the experiment showed that IgG-treated rats had significant decreases in PCP-induced responses for the entire 2-week period compared to rats that had been treated with an inactive saline solution.
Although many details must be worked out before IgG and similar antibodies can be used in long-term treatment of drug abuse, the results from these animal studies are encouraging, Dr. Owens says. If, as these studies suggest, a single injection of IgG can significantly reduce PCP brain concentrations and behavioral effects in rats for extended periods, antibody-based medications might be able to block or significantly blunt the rewarding effects of the drug for a month or more in humans, he says. Thus, if someone in treatment relapsed to drug use, the PCP antibody would diminish the drug's pleasurable effects and reduce the incentive to use it again. "Therefore, this might make a good medication to combine with behavioral approaches in a comprehensive treatment plan to give people a better chance of recovery," Dr. Owens says.
Prenatal Protection From PCP Exposure
Because the PCP antibody would remove the drug from the bloodstream of a pregnant woman, theoretically it would be possible to use it to block the fetal brain damage that prenatal PCP exposure has been shown to cause in rats, Dr. Owens says. "We have no reason to believe that if the antibody were used properly it wouldn't work to pull PCP out of the placenta in the same way it pulls it out of other organs that we have tested, such as the brain and testes," he says.
Pregnant women with deficient immune responses have been given massive doses of antibodies to supplement their immune systems with no ill effects, Dr. Owens points out. "Therefore, it may be possible to give pregnant women the large doses we use in our animal studies," he says. Furthermore, "if the antibody does not harm the mother, it is unlikely that it will harm the fetus." The key is to use forms of the antibody that do not trigger an allergic reaction in the mother or fetus, he says.
"The potential for the PCP antibody to block harmful prenatal effects certainly would be worth examining," says Dr. Jamie Biswas of NIDA's Division of Treatment Research and Development. However, considerable research would be needed to establish the risks to both the mother and fetus of using the antibody versus the potential benefits of blocking PCP's possible fetal brain damage, she says.
Hardin, J.S.; Proksch, J.W.; Wessinger, W.D.; and Owens, S.M. Pharmacodynamics of a monoclonal anti-phencyclidine Fab with broad specificity for phencyclidine-like drugs. Journal of Pharmacology and Experimental Therapeutics 285(3):1113-1122, 1998. [Abstract]
Hardin, J.S.; Wenger, G.R.; Wessinger, W.D.; and Owens, S.M. Monoclonal antibodies as long-term antagonist of phencyclidine (PCP). Clinical Pharmacology and Therapeutics 65(2):153, 1999.
Proksch, J.W.; Gentry, W.B.; and Owens, S.M. Anti-phencyclidine monoclonal antibodies provide long-term reductions in brain phencyclidine concentrations during chronic phencyclidine administration in rats. Journal of Pharmacology and Experimental Therapeutics, 292(3):831-837, 2000. [Abstract]