Scientists at The Scripps Research Institute have shown that an injectable solution can protect mice from an otherwise lethal overdose of cocaine. The findings could lead to human clinical trials of a treatment designed to reverse the effects of cocaine in case of emergency. Cocaine is involved in more than 400,000 emergency-room visits and about 5,000 overdose deaths each year in the United States.
The findings, reported recently in the journal Molecular Pharmaceutics, demonstrate the therapeutic potential of a human antibody against cocaine.
“This would be the first specific antidote for cocaine toxicity,” said Kim Janda, PhD, senior author of the report. A pioneer in the field of vaccines against drugs of abuse, Janda is the Ely R. Callaway, Jr. Chair in Chemistry, a professor in the Department of Immunology and Microbial Science, and director of The Worm Institute for Research and Medicine, all at Scripps Research. “It’s a human antibody so it should be relatively safe, it has a superior affinity for cocaine, and we examined it in a cocaine overdose model that mirrors a real-life scenario,” he said.
Janda and his laboratory colleagues have been developing candidate vaccines against cocaine, heroin, nicotine, and even Rohypnol, the “date-rape” drug. But most of these have been active vaccines - solutions of drug-mimicking molecules that provoke a long-term antibody response against a drug, greatly reducing its ability to reach the brain. These are potentially useful against addiction and relapse, but take weeks to stimulate an effective antibody response and thus are of limited value in drug overdose emergencies, which require a fast-acting antidote. Cocaine is a leading cause of illegal-drug overdoses in developed countries; it can cause hyperthermia, irregular heartbeats, seizures and death.
One possibility for an antidote is a “passive” cocaine vaccine, a ready-made solution of antibodies much like those used to treat snakebite. As Janda and his colleagues have shown in previous research, injected drug-specific antibodies can swiftly remove drug molecules from the bloodstream. This immediately reduces a drug’s direct effects on the heart and nearby organs, but it also pulls the drug from the organ where it does the most damage-the brain. If the drug molecules are small enough to cross the blood-brain barrier, the sudden lowering of their bloodstream concentration causes them to diffuse rapidly out of brain tissue.
Cocaine molecules are small enough to diffuse this way, and in 2005 Janda and his lab reported that injections of a mouse-derived anti-cocaine antibody, GNC92H2, could keep mice alive despite cocaine doses that killed unprotected mice. Mouse antibodies are not ideal for use in humans, though; they are “foreign” enough that human immune systems eventually develop a reaction against them.
This discovery holds promise for future human clinical trials to treat cocaine overdoses. According to the Scripps Institute, cocaine is responsible for more than 400,000 emergency department visits each year. The Centers for Disease Control and Prevention (CDC) cited and about 5,100 deaths from cocaine overdose in the United States in 2008. Cocaine overdose may present as acute psychosis or paranoia, anxiety, agitation, aggressive behavior, sleeplessness, seizures, delirium, rapid heart rate, tremors or hallucinations. It can also cause deadly heart attacks or arrhythmia.
Once it is developed for use in humans, this will be the first specific antidote to cocaine toxicity, according to lead author Kim Janada,Ph.D. director of The Worm Institute for Research and Medicine, at Scripps Research. According to study results, which were published in the March issue of the journal Molecular Pharmaceutics, this “passive vaccine” reversed the motor impairment, seizures and other dangerous symptoms of a cocaine overdose.
The study authors described this vaccine as a composition of pre-formed human antibodies against cocaine that are 10 times more potent in binding cocaine molecules than an active vaccine. This improved potency speeds up their ability to reverse cocaine toxicity, when time is of the essence.
In the new study, Janda and Jennifer B. Treweek, PhD, a research associate in Janda’s laboratory, used a genetically engineered mouse that can produce fully human antibodies against cocaine molecules. The best of these antibodies, GNCgzk, showed ten times the cocaine-binding affinity of GNC92H2, the molecule in the 2005 study.
In a preliminary test, the scientists showed an injection of GNCgzk antibodies 30 minutes before an injection of a lethal cocaine dose greatly reduced the signs of overdose-such as awkward movements and seizures-and kept all treated mice alive. By contrast, about half of untreated mice and 15 percent of GNC92H2-treated mice died.
Unlike other hard drugs, where users overdose for taking too much of the drug, most deaths due to cocaine are accidental. Use of cocaine causes tachyarrhythmias and a marked elevation of blood pressure, which can be life-threatening. This can lead to death from respiratory failure, stroke, cerebral hemorrhage, or heart-failure. Cocaine is also highly pyrogenic, because the stimulation and increased muscular activity cause greater heat production. Heat loss is inhibited by the intense vasoconstriction. Cocaine-induced hyperthermia may cause muscle cell destruction and myoglobinuria resulting in renal failure. Emergency treatment often consists of administering a benzodiazepine sedation agent, such as diazepam (Valium) to decrease the elevated heart rate and blood pressure. Physical cooling (ice, cold blankets, etc…) and paracetamol (acetaminophen) may be used to treat hyperthermia, while specific treatments are then developed for any further complications. There is no officially approved specific antidote for cocaine overdose, and although some drugs such as dexmedetomidine and rimcazole have been found to be useful for treating cocaine overdose in animal studies, no formal human trials have been carried out.
In addition, a history of high blood pressure or cardiac problems puts the patient at high risk of cardiac arrest or stroke, and requires immediate medical treatment. The Center for Disease control states that in 2005, 33,000 people died from cocaine overdose, which is a 60% increase since the year 1990. It’s estimated that 70-80% of these were accidental deaths due to heart failure.
In a test that better simulated a real-life emergency situation, mice were first given a cocaine overdose, and three minutes later were infused with GNCgzk. About half of untreated mice were killed by such a dose. While GNC92H2 reduced that rate to about 28 percent, the new GNCgzk antibodies reduced the mortality rate further, to 20 percent.
More strikingly, a stripped-down version of GNCgzk-F(ab’)2-gzk, which contains only the antibody’s cocaine-binding segments-reduced the mortality to zero, as well as significantly reducing overdose signs such as seizures. It also did so at a much smaller, clinically feasible dose than GNC92H2’s. “There was a reversal of the signs of cocaine toxicity within seconds of the injection,” said Treweek.
Janda and Treweek are now trying to find ways to produce their F(ab’)2-gzk antidote economically and in large quantities. “If we can do that, then there would be no reason not to push it into clinical trials,” Janda said.