Download Vaccine pharmacotherapy for the treatment of

BEHAVIOR CONTROL PSYCHOIMMUNOLOGIC VACCINATIONS
TO ELIMINATE ADDICTIVE AND UNACCEPTABLE BEHAVIORS:
COMPILED BY DR BILL DEAGLE MD SEPT 13TH 2007:
TOXIN CONJUGATED VACCINES:
Celtic Pharmaceutical Holdings, an investment firm that acquired
Xenova in September 2005, launched a Phase II placebo-controlled,
multicenter trial of Xenova's nicotine vaccine, TA-Nic, in the U.K. in May
and will begin a Phase IIa/IIb study in the U.S. this fall, says Patrick C.
O'Connor, Celtic's managing director of clinical development. TA-Nic
uses a nicotine derivative coupled to a recombinant nontoxic B subunit
of cholera toxin. It has been shown to be immunogenic and safe in
Phase I trials and gave indications of increased quit rates.
Nabi Biopharmaceuticals has been working with NIDA to develop and
test NicVax, which consists of a nicotine-like molecule conjugated to
recombinant exotoxin protein A from Pseudomonas aeruginosa.
Vaccines Against Drugs of Abuse: A Viable Treatment Option?
Author: Kantak K.M.1
Source: Drugs, Volume 63, Number 4, 2003 , pp. 341-352(12)
Publisher: Adis International
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Abstract:
Drug addiction is a chronically relapsing brain disorder. There is an urgent
need for new treatment options for this disease because the relapse rate
among drug abusers seeking treatment is quite high. During the past
decade, many groups have explored the feasibility of using vaccines directed
against drugs of abuse as a means of eliminating illicit drug use as well as
drug overdose and neurotoxicity.
Vaccines work by inducing drug-specific antibodies in the bloodstream that
bind to the drug of abuse and prevent its entry into the brain. The majority
of work in this area has been conducted with vaccines and antibodies
directed against cocaine and nicotine. On the basis of preclinical work,
vaccines for cocaine and nicotine are now in clinical trials because they can
offer long-term protection with minimal treatment compliance. In addition,
vaccines and antibodies for phencyclidine, methamphetamine and heroin
abuse are currently under development. An underlying theme in this
research is the need for high concentrations of circulating drug-specific
antibodies to reduce drug-seeking and drug-taking behaviour when the drug
is repeatedly available, especially in high doses.
Although vaccines against drugs of abuse may become a viable treatment
option, there are several drawbacks that need to be considered. These
include:
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a lack of protection against a structurally dissimilar drug that produces
the same effects as the drug of choice;
a lack of an effect on drug craving that predisposes an addict to
relapse; and
tremendous individual variability in antibody formation.
Forced or coerced vaccination is not likely to work from a scientific
perspective, and also carries serious legal and ethical concerns.
All things considered, vaccination against a drug of abuse is likely to work
best with individuals who are highly motivated to quit using drugs altogether
and as part of a comprehensive treatment programme. As such, the medical
treatment of drug abuse will not be radically different from treatment of
other chronic diseases.
Keywords: Drug abuse, treatment; Vaccines, therapeutic use
Language: English
Document Type: Leading article
Affiliations: 1: Laboratory of Behavioral Neuroscience, Department of Psychology, Boston University, Boston, Massachusetts, USA *
Drugs To Fight Addictions
A better understanding of the mechanisms of drug and alcohol
dependence is helping to further development and use of
pharmacotherapies against addictions
Ann Thayer
Addictions, especially alcohol dependence, have been treated largely as behavioral disorders.
Weaknesses in will, character, or faith were among the factors believed to contribute to an addicted
person's dependence. Consequently, for decades, treatment has centered on psychological or behavioral
therapy. Only recently, thanks to improved understanding of the neurologic and physiologic aspects of
addiction, more medication-based treatments have emerged, along with a gradually expanding
willingness to use them.
Pharmacotherapies for treating addictions have actually been around for decades, but only a few
medications have been approved specifically for that purpose, and these have found limited use. Within
the past few years, the number has nearly doubled as one or two new products each for smoking
cessation, opioid abuse, and alcohol dependence have become available. Many researchers working in
the field, as well as pharmaceutical companies developing and marketing the medications, believe this
growth may herald a new phase in addiction pharmacotherapy.
"I believe we are in the midst of a paradigm shift in how alcohol dependence is perceived and then
ultimately how it's treated," says Mark Willenbring, director of the Division of Treatment & Recovery
Research at the National Institute on Alcohol Abuse & Alcoholism (NIAAA). "There is a much more
medical approach emerging; treatment for alcohol dependence at this point is similar in some ways to
where treatment for depression was about 30 years ago."
Behavioral therapies can be effective, he adds. "Most people don't get treatment, and the treatments we
have are not as effective as they need to be," he says. "There are dual problems of expanding access
and improving efficacy, and medications are really going to be a key component." The treatment
community is grappling with the relatively recent recognition that addiction disorders are chronic,
relapsing diseases stemming from genetics and environmental influences and that pharmacotherapies
not only are available but can be effective.
NIAAA and the National Institute on Drug Abuse (NIDA) have been playing critical roles in increasing the
neurobiological and neurochemical understanding of addiction disorders, as well as in running clinical
studies to show where existing and new therapies offer promise. A resulting change, says Francis (Frank)
Vocci, director of NIDA's Division of Pharmacotherapies & Medical Consequences of Drug Abuse, is that
"pharmaceutical companies are starting to look at addiction as a viable indication, something worthy of
evaluating in terms of developing medications."
Industry's involvement has been limited in the past by several factors, according to many people working
in the field. These factors have included deficiencies in the ability to discover and effectively test new
antiaddiction drugs, a scarcity of data-driven proof that drug therapies work, a small market size coupled
with difficulties in reaching doctors and patients, and even cultural resistance, stigma, and other concerns
around such products. The addiction pharmacotherapy market is currently worth only about $2 billion,
reports the research firm Spectra Intelligence. The market is expected to grow to $2.9 billion by 2012,
fueled by increased need, mounting health care and socioeconomic burdens in the hundreds of millions
of dollars, and new products that will add sales and offer proof-of-principle.
About 9% of the U.S. population, or 22.3 million people aged 12 or older, were classified as having a
substance dependence or abuse problem in 2005, according to the Substance Abuse & Mental Health
Services Administration (SAMHSA), part of the U.S. Department of Health & Human Services. In its justreleased survey—September is National Alcohol & Drug Addiction Recovery month—SAMHSA reports
that in this group, 3.3 million used both alcohol and illicit drugs, 3.6 million used just drugs, and 15.4
million used just alcohol. But only 3.9 million people received any kind of treatment, most through selfhelp groups. Another 71.5 million people used tobacco products.
According to Spectra Intelligence's recent analysis, nearly 35 drug candidates are in the pipeline to treat
alcohol, narcotic, and nicotine dependencies. The growing understanding of how addiction plays out is
helping improve the design and testing of new and more efficacious medications. Not only are products
that are more effective expected to emerge, but also, in a similar manner to how doctors treat other
central nervous system (CNS) conditions, these products will provide more options for addressing
complex addictive diseases in different patients.
Drugs of abuse are chemically diverse and thus have very different targets, mechanisms of action, and
manifestations in the body. But addiction's common underpinning lies in how these molecules ultimately
affect the brain's reward pathway, explains Eric J. Nestler in a review article (Nat. Neurosci. 2005, 8,
1445), prepared with support from NIDA. Nestler is chairman of the department of psychiatry and a
member of the Center for Basic Neuroscience at the University of Texas Southwestern Medical Center in
Dallas.
Addictive drugs reward their users, an outcome that encourages repeated use, and they produce
unpleasant symptoms on withdrawal, Nestler says. Addiction also involves associating drug use with
environmental cues and adaptive changes in the brain, believed to contribute to craving and relapse.
Evidence suggests the common circuitry is in the brain's limbic system and, in very simple terms,
ultimately involves either direct or indirect activation of dopaminergic pathways to increase dopamine
levels.
"Because common mechanisms seem to contribute to at least some aspects of all drug addictions,"
Nestler writes, "it might be possible to develop treatments that would be effective for a wide range of
addictive disorders." Drugs targeting the brain's dopamine, glutamate, corticotropin releasing factor
(CRF), opioid, or cannabinoid systems might exert the desired effects. At the same time, he cautions that
drugs should safely and effectively dampen common mechanisms of reward while not adversely affecting
normal function.
Existing pharmacotherapies, he also points out, are specific for the target or receptor of the drug of
abuse, and no treatment aimed at a common mechanism has yet been fully validated across a range of
addictions. Meanwhile, along with identifying various molecular and cellular pathways, receptors, and
neurotransmitters, scientists have found links between genes and the risk of dependence and other
factors involved in addiction. Now they are trying to relate these genetic variations to behavioral
phenotypes of addiction.
In turn, they are creating more predictive and robust animal models. And they are exploring targets and
pharmacotherapeutic agents that run the gamut from agonists, partial agonists, antagonists, and
modulators of appetitive systems in the brain to monoclonal antibodies and even vaccines (Eur. J.
Pharmacol. 2005, 526, 101). The goal is to find pharmacotherapies that not only halt a drug's acute effect
and prevent withdrawal but also block craving and other factors that cause relapse.
ISTOCK PHOTO
SMOKING CESSATION. Nicotine replacement therapies (NRTs) have dominated pharmacological
treatment for smoking. These are patches, gums, lozenges, nasal sprays, and inhalers for delivering
controlled doses of the addictive drug itself. The Food & Drug Administration approved the first NRT gum
for prescription use in 1984, followed by the first patch in 1991. In 1996, both the gum and patches
became over-the-counter (OTC) products. According to NIDA, all NRT products are equally effective,
working about 20% of the time.
Although NRTs ease withdrawal symptoms, they don't control neurotransmitter release or blunt the
addictive effects of nicotine. An option is bupropion, a norepinephrine- and dopamine-reuptake inhibitor.
GlaxoSmithKline (GSK) sells the off-patent drug as Wellbutrin for depression and, since 1997, as Zyban
for smoking cessation. Nortriptyline, a tricyclic antidepressant and norepinephrine reuptake inhibitor, has
been studied and is sometimes used for smoking cessation but isn't approved for this use.
In 2005, GSK had $611 million in sales of OTC smoking cessation products, primarily NRTs. Pfizer has
been the other leading producer of NRTs, but these products are part of the consumer health business
the company is selling to Johnson & Johnson. The total market for nicotine addiction therapies was about
$1.5 billion in 2005, according to Spectra Intelligence, with sales of existing therapies expected to grow
modestly.
The need for new therapies is tremendous, and the market potential is enormous. According to the World
Health Organization, there are 1.3 billion smokers worldwide. Tobacco-related illnesses are the second
leading cause of death among all people, accounting for about 5 million deaths per year. In the U.S.
alone, about 60 million people smoke cigarettes. An estimated 70% say they want to quit, and 40% try
each year. The Centers for Disease Control & Prevention lists smoking as the leading preventable cause
of death.
The first new nonnicotine treatment to come along in a decade is varenicline, launched in August by
Pfizer as the prescription drug Chantix. Its discovery and development took roughly one decade, says
Martin R. Jefson, Pfizer's vice president for CNS discovery. The drug is a pharmacologically unique
chemical entity that works through the same nicotinic receptor population used by the substance of
abuse, he explains. But whereas nicotine is a full agonist, or activator, of the receptor, varenicline is only
a partial agonist, which may be key to its ability to help patients quit and avoid relapse.
"There is good scientific evidence that nicotine targets nicotinic acetylcholine receptors located in a region
of the brain thought to be very central to the process of reward and habituation," Jefson says. A specific
abundant subtype called 4 2 is believed to mediate the reinforcing properties of nicotine. It does so by
binding nicotine and then releasing dopamine; the pleasurable outcome of this event leaves a smoker
wanting to do it again.
"We were looking for something that might offer the benefits of an antagonist, which would block the
rewarding effects of nicotine taken in by relapse smoking, but also something that served as an activator
or agonist of the receptor and provide some relief from the craving and withdrawal that comes with abrupt
cessation," Jefson explains. A partial agonist does this by competing with nicotine itself for the receptor
with comparable or even superior affinity and activating the receptor some but not nearly as much as the
full agonist.
The discovery of varenicline involved screening, optimizing, and testing compounds inspired by the plant
alkaloid (-)-cytisine (C&EN, June 6, 2005, page 36). Cytisine has been used to treat nicotine dependence
in Eastern Europe for more than 40 years (Arch. Inter. Med. 2006, 166, 1553). "We were very gratified to
see that varenicline worked in the clinical setting as we hoped it would based on the preclinical work,"
Jefson adds. It turns out, he explains, that varenicline is a very high-affinity, high-selectivity nicotinic
receptor partial agonist specific for the 4 2 subtype.
Chantix was tested on a few thousand patients in a series of clinical trials. Results of several of these
were published in the Journal of the American Medical Association (JAMA) in early July and in the
Archives of Internal Medicine in August. In general, Chantix showed both short- and long-term
effectiveness, being as much as four times as effective as placebo and twice as effective as Zyban. After
one year without further treatment, about one in five patients who had received Chantix were not
smoking.
Most smokers, even those using a therapy, don't manage to quit, and for those who do, the relapse rate is
extremely high: Less than 10% stay abstinent for more than one year. Pfizer has developed a behavioral
support plan, called GETQUIT, that it is offering at no charge with Chantix to increase the odds. The
company anticipates initially offering the new drug through respiratory care specialists. A patient takes 1
mg twice daily for an initial period of 12 weeks and, if they succeed in quitting, for another 12 weeks to
increase the likelihood of long-term abstinence.
Pharmaceutical industry analysts estimate that Chantix could boost the market for nicotine addiction
therapies by $400 million to $500 million per year. "We saw an opportunity that was interesting
scientifically and medically and where there was commercial opportunity for the right product," Jefson
remarks. "Smoking's impact internationally on health is very dramatic, the prevalence is very high, and it's
a very motivated patient population, which isn't the same across all substance abuse situations."
Response to the studies and to the drug's approval generally has been positive, with the events being
called a step forward for smoking cessation therapy. Issues raised, nonetheless, were the side effects,
generally nausea in as many as 30% of people; nontrivial dropout rates, which are reportedly typical in
smoking cessation trials; and the generalizability to real-world patient situations, as is true of many clinical
studies. In an accompanying JAMA editorial, University of Tennessee health scientists call varenicline a
"definite promise, but no panacea" (J. Am. Med. Assoc. 2006, 296, 94).
They acknowledge that varenicline is associated with higher smoking cessation rates and represents a
new class of drug that offers clinicians a pharmacological alternative with a mode of action different from
that of NRTs or bupropion. But they also note that "clearly, quitting smoking, even with pharmacological
and behavioral assistance, is extremely difficult. Patients currently cannot and probably never will simply
be able to 'take a pill' that will make them stop smoking."
This isn't stopping other drug developers from trying. Sanofi-Aventis' rimonabant, which blocks the
cannabinoid CB1 receptor, is considered a promising candidate. Although the company recently received
positive responses from regulators for the drug, trade-named Acomplia, as a weight management
treatment, neither U.S. nor European regulators have given it the go-ahead for smoking cessation. It is
also being investigated as a treatment for alcohol dependence.
In addition to other cannabinoid CB1 receptor antagonists, compounds under study include the
anticonvulsant topiramate, opioid antagonist naltrexone, and antidepressant fluoxetine, as well as a
nicotinic partial agonist, dianicline, by Sanofi-Aventis and a glycine antagonist for preventing relapse by
GSK. Addex Pharmaceuticals has been testing a dopamine D1 receptor antagonist, but its current clinical
status is unclear.
San Diego-based Somaxon Pharmaceuticals has completed a Phase II clinical study of oral nalmefene,
an opioid receptor antagonist already used intravenously for reversing the effects of opioids after
anesthesia or overdose. It has licensed the compound from Biotie Therapies in Finland for smoking
cessation and impulse control disorders, such as pathological gambling.
Yaupon Therapeutics, created in 2002 by two University of Kentucky professors and pharmaceutical
industry executive Robert Alonso, is studying nornicotine, a tobacco alkaloid structurally similar to nicotine
except it lacks one methyl group. "Nornicotine is very different from nicotine in terms of its pharmacology
and pharmacokinetics," says Peter Crooks, Yaupon's chief scientific officer and pharmaceutical sciences
professor at the University of Kentucky. Although it would work like an NRT, the drug acts on receptor
subtypes different from those that respond to nicotine to partially stimulate dopamine release and has a
longer half-life and better side-effect profile.
"We've determined that one particular optical isomer of nornicotine appears to be most effective as a
potential smoking cessation agent," Crooks adds. "And we've managed over the past year to come up
with a very nice chemical method to inexpensively produce the desired pure enantiomer." The company is
conducting toxicity tests and has received a National Institutes of Health grant that should allow it to begin
Phase I clinical testing early next year.
Tackling the problem differently are a few companies developing nicotine vaccines. Nicotine is a small
molecule that easily passes to the brain undetected by the immune system. The vaccines typically
combine a nicotine derivative and protein carrier to stimulate the immune system to produce nicotine
antibodies. The antibodies soak up nicotine in the bloodstream, prevent it from reaching receptors in the
brain, and thereby block its effect. While this eliminates the pleasurable reward, as well as nicotine's
addictive reinforcing effects, a vaccine isn't expected to ease withdrawal.
Nabi Biopharmaceuticals has been working with NIDA to develop and test NicVax, which consists of a
nicotine-like molecule conjugated to recombinant exotoxin protein A from Pseudomonas aeruginosa.
Preclinical studies have shown that the blocking effect works, while Phase I studies found the vaccine to
be highly immunogenic and safe. The company has completed two Phase II trials on different
formulations and began a Phase IIb, placebo-controlled study at nine sites in May. The study includes
behavioral support and is designed to demonstrate proof-of-concept and determine optimal doses.
Even in Phase II trials not designed to show efficacy, smokers taking the highest dose of NicVax
achieved a 33-40% quit rate versus 9% for placebo with mild to moderate side effects and none of the
typical withdrawal symptoms, explains Thomas E. Rathjen, Nabi's vice president for investor relations.
Nabi attributes the latter effect to a very small amount of nicotine still getting to the brain and moderating
withdrawal while not eliciting a pleasurable response.
Unlike medications that a patient can stop taking, a vaccine "takes the control of the therapy away from
the patient," Rathjen points out. After four or five shots over about three months, sufficient antibody levels
develop and persist for 12 or more months. The 12-month mark seems to be critical, he adds, because if
smokers get that far smoke-free, they have a 70-75% chance of remaining so. And although patients may
smoke, the antibodies can't be overcome with any reasonable amount of relapse smoking. Boosters are
also a possibility for continued treatment.
If all goes well, Nabi anticipates it could start Phase III studies in the second half of 2007. The company
has been discussing appropriate end points for late-stage trials with regulators, Rathjen says, and already
manufactures the vaccine at commercial scale in its Boca Raton, Fla., facility. Plans are to look for a
pharmaceutical partner to market the vaccine through primary care physicians. In March, FDA granted
NicVax fast-track approval status, designed to facilitate the development and expedite review of products
for unmet medical needs.
Similarly, Switzerland-based Cytos Biotechnology is developing Cyt002-NicQb, consisting of nicotine
attached to a viruslike particle called Qb. The company says its vaccine is safe, well-tolerated, and highly
immunogenic. In a Phase II dose-ranging study, the company saw a 42% long-term abstinence rate
among a subgroup of patients with high antibody levels compared with 21% for the placebo group. Since
lower antibody levels weren't effective, Cytos has been optimizing the formulation and dosage to achieve
high levels in as many patients as possible in future studies.
Meanwhile, Celtic Pharmaceutical Holdings, an investment firm that acquired Xenova in September 2005,
launched a Phase II placebo-controlled, multicenter trial of Xenova's nicotine vaccine, TA-Nic, in the U.K.
in May and will begin a Phase IIa/IIb study in the U.S. this fall, says Patrick C. O'Connor, Celtic's
managing director of clinical development. TA-Nic uses a nicotine derivative coupled to a recombinant
nontoxic B subunit of cholera toxin. It has been shown to be immunogenic and safe in Phase I trials and
gave indications of increased quit rates.
"The real downfall for a lot of people is not actually stopping, even though they go through an acute
withdrawal phase; it's when they subsequently take the first cigarette and it feels so good," O'Connor
says. The idea is that by raising antibody levels slowly, people will get less pleasure out of smoking and
be able to quit. "But then, if they do relapse, they won't get that huge reinforcement from the first
cigarette, because the antibodies would mop up the nicotine and not allow it to get into the brain," he
says.
"There is a major gap in the market for something more effective, and the scale of the problems related to
smoking is so huge that anything remotely useful in helping people to quit and stay quit is clearly going to
find a place," says Michael Earl, Celtic's managing director for commercialization. "But I don't think there
will be a magic bullet that solves everybody's problems." He anticipates further development will explore
how vaccines, counseling, and other pharmacotherapies work alone or together for patient management.
GETTY IMAGES
DRUG ADDICTION. New doors may be opening as well for pharmacotherapies to treat addictions to
other drugs, such as heroin, cocaine, and methamphetamine. For more than 30 years, methadone
maintenance therapy has been the leading treatment method. Methadone is a long-acting, synthetic
opiate administered orally to prevent withdrawal, block the effects of illicit opioid use, and diminish
craving. Patients stabilized on this sustained-agonist therapy can function normally. Mallinckrodt
Pharmaceutical is the leading bulk producer of the generic drug.
"There are probably about 250,000 people on methadone," NIDA's Vocci says. "But there's an estimated
1 million heroin addicts in the U.S. and anywhere between 1.5 million and 4 million people who have a
problem with prescription opiates." The system, he believes, is constrained by limited public funding and
access to treatment clinics. Europe, meanwhile, has an estimated 1.1 million intravenous drug users,
70% of whom are said to be untreated.
For about 10 years starting in 1993, methadone wasn't alone; levo-alpha-acetylmethadol was available,
but then Roxane Laboratories ceased making it following reports of severe adverse events. Naltrexone, a
synthetic opiate antagonist originally marketed by DuPont as Trexan in 1984 but is now off-patent, can be
used after a patient undergoes opiate detoxification. It blocks the effects of self-administered opiates, so it
can prevent relapse. It also is used to reverse acute opiate overdose. Other drugs used for detoxification
and withdrawal are clonidine and lofexidine.
Without effective counseling or monitoring, patient compliance with addiction therapies can be a problem.
To improve compliance, several companies are creating new formulations. DrugAbuse Sciences (DAS),
based in Paris, has a sustained-release form of naltrexone for once-monthly injection. The company has
it in Phase II clinical trials for opioid dependence and in Phase III for alcohol dependence. DAS and Titan
Pharmaceuticals both are developing sustained-release buprenorphine. Titan expects to begin a Phase II
clinical trial of its six-month version soon, while DAS anticipates starting a Phase I trial by 2007 for its
once-per-month form.
Approved in the U.S. in 2002, buprenorphine was the first new treatment to arrive in more than a decade.
Like methadone, it is a substitution therapy with the potential for abuse, although it has weaker opiate
effects. It blocks cravings and can prevent withdrawal. In different regional markets, Schering-Plough and
Reckitt Benckiser sell an oral form as Subutex and an oral combination of buprenorphine and naloxone
as Suboxone.
Opioids attach to opioid receptors in the brain, spinal cord, and gastrointestinal tract and block the
transmission of pain and cause neurotransmitter release in the brain's reward center. Buprenorphine acts
as a partial agonist at the µ-opioid receptor and an antagonist at the -opioid receptor subtypes. The
structufrally similar compounds naloxone, nalmefene, and naltrexone have antagonistic effects at various
µ-, -, and -opioid receptors (Chemistry Today 2006, 24, 54) and thereby block the neurochemical
reward and reinforcement system.
The combination of drugs in Suboxone is designed to minimize misuse. Naloxone is ineffective when
taken orally, but it attenuates buprenorphine's agonist effect when Suboxone is abused by injection.
According to an article in the July 22 issue of the Lancet, Subutex smuggled in from Europe—it was first
approved in France in 1996—has become a major drug of abuse in Russia. In late July, European
regulators recommended marketing approval for Suboxone.
In Europe, the prescription of opioids by doctors for treating addictions is less restricted than it is in the
U.S. When the U.S. Congress passed the Drug Addiction Treatment Act (DATA) in 2000, it brought about
a major change for patients in that treatment could take place in the privacy of a doctor's office rather than
a rehabilitation clinic. The act allows certified physicians to prescribe certain controlled substances
approved by FDA for the treatment of addictions.
Subutex and Suboxone are currently the only drugs qualified under DATA. A recent study reported in the
New England Journal of Medicine (2006, 355, 365) found that office-based treatment combining
Suboxone and brief counseling was effective in substantially reducing drug use in about 40-50% of
patients.
No drugs have been approved for cocaine addiction, despite it being a large problem, although a
significant number of candidates have been and continue to be tested (Eur. J. Pharmacol. 2005, 526,
101). For several years, NIDA has aggressively pursued this area and, more recently, methamphetamine
abuse, Vocci says.
In 1990, NIDA set up its Medications Development Division to address the need for such
pharmacotherapies. Its approach has been to support and coordinate the testing of marketed
medications, whose properties suggest they might be effective, as a rapid and less expensive route to
new treatments, as well as the discovery and investigation of new compounds. About 65 existing
medications have been tested and more than 3,000 compounds identified and evaluated.
Disulfiram, one of the few existing pharmacotherapies for alcohol dependence, has given the most
consistent and reproducible results in cocaine studies, Vocci says. It works as an aversion therapy,
because its interaction with alcohol produces undesirable physical effects. In cocaine users, disulfiram
produces an unpleasant sense of hyperstimulation, likely attributable to enhanced dopamine activity.
Cocaine is believed to act as a dopamine-reuptake inhibitor, and disulfiram inhibits dopamine hydroxylase, which metabolizes dopamine.
"There are about half a dozen other drugs that have given us positive signals in reducing cocaine use in
double-blind, placebo-controlled trials," Vocci says. "We are in the process of doing confirmatory
evaluations." The drugs include topiramate, modafinil, tiagabine, propranolol, ondansetron, naltrexone,
and a combination of disulfiram and naltrexone. Many are existing CNS drugs that act on similar targets
affected by drugs of abuse, or are useful in clinical populations where other conditions, such as
depression, occur along with drug abuse.
For example, some antiepileptic drugs have multiple mechanisms of action and, in addition to controlling
seizures, can reduce obsessive or compulsive thoughts that may be connected to treating drug craving,
Vocci explains. Similarly, the anticonvulsant topiramate, sold by Johnson & Johnson as Topamax, causes
weight loss and may affect other appetitive mechanisms.
Topiramate indirectly influences dopamine levels by activating -aminobutyric acid (GABA), an inhibitory
neurotransmitter, and blocking glutamate, an excitatory neurotransmitter. According to NIDA, small-scale
clinical studies have shown it helps cocaine-addicted individuals remain drug-free for three or more
weeks—possibly enough time, when combined with behavior therapy, to offer a good chance for longterm cessation.
Modafinil, a drug that promotes wakefulness and is sold by Cephalon as Provigil, enhances glutamate
levels. Animal studies have shown that repeated exposure to cocaine depletes glutamate in areas of the
brain related to the development of addiction. And an increase in glutamate levels blocks cocaine self-
administration in rats. University of Pennsylvania researchers have already reported positive clinical trial
results, and results from a major trial are expected later this year, Vocci says.
Tiagabine, an anticonvulsant sold by Cephalon as Gabitril, is also being tested. The drug is a selective
GABA reuptake inhibitor that increases GABA levels by selectively binding to GAT-1, the predominant
GABA uptake transporter. If the company's products are found to work, Cephalon CEO Frank Baldino Jr.
says it would be a "big step forward for drug abuse therapy" and one the company would support if it sees
decent market opportunities.
Catalyst Pharmaceutical Partners (CPP) of Coral Gables, Fla., is developing vigabatrin for cocaine and
other drug addictions. Vigabatrin, a -vinyl derivative of GABA, works by inhibiting the enzyme that
breaks down GABA. The company licensed the compound from Brookhaven National Laboratory, which
had conducted about a decade of addiction-related research. Sanofi-Aventis markets the drug as Sabril
for epilepsy outside the U.S. CPP has completed two clinical trials in Mexico and has the go-ahead from
FDA to begin a Phase I trial in the U.S.
There's clearly much more to treating addiction than simply blocking reward systems. Areas for discovery
include finding existing or new compounds that modulate appetitive systems in the brain, Vocci says.
Such systems, and the dopamine system is one of these, alert human beings to internal and external
stimuli and shape behavior over time. "The stimuli of greatest importance are probably conditioned cues,
mood and affect changes, drug priming, and stress," he explains. "So we are looking at medications that
can block these processes."
A formerly dependent individual responds more strongly to an initial intake of a drug or alcohol than does
a nondependent individual and thus is primed for further consumption. Animal and clinical studies have
shown that dependent individuals also interpret stress almost as if it were a low drug dose that activates
their dopamine systems. And stress, combined with a conditioned cue or trigger, can lead to relapse.
Drugs that might block priming include dopamine D3 receptor antagonists, D3 receptor partial agonists,
cannabinoid antagonists, and narcotic antagonists, Vocci says, whereas antistress compounds include
CRF antagonists, vasopressin 1B antagonists, orexin antagonists, and certain glutamate antagonists.
"There are a host of approaches, and some companies are working with us right now at the preclinical
and clinical pharmacology levels, and we're looking at moving into clinical studies."
Another approach is aimed at drugs that affect cognition. "Five or 10 years ago, I would have said these
are a great idea, but we don't know much about drugs that would affect cognition in a way we want,"
Vocci comments. Now, drugs are emerging that can enhance cognition, increase attention, stop
persistently recurring thoughts, increase inhibitory responses to stimuli, or decrease impulsiveness and
risk-taking behaviors. Addressing these traits, which may be genetic or acquired through repeated drug
abuse, is believed to be relevant to mitigating addictive behaviors, he says.
"When someone decides drug use is going to be an organizing principle of their life, they are addicted,
and what you need to do is to alter their cognition in order to alter their behavior," Vocci explains. "There
are cognitive behavioral therapies, and they may work in some of the population. But it's the others for
whom we're looking for medications, because they are the ones that relapse and continue to use drugs."
As in nicotine addiction, vaccines are also in development. Celtic has in development a cocaine vaccine
called TA-CD that consists of a cocaine derivative conjugated to a cholera-toxin protein. The company
reported preliminary results this summer from two Phase II studies supported in part by NIDA. After the
body develops antibodies, the rate at which cocaine can pass into the brain is blunted as long as the
antibodies are present.
Studies performed at Columbia University nicely showed a reduction in cocaine's binding to dopamine
transponders, O'Connor says. "If you get a reduction greater than about 45%, you actually blunt the
euphoric effect." In clinical trials, patients with high antibody levels and reports of strongly diminished
pleasure actually reduced their cocaine use, rather than trying to increase it to overcome the vaccine.
Whereas people addicted to nicotine may be able to remain abstinent after 12 weeks of treatment, the
therapeutic window may be two to three years or longer for cocaine.
"We are discussing with NIDA—and planning to with FDA—the whole issue of what is a successful
treatment for a patient addicted to cocaine," O'Connor says. "Obviously, the optimum goal would be that
everyone would quit, but that may not be attainable, and what may be of real interest is that patients
reduce their use of cocaine and become more productive members of society." Celtic anticipates having
TA-CD in Phase III trials by late 2007.
"There are 300,000 to 400,000 people actively seeking help with their cocaine addiction in the U.S., but
that probably only scratches the surface of whom you could access with an effective outpatient therapy,"
Celtic's Earl says. Estimates place the number closer to 10 million together in the U.S. and Western
Europe where, he says, it is a rapidly growing problem and high on government and law enforcement
agendas. "Our expectation is that when an effective product becomes available the uptake will be pretty
rapid," Earl says.
Celtic has arrangements for manufacturing the vaccine and envisions finding a larger company to
commercialize it. "At the appropriate time, we will auction our programs to an appropriate universe of big
pharma companies positioned to make the best of them in the marketplace," says Stephen Evans-Freke,
Celtic's managing general partner. He expects interest will be high, since the "major pharmaceutical
companies have only very recently woken up to the scale of the medical need and therefore the
commercial opportunity in treating drug addiction."
Other medications being tested for cocaine and for methamphetamine addictions include selegiline, used
to treat Parkinson's disease; baclofen, used for muscle spasms; and ondansetron, which prevents nausea
during chemotherapy. Methamphetamine has an even greater effect on dopaminergic systems than
cocaine, and there are reportedly an estimated 350,000 heavy users in the U.S. alone. The smokingcessation medication bupropion has recently been found to reduce drug use and craving in low-tomoderate methamphetamine users, or those who use the drug fewer than 18 days per month, Vocci says.
InterveXion Therapeutics in Little Rock, Ark., has received a $3 million grant from NIDA that is helping the
firm prepare for clinical testing of monoclonal antibody (mAb) treatments. "We expect to meet with FDA
just after the first of the year and hopefully start clinical trials as soon as next June," says President and
CEO R. Barry Holtz. The company's first candidate for testing, InterveXin-PCP, targets phencyclidine
(PCP) abuse and is to be followed soon after by InterveXin-METH for treating methamphetamine abuse.
Initially, Holtz explains, the company will investigate the treatment of acute cases using passive or
nonimmunogenic mAbs to bind with high affinity to, and thereby neutralize, the drug of abuse. The
technology came out of the laboratory of S. Michael Owens, professor of pharmacology and toxicology at
the University of Arkansas for Medical Sciences and director of the UAMS Center for Alcohol & Drug
Abuse. He also serves as InterveXion's chief scientific officer.
"It's important to detoxify patients proactively in the emergency room," Holtz says, "because, for example,
the problem with methamphetamine is that it binds permanently to receptors in the brain and destroys
them. So there is no recovery." Long term, methamphetamine use alters activity in the dopamine systems
associated with motor control and verbal learning, as well as affecting areas of the brain connected to
emotion and memory.
After several years of preclinical work, the company is producing the antibodies in an alfalfa-based
system with the help of Medicago in Quebec. "In the long run, this should reduce costs quite a bit," Holtz
explains, especially in methamphetamine cases where patients often have very high levels of the drug in
their bodies and large amounts of antibody will be needed. Because of the long half-life of the mAbs, the
therapy will also be used to help recovering addicts overcome their dependence and to prevent or reduce
adverse effects in chronic users.
Meanwhile, DAS has advanced anti-cocaine and anti-methamphetamine antibodies as far as preclinical
development. It has put these products on hold, however, as it works on other products. One of these is
DAS-431, a dopamine D1 receptor agonist licensed from Abbott Laboratories in 2000. Abbott tested the
compound in Phase IIa studies for cocaine addiction and saw positive results, according to DAS, which
expects to begin Phase IIb studies in 2007.
Yaupon Therapeutics, meanwhile, has funding from NIDA and anticipates starting Phase II studies of the
dopamine-modulating agent lobeline for treating methamphetamine addiction in early 2007. Preclinical
studies have found lobeline to be effective in animal models and that it also protects dopamine-producing
neurons. Like Yaupon's other drug candidates, lobeline is a plant alkaloid; the compound comes from the
Indian tobacco plant and has been known for centuries.
"It was defined as a nicotinic receptor agonist in most of the old literature," explains University of
Kentucky professor of pharmaceutical sciences and Yaupon founder Linda Dwoskin. "From our data,
however, we figured out that in the central nervous system it's actually acting as a nicotinic receptor
antagonist." She notes that lobeline's use as a smoking cessation agent had been studied decades earlier
without definitive results.
"We've also looked at interactions with dopaminergic systems and found that lobeline is a potent inhibitor
of the vesicular monoamine transporter 2, which is the protein that stores dopamine in vesicles for
release," Dwoskin adds. As such, it functions to antagonize the effects of amphetamine stimulants and
prevents the amphetamine-induced release of dopamine. It does so by binding noncompetitively at an
allosteric site, and because of this mechanism, its effect can't be overridden by increased intake of the
drug of abuse.
Phase I work was carried out through a clinical trials agreement with NIDA. "They have helped us
tremendously in getting this compound into the clinic," Crooks says. "It's a partnership that has really
provided a lot of basic support that normally you wouldn't expect to have when commercializing a product
on your own." Crooks and Dwoskin's work has continued in the synthesis and development of lobeline
analogs to both test the target mechanism and find more selective and novel inhibitors.
"The mechanisms of drug abuse and treatment are complex, and I don't know that we are going to be
able to find any one medication that works," Vocci says. "Most of the time in CNS pharmacology, it seems
like the 'dirty' drugs with multiple mechanisms work best." Then, once effective pharmacotherapies are
found, the task is to reduce side effects. "For example, newer selective serotonin reuptake inhibitor
antidepressants don't work any better than the old tricyclics, but they do have fewer risks," he adds. And,
in treating drug abuse, as for other disorders, combinations of medications may play a role.
The market for narcotic addiction therapies is about $440 million and is not expected to grow between
now and 2012, on the basis of current therapeutics, reports Spectra Intelligence. The entrance of any one
new medication, especially one that creates a new market sector around cocaine dependency, could be a
significant boost. If approved, for example, products with the potential of $300 million to $400 million in
annual sales include TA-CD and long-acting buprenorphine.
ISTOCK PHOTO
ALCOHOLISM. In contrast to the market for narcotic addiction therapies, Spectra Intelligence says the
alcohol addiction medication market was just $125 million in 2005, but forecasts it to grow more than
sixfold to $840 million by 2012. The small size today is despite a total potential market of 30 million or
more people in the U.S., Europe, and Japan. Growth will come largely from the very recent launches of
Vivitrol, developed by Alkermes and marketed by Cephalon, and of Campral, which has been gaining
ground since FDA approved Forest Laboratories' version in 2004.
For about 45 years, the aversive agent disulfiram, sold by Odyssey Pharmaceuticals as Antabuse, was
the only treatment. Today, some researchers consider it ineffective at best and often dangerous, as well
as antiquated since it doesn't target known neurochemical mechanisms in alcohol addiction. Instead, it
works by inhibiting aldehyde dehydrogenase, an enzyme that converts acetaldehyde to acetic acid, which
leads to a buildup of acetaldehyde in the body. After taking disulfiram and then consuming alcohol, a
person experiences nausea, flushing, headaches, and chest pains. The drug also can have more severe
adverse effects, including death. Many patients simply stop taking it.
In 1994, an oral form of the opioid antagonist naltrexone, renamed ReVia, was approved by FDA for
treating alcoholism; it is now sold as a generic drug under many different names. The drug's safety profile
is good at lower doses, although it can cause liver failure at excessive doses and thus bears a warning on
its label, which some in the field say has limited its use. It generally has been considered moderately
effective in reducing drinking and cravings.
Alcohol dependence, with relapse rates of more than 75% after one year, and other addictions often
require extended treatment and retreatment. Patient compliance is a serious issue with oral medications,
according to David R. Gastfriend, Alkermes' vice president of medical affairs. "About 30 years ago, NIH
issued a call for help to develop technologies for extended-release preparations," he says. With seed
money from NIAAA and NIDA, Alkermes spent about six years developing Vivitrol, which was approved in
April.
Vivitrol is naltrexone embedded in polymer microspheres for once-monthly intramuscular injection.
Clinical studies have demonstrated that patients like the new formulation and can tolerate it and that its
safety profile is good, he says. Results also show that Vivitrol helped decrease heavy drinking and
prolong abstinence. In addition, the priming effect, which causes acute craving, is reduced. In clinical
studies, patients used Vivitrol for at least six months, but in practice, a patient and physician will
determine the duration of treatment.
FDA has approved Vivitrol for patients who have initiated abstinence, a group in which the drug has been
found to work best and one consisting of individuals who essentially have chosen to address their
dependence. It also is to be used in combination with psychosocial treatment. Although being abstinent or
even entering treatment may be a hurdle, Gastfriend says, "the real message is that this is a potentially
life-threatening disease, it's a medical condition, and it has to be taken seriously, and this is a serious
medicine.
"We know that out of the 8 million or 9 million people in America with alcohol dependence, maybe
100,000 get medication, which is essentially nobody," he says, although about 2 million per year seek
treatment. "Since 1935, at the outset of the Alcoholics Anonymous movement, we've had one major
approach to treating alcohol dependence, and that is talking. And we have taken that, it seems, about as
far as we are going to get with it," he says. He believes medications will be a crucial part of future
treatment.
Although there are many different, rigorous approaches to behavioral or psychosocial therapy that all
seem to do equally well, he says, "none of them stabilizes the chemical or neurological origins of this
disease in the brain" as naltrexone is believed to do. "It's only through the science of neurotransmitter
receptors that we are able to add another conceptual approach to stabilize the circuitry of reward systems
in the limbic areas of the brain and address cognitive learning processes in the cortex for recovery."
Most physicians have approached addiction by prescribing abstinence, since they didn't favor
"substituting dependence on one drug for another," Cephalon's Baldino remarks. "There's been a dearth
of products and very low success rate for the abstinence route, and with a drug like Vivitrol, you really can
improve today's standard of care." Cephalon intends to introduce Vivitrol first through addiction specialists
to gain experience with them, then expand it to others, such as psychiatrists focusing on addiction, and
eventually to primary care physicians.
"Primary care physicians will be an important audience because patients may be more likely to discuss
their problems with them," he says. A recent clinical study, "Combining Medications and Behavioral
Interventions for Alcoholism," or COMBINE, "really underscores the value of the combination of
pharmacotherapy and psychosocial support," he says, and should help physicians realize that there is
more they can do for patients. NIAAA recently issued guidelines supporting the combination of therapies.
Cephalon will offer a program called VIP3, or Vivitrol Information for Patients, Physicians & Providers, to
integrate support services for all three groups as part of its commercialization strategy. Three years ago, it
would have been extremely difficult to get doctors to consider using a pharmacotherapy, Baldino says,
"but we're happy to have a new drug to launch into today's environment" that is more receptive to
pharmacotherapy. In 2005, Cephalon signed a $490 million deal with Alkermes to market the drug.
"Large pharmaceutical companies historically have not gone into small emerging markets, which
fortunately is good for smaller companies like us," he says. "The current alcohol dependence market is
not an attractive market, and there are only a couple of players here." He believes, however, that if Vivitrol
does well, it will spark the interest of other pharmaceutical companies, bring more investment in R&D, and
eventually give patients more choices.
Meanwhile, Finnish biotech company Biotie Therapies is testing an oral form of nalmefene for alcohol
dependence and for impulse disorders. "Opiate receptor antagonism has a solid base in treating
dependence disorders," Biotie CEO Timo Veromaa says, "and nalmefene has a better bioavailability than
naltrexone, is longer lasting, and does not have the liver toxicity issues." Side effects are those common
to the overall class of opiate antagonists, he adds.
The company has been working for several years to show the drug's efficacy in reducing heavy drinking,
rather than achieving or maintaining abstinence. "We have taken a completely new look at this and
devised a clinical development program from the opposite viewpoint," Veromaa explains, since he says
results for abstinence-oriented therapies have largely been extremely poor and relapse rates very high.
Unlike other therapies, Biotie's nalmefene has been designed to be used on demand. "Patients are
advised to take one tablet per day as needed, when drinking is imminent—and these people know when
they are going to drink," Veromaa says. "Because nalmefene takes away the craving, it leads to the ability
to resist urges to drink excessively." In one large, late-stage clinical trial, nalmefene reduced heavy
drinking by almost 50%.
"We have completed two Phase III clinical studies and are now going into the registration phase in
Europe for alcohol dependence," Veromaa says. Approval is anticipated first in the U.K. in 2007, followed
by other European countries in 2008. Biotie will manufacture the drug. It has signed on Britannia
Pharmaceuticals as a marketing partner for the U.K. and Ireland and is finding others in other markets
outside the U.S. Somaxon Pharmaceuticals has licensed North American rights to nalmefene but is not
yet pursuing it for alcohol dependence.
Forest Laboratories' business model is to look for products in areas of unmet medical need, where the
mechanisms are unique, or where there may be some distinct safety or efficacy advantage, explains
Jeffrey M. Jonas, Forest executive vice president and medical officer. The company licensed Campral
from Merck KGaA in Europe and has been marketing it in the U.S. since 2004. How the drug works in
alcohol dependence is not well understood, but it is thought to modulate glutamatergic activity, possibly
reducing glutamate levels and alcohol withdrawal symptoms.
"It's believed that alcoholics develop compensatory mechanisms in the brain because of chronic alcohol
use, and when alcohol is removed, they develop cravings due to changes in the neurochemistry," Jonas
says, "and somehow Campral stabilizes the neurochemistry." The drug, given as two 333-mg tablets
twice daily, is to be used along with psychosocial therapy in patients who have been abstinent. Jonas
says that taking a medication routinely may actually be positive for patients "for whom having a
reconfirmation of treatment is important in acknowledging their illness."
Results from clinical trials suggest that after as long as a year patients that had used Campral were about
two or three times more likely to achieve complete abstinence than those on placebo, Jonas explains,
"and we think that's a meaningful effect." In contrast to pharmacotherapies and clinical trials targeting a
reduction in drinking, Jonas says, "we have to believe that the ability to sustain abstinence is probably the
gold standard for treating alcoholism."
The results of the COMBINE study, published in the May 3 issue of JAMA, have sparked a great deal of
discussion. NIAAA launched the 1,400-patient multicenter study in 2001 to identify the most effective
treatments for alcohol dependence. In addition to naltrexone, the study included acamprosate and a
combination of the two drugs, all given along with medical management or behavioral support.
Acamprosate had been widely studied and used in Europe since 1989, where the vast majority of clinical
studies have shown it helps individuals maintain abstinence, before being approved on the basis of these
data in the U.S.
Although treatment using naltrexone performed slightly better than placebo in the study, acamprosate
alone or in combination with naltrexone, did not—much to many people's surprise (J. Am. Med. Assoc.
2006, 295, 2075). The trial has raised differing views about study design, including questions around
population differences in determining efficacy and applicability to real-world settings. Maybe most
important, it highlights the challenge in finding effective treatments.
"Alcoholism is a difficult illness to treat," Jonas says. "It is a very complicated mix of psychological drives
and physiologic drives." This often makes it difficult for medications to show an effect, which makes
treatment for this kind of disorder daunting and, in turn, makes the impact of these drugs somewhat less
dramatic. Further complicating matters, patients also often have a gamut of psychosocial problems and
coexisting conditions, such as depression and anxiety.
It's not unusual to find that a drug may work in some trials and not in others, and the reason why isn't
always clear, says Raye Z. Litten, coleader of NIAAA's medications development team and COMBINE's
government director. And all medications don't work in all patients. "We know, for example, that
acamprosate and naltrexone don't work for everyone, but that doesn't mean they don't help some
people," he says. The institute is still conducting an exploratory analysis of the COMBINE data to see
whether they can identify who did and didn't respond.
"If you could predict the population a drug would work in, you would undoubtedly see a better effect and
more consistent results," Litten says, "and be able to deliver medications in a more effective, more
reliable, and safer manner." The need for personalized treatment is evident in alcohol dependence,
according to NIAAA researchers whose work has helped determine that complex mechanisms underlie
the disease, which likely is not a single disorder but many with common defining features.
"The disease phenotype is a product of the interaction of genes and the environment," says Markus
Heilig, chief of the Laboratory of Clinical & Translational Studies at NIAAA. At one extreme, people have a
genetic susceptibility, and progress is being made in identifying genetic variations. At the other, the
disease is shaped by environmental factors. "What people fail to appreciate is that the major
environmental factor is alcohol itself," he adds. Cycles of intoxication and withdrawal over a sufficiently
long time trigger neuroadaptive changes.
Thus, in very simple terms, neurochemical imbalances that manifest as the same apparent dependence
on alcohol can arise from either genetics or environment, or actually a combination of both sources.
Neuroadaptive and genetically susceptible individuals, and others in between, react differently to alcohol,
to factors such as stress, and to pharmacotherapies. Understanding and identifying these mechanisms
and their manifestations has implications for both finding drugs and the patients in which they'll work and
may even influence clinical trial design.
For example, a genetic variation found in the µ-opioid receptor enhances the pleasurable effects of
alcohol, Heilig says. "And blocking that receptor would be expected to have more of an effect in people
with that variation than in others." Pharmacogenetic data—namely, a predictive positive therapeutic
response to naltrexone—have emerged to support this hypothesis, he adds. Similarly, a hallmark of some
neuroadaptive alcoholics is a hyperglutamatergic state; acamprosate reverses the effect in alcoholdependent animals but has no effect in those not adapted to alcohol.
"We have right now about six to seven preclinically very well-validated targets" that have fulfilled specific
requirements, Heilig says. "They have to be compounds that either already have properties that are
useful for clinical development or that we can hopefully optimize to that stage, and there needs to be a
serious pharmaceutical company willing to support development." It can be difficult to find partners for offpatent drugs, even when the compounds hold promise or NIAAA assumes the development risk, because
they offer no earning potential.
Nevertheless, interest on the part of pharmaceutical companies is increasing for a number of reasons,
says Mark Egli, coleader of the NIAAA medications development team, including companies' need for
new products and the size of the potential market. They also are attracted to new animal models for
evaluating compounds based on a significantly improved understanding of the mechanisms of alcohol
dependence and addiction in general, he says. As proof of companies' growing interest, one can look
back 10 years when no major company had any large-scale clinical trials under way in this area; since
then there have been at least a dozen.
NIAAA itself has more than 50 clinical trials under way for alcohol dependence and related conditions. It
has been exploring existing medications, such as topiramate, gabapentin, valproate, ondansetron,
baclofen, aripiprazole, memantine, and rimonabant. It also has been investigating new compounds
targeting opioid, serotonin, GABA, dopamine, glutamate, cannabinoid, CRF, adenosine, and
neuropeptide Y receptors. Egli has coauthored two recent reviews on the subject with Heilig (Pharmacol.
Ther. 2006, 111, 855) and with Litten and others (Expert Opin. Emerging Drugs 2005, 10, 323).
Clearly, when it comes to alcohol dependence, it's not all about dopamine. "Dopamine is a very important
neurotransmitter that's involved in many aspects of behavior, and it got a lot of attention because of its
role in reinforcement and reward," Egli says. "It's certainly part of the equation, but because alcohol
affects so many systems in the body, and because there is no one single receptor to target, finding drugs
that work may be more complex than for other addictions."
"Before naltrexone and acamprosate were approved, many people were saying we'd never get a drug
through FDA because there was no receptor to target," Litten says. Both drugs are now approved in
about 29 countries. "Maybe it's a small step in curing alcoholism, but it's certainly a big step for
researchers," he says. It demonstrates both the progress in basic science over the past 10 to 15 years
and the possibility for success in development and approval. Work is expected to continue on establishing
targets, validating models, and finding genetic markers.
NIAAA is taking steps to address development issues. "We are finalizing the formation of an integrated
medication development program here at the institute," Willenbring says. "For a long time, we have been
funding extramural research, but now we are more systematically providing a certain set of services and
strategies that we hope will serve as a complement to industry." The idea is to facilitate early-stage
clinical development and proof-of-concept stages and not replicate industry's capabilities in either drug
discovery or large-scale efficacy and safety trials.
NIAAA also is hoping to access libraries of compounds at pharmaceutical companies. "We're in dialogue
with various pharmaceutical companies about compounds they have but aren't going to pursue, or they'll
come to us because they believe something might be effective," Willenbring explains. The institute then
might conduct preclinical research and even initial clinical trials with the hope of having something to
hand back that a company will want to develop further.
Willenbring believes there will be considerable advances in pharmacotherapy. "There are so many
potential targets, which is both good and bad news," he says. "It means there are a lot of opportunities,
but it also means we are unlikely to find a single medication that's going to make a really big difference
because the disease is so complex." Instead, at least near term, successful treatment strategies will
probably involve medications with multiple actions or multiple medications as doctors learn more about
what is available, is effective, and works best for their patients.
In the past, addiction treatment has been handled largely by specialists rather than within general health
care, but there aren't that many specialists, and awareness about pharmacological approaches has been
limited. Marketing has also been lackluster, and thus there's been little market penetration. "One of the
biggest problems we have is that the drugs are not being used because we don't have the infrastructure
set up to provide treatment," Willenbring says. Although there are expectations for another six or more
new addiction medications within the next 10 years, it will require change to make these treatment options
available.
Chemical & Engineering News
ISSN 0009-2347
Copyright © 2006 American Chemical Society
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Vaccines Against Drugs of Abuse: A Viable Treatment Option?
Leading Article
Drugs. 63(4):341-352, 2003.
Kantak, Kathleen M.
Abstract:
Drug addiction is a chronically relapsing brain disorder. There is an urgent need for new treatment options for
this disease because the relapse rate among drug abusers seeking treatment is quite high. During the past
decade, many groups have explored the feasibility of using vaccines directed against drugs of abuse as a
means of eliminating illicit drug use as well as drug overdose and neurotoxicity.
Vaccines work by inducing drug-specific antibodies in the bloodstream that bind to the drug of abuse and
prevent its entry into the brain. The majority of work in this area has been conducted with vaccines and
antibodies directed against cocaine and nicotine. On the basis of preclinical work, vaccines for cocaine and
nicotine are now in clinical trials because they can offer long-term protection with minimal treatment
compliance. In addition, vaccines and antibodies for phencyclidine, methamphetamine and heroin abuse are
currently under development. An underlying theme in this research is the need for high concentrations of
circulating drug-specific antibodies to reduce drug-seeking and drug-taking behaviour when the drug is
repeatedly available, especially in high doses.
Although vaccines against drugs of abuse may become a viable treatment option, there are several drawbacks
that need to be considered. These include:
I. a lack of protection against a structurally dissimilar drug that produces the same effects as the drug of
choice;
II. a lack of an effect on drug craving that predisposes an addict to relapse; and
III. tremendous individual variability in antibody formation.
Forced or coerced vaccination is not likely to work from a scientific perspective, and also carries serious legal
and ethical concerns.
All things considered, vaccination against a drug of abuse is likely to work best with individuals who are highly
motivated to quit using drugs altogether and as part of a comprehensive treatment programme. As such, the
medical treatment of drug abuse will not be radically different from treatment of other chronic diseases.
Copyright 2003 Adis Data Information BV
Novel pharmacotherapeutic approaches for the treatment of drug addiction and craving
Christian A Heidbreder and Jim J Hagan
Department of Biology, Centre of Excellence for Drug Discovery in Psychiatry, GlaxoSmithKline
Pharmaceuticals, Via A. Fleming 4, 37135 Verona, Italy
Available online 23 December 2004.
Pharmacological agents have shown limited efficacy and consistency in the treatment of drug addiction.
Hence, the development of new medications with improved long-term efficacy and reduced side effects
should be given a high priority given the costs to society associated with drug abuse and drug-related
pathologies. Neurochemical systems can be significantly altered by repeated exposure to drugs of abuse.
These long-term molecular and neurochemical changes might, in turn, explain the core features of
addiction — the compulsive seeking and taking of the drug — as well as the risk of relapse.
Abbreviations: 5-HT, serotonin; CRF, corticotropin-releasing factor; DA, dopamine; GABA, γaminobutyric acid; GR, glucocorticoid receptor; mGluR, metabotropic glutamate receptor; MPEP, 2methyl-6-(phenylethynyl)-pyridine; nAChR, nicotinic receptor; NMDA, N-methyl-D-aspartate
Current Opinion in Pharmacology
Volume 5, Issue 1, February 2005, Pages 107-118
A novel bivalent morphine/heroin vaccine that prevents relapse to heroin addiction in rodents
Benito Anton , and Philippe Leff
Laboratory of Molecular Neurobiology and Addictive Neurochemistry, National Institute of Psychiatry,
Ramón de la Fuente Muñiz, Calz., México-Xochimilco #101, México D.F.C.P. 14370, Mexico
Received 9 August 2005; revised 2 December 2005; accepted 12 January 2006. Available online 8
February 2006.
Abstract
Both pre-clinical and clinical studies make feasible the use of vaccines as novel therapeutic medications
to treat drug addiction. No reports to date have shown the development of structural models of opiate
candidate vaccines for treating human addiction to such compounds. Here we report on the initial
development of a novel structural formulation of a bi-valent vaccine against morphine/heroin. This vaccine
was able to trigger and establish a high titer antibody response to haptenized drug with antibodies
displaying equivalent specificities for both morphine and heroin. Such antibodies did not cross-recognize
structurally dissimilar opiate medications. Furthermore, the evaluation of the potential therapeutic
effectiveness of this vaccine was targeted to relapse prevention using a schedule of heroin delivery in the
rat self-administration model. Antibodies against heroin blocked its reinforcing effects in rodents. The type
of carrier protein used in this vaccine allows further evaluation of its potential therapeutic value for
preventing relapse to heroin addiction in humans.
Keywords: Vaccine; Morphine/heroin; Immunoprotection; Opiates; Active immunization; Prevention;
Addiction
Corresponding author. Tel.: +52 56 55 28 11x532; fax: +52 55 13 37 22.
Vaccine
Volume 24, Issue 16, 12 April 2006, Pages 3232-3240
Vol. 69, No. 3, 2002
Journal Home
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View or print article as PDF (49 KB)
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Medline Abstract (ID 12097758)
Medline Related Articles
Download Citation
Thematic Review Series
A Vaccine for Nicotine Dependence: Targeting the Drug Rather
than the Brain
Paul Pentela, David Malinb
aHennepin
bUniversity
County Medical Center, Minneapolis, Minn., and
of Houston-Clear Lake, Houston, Tex., USA
Address of Corresponding Author
Respiration 2002;69:193-197 (DOI: 10.1159/000063617)
Outline
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Key Words
Abstract
Rationale
Mechanism of Action
Questions Regarding the Potential Clinical Use of Vaccination
Potential Clinical Applications
Acknowledgment
References
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Author Contacts
Article Information
Publication Details
Drug Dosage / Copyright
Key Words
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Nicotine
Tobacco
Smoking
Vaccine
Immunization
Abstract
Nicotine is the principal addictive component of tobacco. Vaccination of rats against
nicotine elicits the production of nicotine-specific antibodies which can bind and
sequester nicotine in serum and extracellular fluid, reduce nicotine distribution to
brain, and reduce many of nicotine's physiologic and behavioral effects. Vaccination
reduces the distribution to brain of both a single nicotine dose and chronic nicotine
infusion at rates approximating cigarette smoking. The passive transfer of nicotinespecific antibodies (from vaccinated rabbits) into rats attenuates numerous actions
of nicotine: increases in blood pressure and locomotor activity, the induction of
nicotine dependence, the relief of nicotine withdrawal by subsequent nicotine and
the stimulus properties that allow rats to discriminate a nicotine from a saline
injection. Vaccination of rats against nicotine also reduces nicotine-induced
dopamine release in the reward pathway of the brain and the reinstatement of
nicotine responding, a model for relapse. Because nicotine vaccines target the drug
rather than the brain, and the antibodies themselves do not cross the blood-brain
barrier, immunization should circumvent the central nervous system side effects that
limit the usable dosage of other medications for tobacco dependence. Nicotine
vaccines have not yet been tested in humans. The effects of these vaccines in rats
are highly dependent upon the concentration of antibody in serum, and are more
often partial than complete. If effective for treating tobacco dependence in humans,
vaccination will likely benefit from concurrent use of counseling (as is the case with
other medications for smoking cessation) and perhaps from its combination with
other medications that act via different mechanisms.
Copyright © 2002 S. Karger AG, Basel
rationale
Vaccination was first suggested as a strategy for treating drug dependence more
than 25 years ago [1]. Vaccines are now being studied in animals as possible
treatments for addictions to nicotine, cocaine, methamphetamine and phencyclidine
[2, 3, 4, 5]. One of these, a cocaine vaccine, has entered clinical trials [6]. The term
'vaccine' is accurate but perhaps unfortunate, as it suggests the complete and
unsurmountable protection afforded by many vaccines for infectious diseases. In the
setting of drug dependence, vaccines are intended to elicit the production of
antibodies which will bind the drug in question and alter its pharmacokinetics in a
manner that is therapeutically helpful. The major aim is to reduce the extent or rate
of drug distribution to the brain. This mechanism, although novel, is more analogous
to a medication than to vaccination against an infectious disease. With this caveat,
vaccines for drug addictions represent an intriguing new approach to treatment of
drug dependence. Because their mechanism of action is quite different from existing
medications, they may provide additive efficacy, or prove helpful for different aspects
of addiction. Some practical features of vaccination, such as long-lasting effects and
avoiding the need for daily medication, may also prove attractive. The potential
application of vaccination to tobacco dependence is of particular interest because
other currently available medications are not effective in all patients [7].
Nicotine is the principal addictive component of tobacco, acting in the brain to
produce a variety of neural effects that initiate and maintain tobacco dependence [8].
Not surprisingly, efforts to develop medications for tobacco dependence have
focused on either stimulating or inhibiting the neural pathways involved in nicotine
addiction. Targeting these neural pathways has contributed greatly to improved
smoking cessation rates, but this approach has limitations as well. The brain
pathways involved in nicotine addiction also serve a variety of essential endogenous
functions ranging from the perception of pleasure to alterations in movement, mood,
memory and cognition. In altering these pathways to treat nicotine addiction,
medications may alter normal functions as well, leading to side effects or to limits on
the dose of medication that can be used. Analogous considerations have limited the
clinical use of medications for other kinds of drug addictions.
mechanism of action
The amount of nicotine reaching the brain, and the rate at which it does so, are
important determinants of the initiation and maintenance of smoking [9]. Within
limits, higher doses of nicotine are more rewarding than lower doses, and more rapid
delivery of nicotine to the brain is more rewarding than slower delivery (for example,
a cigarette is more rewarding than a nicotine patch). Thus the rate and extent of
nicotine distribution to brain provide potential therapeutic targets in which therapy is
directed at the drug rather than the brain. Vaccines against nicotine elicit the
production of nicotine-specific antibodies which can bind nicotine with a high affinity
and sequester it in serum and extracellular fluid. The antibodies themselves are too
large to cross the blood-brain barrier, so that administered nicotine which becomes
bound to antibody is also excluded from the brain. In this way, vaccination can
potentially alter the amount of nicotine reaching the brain. Vaccination may also
reduce the rate at which nicotine enters the brain, although the mechanism by which
this occurs is less clear. Since antibody is largely excluded from the brain, central
nervous system side effects of vaccination are not expected, and no adverse effects
of vaccination have been reported in animal studies to date.
Nicotine itself is a small molecule that is not immunogenic. Vaccines consist of
nicotine attached to a foreign carrier protein by a short linker. In rats, a series of 2-4
injections of vaccine over 4-8 weeks elicits high titers (serum concentrations) of
antibodies that are highly specific for nicotine and which do not bind nicotine
metabolites or acetylcholine, the endogenous ligand of nicotinic receptors [4, 10].
When vaccinated rats are given a single dose of nicotine equivalent (on a mg/kg
basis) to the nicotine absorbed from 2 cigarettes by a smoker, the distribution of
nicotine to brain 1-3 min later is reduced by over 60% [4]. Even when rats receive
chronic nicotine doses equivalent to that of a heavy smoker, vaccination remains
effective in reducing the early distribution of each nicotine dose to brain [11].
Are these effects large enough to meaningfully alter nicotine's actions? In this issue
of Respiration, de Villiers et al. [12] report that vaccination of rats reduces the
nicotine-induced release of dopamine from the nucleus accumbens, a
neurochemical event that is thought to be a key mediator of nicotine dependence.
Passive immunization of rats (infusion of nicotine-specific antibodies produced in
rabbits) reduces the pressor effect and the increase in locomotor activity resulting
from a single dose of nicotine [4]. Some caution is needed in interpreting these
findings in that the doses of antibody used for passive immunization may be higher
than those generally achieved by vaccination. However, they do provide proof of the
principle that nicotine-specific antibodies can blunt some of nicotine's effects.
Passive immunization of rats also reduces the ability of rats to distinguish a single
dose of nicotine from a dose of saline, and the ability of nicotine to relieve signs of
nicotine abstinence following withdrawal from nicotine in nicotine-dependent rats [13,
14]. These findings suggest a potential role for vaccination in the prevention of
relapse. Cigarette smokers who quit and experience withdrawal and craving often
resume smoking because they slip and smoke a cigarette, which relieves their
discomfort. If vaccination rendered cigarettes ineffective in producing reinforcement
or relieving withdrawal symptoms, smokers who slip might be less likely to continue
smoking. Initial studies of rats trained to self-administer nicotine via an intravenous
cannula support this possibility. If rats trained in this manner have their nicotine
replaced by saline, responding declines but can be markedly increased again
(reinstated) by a single 'priming' dose of nicotine. In this issue of Respiration,
Lindblom et al. [15] report that vaccination of rats reduces the ability of the priming
dose to reinstate nicotine-seeking behavior. Vaccination of rats prior to being trained
to self-administer nicotine also reduces the acquisition of this behavior (unpubl.
data). Although these results appear promising, their relevance to smoking behavior
in humans is not entirely clear. Rat models of nicotine dependence differ from
cigarette smoking in many ways, including the route of drug administration
(intravenous or intraperitoneal in rats vs. inhalation in humans), nicotine dose
(required doses are generally higher in rats owing to more rapid nicotine
metabolism), and behavioral accompaniments such as conditioned cues or social
context. Studying a wider variety of animal models may be helpful but ultimately
clinical trials will be needed to answer this question.
Other pharmacokinetic mechanisms may contribute to the behavioral effects of a
nicotine vaccine. Smokers who are given methoxsalen, an inhibitor of nicotine
metabolism, smoke fewer cigarettes, presumably because slower nicotine
elimination delays the onset of craving after a cigarette [16]. Vaccination of rats also
slows nicotine elimination 3- to 6-fold by making it less available for hepatic
metabolism [17]. Slowed nicotine metabolism could possibly be useful clinically to
reduce smoking as a harm reduction measure, or as a transitional goal toward
cessation.
While the general concept is straightforward, much remains to be learned about the
mechanism by which vaccination alters nicotine distribution to tissues. The doses of
nicotine administered to rats in the experiments cited above often exceeded the
calculated binding capacity of antibody for nicotine, yet the vaccine remained
effective. For example, the antibody present in a vaccinated rat with a high antibody
titer has been estimated to have a binding capacity equal to the nicotine absorbed
from 2 cigarettes by a smoker (on a mg/kg basis). Nevertheless, vaccination reduces
nicotine distribution to brain even when rats receive the equivalent of 6 packs of
cigarettes daily, or a single intraperitoneal nicotine dose equivalent to 67 cigarettes
(although it is less effective than with lower nicotine doses) [11, 18]. It is unclear why
vaccination remains effective under these circumstances, but the observation is
clearly relevant to its potential clinical use. Interestingly, this discrepancy between
antibody binding capacity and drug dose has been reported with vaccines for
cocaine and phencyclidine as well [5, 19]. Possibly vaccination alters drug
distribution to brain to a greater extent than to other organs. Understanding and
exploiting this phenomenon may prove helpful in optimizing vaccine efficacy.
Antibodies induced by vaccination generally have a high affinity for nicotine, but it is
unclear whether there is an optimal affinity for this application. Tighter binding of
nicotine may maximize its effects on nicotine distribution, but could also favor
saturation of the antibody with nicotine, rendering it less effective. It is difficult to
systematically study this question with vaccination, which elicits polyclonal
antibodies with varying affinities for nicotine. Passive immunization by infusion of
monoclonal antibodies having defined characteristics would be helpful in this regard,
and could also be of interest therapeutically. While vaccination has the advantages
of infrequent dosing and a potentially long-lasting effect, passive immunization would
allow the selection of antibodies with optimized affinity and would allow control of the
dose. If it proves difficult to achieve effective antibody titers with vaccination in
humans, passive immunization would offer an alternative strategy for overcoming
this problem.
questions regarding the potential clinical use of vaccination
Taken together, these data suggest that vaccination may have effects that would be
useful in the treatment of nicotine dependence. Whether vaccination will prove
clinically useful is still unclear and will hinge upon a variety of pharmacokinetic and
behavioral factors. In rats, pharmacokinetic effects of vaccination are greatest in
those with the highest titers of antibody in serum. This suggests that it will be
important to achieve high antibody titers in humans in order for the vaccine to be
effective. In general, antibody titers in humans vaccinated against infectious agents
are lower than those achieved in animals, perhaps because the aggressive
vaccination schedules and more potent adjuvants (chemicals added to the
immunogen to enhance the immune response) typically used in animals cannot be
used in humans. Nicotine vaccine effects are seen in rats when about 1% of their
total IgG is nicotine-specific antibody. In humans, such high concentrations of
specific antibodies can sometimes be induced by vaccines, but concentrations 1-2
orders of magnitude lower are more common. Clearly, efforts to optimize the
immune response in humans will be needed to maximize the efficacy of a nicotine
vaccine.
A key question regarding he use of vaccination is whether smokers will attempt to
compensate for reduced nicotine effects by increasing their smoking, either
deliberately or unintentionally. Since vaccine efficacy depends upon both the
concentration of nicotine-specific antibodies in serum and the magnitude of the
nicotine dose, compensation may be possible. Animal studies of this question may
be helpful but clinical trials will likely be needed to assess the extent to which
compensation compromises vaccine efficacy.
potential clinical applications
Assuming some degree of efficacy, how might a nicotine vaccine be used clinically?
Vaccination is not likely to duplicate or replace existing medications. One important
effect of nicotine replacement therapy, bupropion and nortriptyline is to reduce the
severity of tobacco withdrawal. Vaccination is not expected to do this, unless slowing
nicotine elimination has a moderating effect on withdrawal severity. The main effect
of vaccination is rather to blunt the rewarding effects of nicotine, something which
existing therapies do to only a limited extent. Thus vaccination may complement the
actions of existing medications or prove useful in combination with them.
Consideration of nicotine dose may also dictate how vaccination could be useful.
Even though vaccination can alter the pharmacokinetics of large doses of nicotine, it
is most effective when the nicotine dose is modest. Consequently, vaccination may
be better suited to relapse prevention, in which the goal is to block the priming effect
of a few puffs or a few cigarettes, than to smoking cessation where the antibody will
be presented with large cumulative daily doses of nicotine. Fortunately, vaccination
can be achieved even in the presence of nicotine so that smokers could be
vaccinated while they are still smoking, in preparation for a quit attempt [11]. A
possible role for vaccination in primary prevention of smoking among high risk teens
(e.g. those who are already smoking once or twice a month) could also be
envisioned, but this will require not only efficacy but considerable confidence in
vaccine safety.
Most importantly, vaccination is not likely to supplant the critical role of counseling in
smoking cessation. Medications approximately double the quit rate achieved with
counseling alone, but are only minimally effective when used without counseling.
There is a widespread consensus that the most effective strategy for smoking
cessation is concurrent use of counseling and medications. There is no reason to
expect that vaccination would be any different in this regard.
acknowledgment
This study was supported by NIDA grants DA10714 and DA13327. Disclosure: Both
authors currently collaborate with, and have been consultants to, Nabi.
References
1
Bonese KF, Wainer BH, Fitch FW, Rothberg RM, Schuster CR: Changes in
heroin self-administration by a rhesus monkey after morphine immunization.
Nature 1974;252:708-710.
2
Byrnes-Blake KA, Carroll FI, Abraham P, Owens SM: Generation of anti(+)methamphetamine antibodies is not impeded by (+)methamphetamine
administration during active immunization of rats. Int Immunopharmacol
2001;1:329-338.
3
Kantak KM, Collins SL, Lipman EG, Bond J, Giovanoni K, Fox BS:
Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat selfadministration model. Psychopharmacology (Berl) 2000;148:251-262.
4
Pentel PR, Malin DH, Ennifar S, Hieda Y, Keyler DE, Lake JR, Milstein JR,
Basham LE, Coy RT, Moon JW, Naso R, Fatton A: A nicotine conjugate
vaccine reduces nicotine distribution to brain and attenuates its behavioral
and cardiovascular effects in rats. Pharmacol Biochem Behav 2000;65:191198.
5
Proksch JW, Gentry WB, Owens SM: Anti-phencyclidine monoclonal
antibodies provide long-term reductions in brain phencyclidine
concentrations during chronic phencyclidine administration in rats. J
Pharmacol Exp Ther 2000;292:831-837.
6
Kosten TR, Rosen M, Bond J, Settles M, Roberts JS, Shields J, Lack L, Fox
B: Human therapeutic cocaine vaccine: Safety and immunogenicity. Vaccine
2002;20:1196-1204.
7
Fiore MC, Bailey MC, Cohen SJ: Treating Tobacco Use and Dependence.
Clinical Practice Guideline. Rockville, US Department of Health and Human
Services, Public Health Service, 2000.
8
Benowitz NL: Drug therapy: Pharmacologic aspects of cigarette smoking
and nicotine addition. N Engl J Med 1988;319:1318-1330.
9
Benowitz NL: Pharmacology of nicotine: Addiction and therapeutics. Annu
Rev Pharmacol Toxicol 1996;36:597-613.
10
Hieda Y, Keyler DE, Vandevoort JT, Kane JK, Ross CA, Raphael DE,
Niedbalas RS, Pentel PR: Active immunization alters the plasma nicotine
concentration in rats. J Pharmacol Exp Ther 1997;283:1076-1081.
11
Hieda Y, Keyler DE, Ennifar S, Fattom A, Pentel PR: Vaccination against
nicotine during continued nicotine administration in rats: Immunogenicity of
the vaccine and effects on nicotine distribution to brain. Int J
Immunopharmacol 2000;22:809-819.
12
de Villiers SHL, Lindblom N, Kalayanov G, Gordon S, Malmerfelt A,
Johansson AM, Svensson TH: Active immunization against nicotine
suppresses nicotine-induced dopamine release in the rat nucleus
accumbens shell. Respiration 2002;69:247-253.
13
Malin DH, Alvarado CL, Woodhouse KS, Karp H, Urdiales H, Lay D: Passive
immunization against nicotine attenuates nicotine discrimination. Life Sci, in
press.
14
Malin DH, Lake JR, Lin A, Saldana M, Balch L, Irvin ML, Chandrasekara H,
Alvarado CL, Hieda Y, Keyler DE, Pentel PR, Ennifar S, Basham LE, Naso
R, Fattom A: Passive immunization against nicotine prevents nicotine
alleviation of nicotine abstinence syndrome. Pharmacol Biochem Behav
2001;68:87-92.
15
Lindblom N, de Villiers SHL, Kalayanov G, Gordon S, Johansson AM,
Svensson TH: Active immunization against nicotine prevents reinstatement
of nicotine-seeking behavior in rats. Respiration 2002;69:254-260.
16
Sellers EM, Kaplan HL, Tyndale RF: Inhibition of cytochrome P450 2A6
increases nicotine's oral bioavailability and decreases smoking. Clin
Pharmacol Ther 2000;68:35-43.
17
Keyler DE, Hieda Y, St Peter J, Pentel PR: Altered disposition of repeated
nicotine doses in rats immunized against nicotine. Nicotine Tob Res
1999;1:241-249.
18
Tuncok Y, Hieda Y, Keyler DE, Brown S, Ennifar S, Fattom A: Inhibition of
nicotine-induced seizures in rats by combining vaccination against nicotine
with chronic nicotine infusion. Exp Clin Psychopharmacol 2001;9:228234.
19
Fox BS, Kantak KM, Edwards MA, Black KM, Bollinger BK, Botka AJ,
French TL, Thompson TL, Schad VC, Greestein JL, Gefter ML, Exley MA,
Swain PA, Briner TJ: Efficacy of a therapeutic cocaine vaccine in rodent
models. Nat Med 1996;2:1129-1132.
Author Contacts
Paul Pentel, MD
Departments of Medicine and Pharmacology, Hennepin County Medical Center
University of Minnesota, 701 Park Avenue South
Minneapolis, MN 55415 (USA) Tel. +1 617 347 6426
Fax +1 612 904 4366, E-Mail [email protected] or [email protected]
Article Information
Previous articles in this series:1. Balfour DJK: The neurobiology of tobacco
dependence: A commentary. Respiration 2002;69:7-11.2. Etter J-F: Using new
information technology to treat tobacco dependence. Respiration 2002;69:111-114.
Number of Print Pages : 5
Number of Figures : 0, Number of Tables : 0, Number of References : 19
Publication Details
Respiration (International Review of Thoracic Diseases)
Founded 1944 as 'Schweizerische Zeitschrift für Tuberkulose und Pneumonologie'
by E. Bachmann, M. Gilbert, F. Häberlin, W. Löffler, P. Steiner and E. Uehlinger,
continued 1962-1967 as 'Medicina Thoracalis' as of 1968 as 'Respiration', H. Herzog
(1962-1997)
Official Journal of the European Association for Bronchology and Interventional
Pulmonology
Vol. 69, No. 3, Year 2002 (Cover Date: May-June 2002)
Journal Editor: C.T. Bolliger, Cape Town
ISSN: 0025-7931 (print), 1423-0356 (Online)
For additional information: http://www.karger.com/journals/res
Drug Dosage / Copyright
Drug Dosage: The authors and the publisher have exerted every effort to ensure that
drug selection and dosage set forth in this text are in accord with current
recommendations and practice at the time of publication. However, in view of
ongoing research, changes in goverment regulations, and the constant flow of
information relating to drug therapy and drug reactions, the reader is urged to check
the package insert for each drug for any changes in indications and dosage and for
added warnings and precautions. This is particularly important when the
recommended agent is a new and/or infrequently employed drug. Copyright: All
rights reserved. No part of this publication may be translated into other languages,
reproduced or utilized in any form or by any means, electronic or mechanical,
including photocopying, recording, microcopying, or by any information storage and
retrieval system, without permission in writing from the publisher or, in the case of
photocopying, direct payment of a specified fee to the Copyright Clearance Center.
© 2007 S. Karger AG, Basel
Last update: 14/9/2004
Related Articles, Links
Drug Alcohol Depend. 1997 Dec 15;48(3):153-8.
Development of a therapeutic vaccine for the treatment of cocaine
addiction.
Fox BS.
ImmuLogic Pharmaceutical Corporation, Waltham, MA 02154, USA. [email protected]
No pharmacotherapies have yet been approved for the treatment of cocaine addiction. One
new approach is to block the effects of cocaine with anti-cocaine antibodies induced by a
therapeutic cocaine vaccine. A cocaine vaccine has been developed which induces a cocainespecific antibody response in rodents. The antibody binds to cocaine in the circulation and can
be shown to inhibit the ability of cocaine to enter the brain. Furthermore, anti-cocaine antibody
can inhibit cocaine self-administration in rats. These data suggest that a cocaine vaccine may be
a powerful therapeutic tool. The intent is to immunized motivated patients with the vaccine as
part of a comprehensive treatment program. If the patient uses cocaine after being vaccinated,
the antibody will inhibit the reinforcing activity of cocaine and decrease the likelihood of
relapse.
Publication Types:
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Research Support, U.S. Gov't, P.H.S.
MeSH Terms:
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Animals
Antigen-Antibody Complex/pharmacology
Behavior, Addictive/drug therapy
Blood-Brain Barrier
Brain Chemistry
Carrier Proteins/pharmacology
Cocaine/administration & dosage
Cocaine/blood
Cocaine/immunology*
Cocaine/pharmacokinetics
Cocaine-Related Disorders/drug therapy*
Cocaine-Related Disorders/immunology
Disease Models, Animal*
Humans
Immunization, Passive
Mice
Rats
Self Medication
Serum Albumin, Bovine/pharmacology
Vaccines/pharmacology*
Substances:
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Antigen-Antibody Complex
Carrier Proteins
Serum Albumin, Bovine
Vaccines
Cocaine
PMID: 9449013 [PubMed - indexed for MEDLINE]
PUBMED NATIONAL LIBRARY OF MEDICINE
VACCINES AGAINST ADDICTIVE BEHAVIORS:
Items 1 - 20 of 116
1:
Fox BS.
Page
1
of 6 Next
Related Articles, Links
Development of a therapeutic vaccine for the treatment of cocaine addiction.
Drug Alcohol Depend. 1997 Dec 15;48(3):153-8.
PMID: 9449013 [PubMed - indexed for MEDLINE]
2:
Kantak KM, Collins SL, Bond J, Fox BS.
Related Articles, Links
Time course of changes in cocaine self-administration behavior in rats during immunization with
the cocaine vaccine IPC-1010.
Psychopharmacology (Berl). 2001 Jan;153(3):334-40.
PMID: 11271406 [PubMed - indexed for MEDLINE]
3:
Fox BS, Kantak KM, Edwards MA, Black KM, Bollinger BK, Botka AJ, French TL,
Thompson TL, Schad VC, Greenstein JL, Gefter ML, Exley MA, Swain PA, Briner TJ.
Related Articles,
Links
Efficacy of a therapeutic cocaine vaccine in rodent models.
Nat Med. 1996 Oct;2(10):1129-32.
PMID: 8837612 [PubMed - indexed for MEDLINE]
4:
Hall W, Carter L.
Related Articles, Links
Ethical issues in using a cocaine vaccine to treat and prevent cocaine abuse and dependence.
J Med Ethics. 2004 Aug;30(4):337-40.
PMID: 15289512 [PubMed - indexed for MEDLINE]
5:
Kantak KM, Collins SL, Lipman EG, Bond J, Giovanoni K, Fox BS.
Related Articles, Links
Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model.
Psychopharmacology (Berl). 2000 Feb;148(3):251-62.
PMID: 10755738 [PubMed - indexed for MEDLINE]
6:
Carrera MR, Ashley JA, Zhou B, Wirsching P, Koob GF, Janda KD.
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Sparenborg S, Vocci F, Zukin S.
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Gorelick and Cohen in the immediately succeeding articles (see pages 153-174).
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Kantak KM.
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Kosten TR, Biegel D.
Therapeutic vaccines for substance dependence.
Expert Rev Vaccines. 2002 Oct;1(3):363-71. Review.
PMID: 12901575 [PubMed - indexed for MEDLINE]
10:
Xi ZX, Newman AH, Gilbert JG, Pak AC, Peng XQ, Ashby CR Jr, Gitajn L,
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Gardner EL.
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cocaine-induced reinstatement of drug-seeking behavior in rats.
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PMID: 16205781 [PubMed - indexed for MEDLINE]
11:
Milivojevic N, Krisch I, Sket D, Zivin M.
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reinstatement of cocaine-seeking in rats.
Naunyn Schmiedebergs Arch Pharmacol. 2004 Jun;369(6):576-82. Epub 2004 May 7.
PMID: 15138661 [PubMed - indexed for MEDLINE]
12:
Cohen PJ.
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Immunization for prevention and treatment of cocaine abuse: legal and ethical implications.
Drug Alcohol Depend. 1997 Dec 15;48(3):167-74.
PMID: 9449015 [PubMed - indexed for MEDLINE]
13:
Carrera MR, Meijler MM, Janda KD.
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Cocaine pharmacology and current pharmacotherapies for its abuse.
Bioorg Med Chem. 2004 Oct 1;12(19):5019-30. Review.
PMID: 15351386 [PubMed - indexed for MEDLINE]
14:
[No authors listed]
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A shot against cocaine addiction.
Lab Anim (NY). 2001 Apr;30(4):12-3. No abstract available.
PMID: 11385738 [PubMed - indexed for MEDLINE]
15:
Schabacker DS, Kirschbaum KS, Segre M.
Related Articles, Links
Exploring the feasibility of an anti-idiotypic cocaine vaccine: analysis of the specificity of
anticocaine antibodies (Ab1) capable of inducing Ab2beta anti-idiotypic antibodies.
Immunology. 2000 May;100(1):48-56.
PMID: 10809958 [PubMed - indexed for MEDLINE]
16:
Martell BA, Mitchell E, Poling J, Gonsai K, Kosten TR.
Related Articles, Links
Vaccine pharmacotherapy for the treatment of cocaine dependence.
Biol Psychiatry. 2005 Jul 15;58(2):158-64.
PMID: 16038686 [PubMed - indexed for MEDLINE]
1: Biol Psychiatry. 2005 Jul 15;58(2):158-64.
Links
Vaccine pharmacotherapy for the treatment of cocaine
dependence.
Martell BA, Mitchell E, Poling J, Gonsai K, Kosten TR.
Section of General Internal Medicine, Yale University School of Medicine, New
Haven, Connecticut, USA. [email protected]
BACKGROUND: Cocaine abuse has no established pharmacotherapy, but active
immunotherapy with a cocaine vaccine shows promise as a therapeutic
intervention. METHODS: An open label, fourteen week, dose-escalation study
evaluated the safety, immunogenicity, and clinical efficacy of a novel human
cocaine vaccine (TA-CD) in eighteen cocaine dependent subjects. Ten subjects
(400 microg total dose group) received four-100 microg injections over the
course of eight weeks. Subsequently, eight subjects (2000 microg total dose
group) received five-400 microg vaccinations over twelve weeks. Intent to treat
analysis of thrice weekly urine toxicologies and cocaine antibody titers were
compared. RESULTS: Sixteen of 18 subjects completed the study. There were no
serious adverse reactions and the vaccine was well tolerated. The 2000 microg
total dose group had a significantly higher mean antibody titer response (2000
units) as compared to the 400 microg total dose group (1000 units) (p = .05). The
2000 microg group was more likely to maintain cocaine free urines than those in
the 400 microg group (Z = -3.12, p = .002). Despite relapse in both groups, most
reported an attenuation of cocaine's usual euphoric effects at the six month
follow-up time points (63% in the 400 microg and 100% in the 2000 microg
groups). CONCLUSIONS: The conjugated cocaine vaccine was well tolerated
and cocaine specific antibodies persisted at least six months. The likelihood of
using cocaine decreased in subjects who received the more intense vaccination
schedule.
PMID: 16038686 [PubMed - indexed for MEDLINE]
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Ther. 2003]
Immunogenicity and reactogenicity of a novel vaccine for human papillomavirus
16: a 2-year randomized controlled clinical trial. [Mayo Clin Proc. 2005]
Therapeutic vaccines for substance dependence. [Expert Rev Vaccines. 2002]
See all Related Articles...
17:
Gorelick DA, Gardner EL, Xi ZX.
Related Articles, Links
Agents in development for the management of cocaine abuse.
Drugs. 2004;64(14):1547-73. Review.
PMID: 15233592 [PubMed - indexed for MEDLINE]
18:
Doron R, Fridman L, Gispan-Herman I, Maayan R, Weizman A, Yadid G.
Related Articles, Links
DHEA, a neurosteroid, decreases cocaine self-administration and reinstatement of cocaineseeking behavior in rats.
Neuropsychopharmacology. 2006 Oct;31(10):2231-6. Epub 2006 Jan 18.
PMID: 16421515 [PubMed - indexed for MEDLINE]
19:
Wise RA, Ranaldi R.
Cocaine vaccines revisited.
Nat Med. 1996 Oct;2(10):1073-4. No abstract available.
PMID: 8837598 [PubMed - indexed for MEDLINE]
Related Articles, Links
20:
Green-Sadan T, Kuttner Y, Lublin-Tennenbaum T, Kinor N, Boguslavsky Y,
Margel S, Yadid G.
Related Articles, Links
Glial cell line-derived neurotrophic factor-conjugated nanoparticles suppress acquisition of
cocaine self-administration in rats.
Exp Neurol. 2005 Jul;194(1):97-105.
PMID: 15899247 [PubMed - indexed for MEDLINE]
1: Exp Neurol. 2005 Jul;194(1):97-105.
Links
Glial cell line-derived neurotrophic factor-conjugated
nanoparticles suppress acquisition of cocaine selfadministration in rats.
Green-Sadan T, Kuttner Y, Lublin-Tennenbaum T, Kinor N, Boguslavsky Y, Margel S,
Yadid G.
Neuropharmacology Laboratory, Faculty of Life Sciences and the Leslie and
Susan Gonda (Goldshmied) Multidisciplinary Brain Research Center, Bar-Ilan
University, Ramat-Gan, Israel.
The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) may
have therapeutic potential for preventing and treating cocaine addiction.
Previously, we found that transplantation of a GDNF-expressing astrocyte cell
line into the striatum and nucleus accumbens attenuates cocaine-seeking behavior
in Sprague-Dawley rats. However, as a potential treatment for humans, cell
transplantation presents several technical and ethical complications.
Nanoparticulate systems are a safe and effective method for introducing
exogenous compounds into the brain. Therefore, we examined the effect of
GDNF-conjugated nanoparticles microinjected into the striatum and nucleus
accumbens on cocaine self-administration in rats. GDNF-conjugated
nanoparticles blocked the acquisition of cocaine self-administration compared to
control treatments. Furthermore, a cocaine dose response demonstrated that
decreased lever response in rats that received GDNF-conjugated nanoparticles
persisted after substitution with different cocaine doses. This effect is not due to a
non-specific disruption of locomotor or operant behavior, as seen following a
water operant task. The current study is one of the first demonstrations that drugconjugated nanoparticles may be effective in treating brain disorders. These
findings suggest that GDNF-conjugated nanoparticles may serve as a novel
potential treatment for drug addiction.
PMID: 15899247 [PubMed - indexed for MEDLINE]
Related Links





Transplantation of glial cell line-derived neurotrophic factor-expressing cells
into the striatum and nucleus accumbens attenuates acquisition of cocaine selfadministration in rats. [Eur J Neurosci. 2003]
Antisense-induced reduction in nucleus accumbens cyclic AMP response
element binding protein attenuates cocaine reinforcement. [Neuroscience.
2006]
Administration of the D2 dopamine receptor antagonist sulpiride into the shell,
but not the core, of the nucleus accumbens attenuates cocaine priminginduced reinstatement of drug seeking. [Neuropsychopharmacology. 2006]
Influence of neurotrophic factors on morphine- and cocaine-induced
biochemical changes in the mesolimbic dopamine system. [Neuroscience. 1995]
Time-dependent increases in brain-derived neurotrophic factor protein levels
within the mesolimbic dopamine system after withdrawal from cocaine:
implications for incubation of cocaine craving. [J Neurosci. 2003]
See all Related Articles...
Items 21 - 40 of 116
21:
Previous Page
2
Vorel SR, Ashby CR Jr, Paul M, Liu X, Hayes R, Hagan JJ, Middlemiss DN, Stemp G,
Gardner EL.
of 6 Next
Related Articles,
Links
Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward
in rats.
J Neurosci. 2002 Nov 1;22(21):9595-603.
PMID: 12417684 [PubMed - indexed for MEDLINE]
22:
Platt DM, Rowlett JK, Spealman RD.
Related Articles, Links
Behavioral effects of cocaine and dopaminergic strategies for preclinical medication
development.
Psychopharmacology (Berl). 2002 Oct;163(3-4):265-82. Epub 2002 Jul 17. Review.
PMID: 12373428 [PubMed - indexed for MEDLINE]
23:
Morgan D, Roberts DC.
Related Articles, Links
Sensitization to the reinforcing effects of cocaine following binge-abstinent self-administration.
Neurosci Biobehav Rev. 2004 Jan;27(8):803-12. Review.
PMID: 15019429 [PubMed - indexed for MEDLINE]
24:
Szumlinski KK, McCafferty CA, Maisonneuve IM, Glick SD.
Related Articles, Links
Interactions between 18-methoxycoronaridine (18-MC) and cocaine: dissociation of behavioural
and neurochemical sensitization.
Brain Res. 2000 Jul 21;871(2):245-58.
PMID: 10899291 [PubMed - indexed for MEDLINE]
25:
Schenk S.
Related Articles, Links
Effects of GBR 12909, WIN 35,428 and indatraline on cocaine self-administration and cocaine
seeking in rats.
Psychopharmacology (Berl). 2002 Mar;160(3):263-70. Epub 2002 Jan 24.
PMID: 11889495 [PubMed - indexed for MEDLINE]
26:
Bunce CJ, Loudon PT, Akers C, Dobson J, Wood DM.
Related Articles, Links
Development of vaccines to help treat drug dependence.
Curr Opin Mol Ther. 2003 Feb;5(1):58-63. Review.
PMID: 12669472 [PubMed - indexed for MEDLINE]
1: Curr Opin Mol Ther. 2003 Feb;5(1):58-63. Links
Development of vaccines to help treat drug
dependence.
Bunce CJ, Loudon PT, Akers C, Dobson J, Wood DM.
Xenova Research Ltd, 310 Cambridge Science Park, Cambridge, CB4 0WG, UK.
[email protected]
The social and economic consequences of drug addiction are immense. Although
many methods are adopted to treat addiction, including therapeutic intervention
and counseling, the long-term success rate has been limited and there continues to
be a need for more effective treatments. A novel approach that has sparked a
significant degree of interest recently is the use of vaccines designed to raise
specific antibodies against drugs of abuse. Antibodies that prevent addictive
substances crossing the blood-brain barrier may prove to be an effective
mechanism that will help prevent relapse during efforts to abstain from the drug.
Proof-of-principle for this approach has been established in numerous animal
models. Currently a cocaine vaccine is in phase II clinical trials and, more
recently, two vaccines to nicotine have entered phase I trials. Key efficacy trials
are required to establish the true potential of these therapeutic vaccines.
PMID: 12669472 [PubMed - indexed for MEDLINE]
Related Links





Vaccines against drugs of abuse: a viable treatment option? [Drugs. 2003]
Therapeutic vaccines for substance dependence. [Expert Rev Vaccines. 2002]
Development of immunopharmacotherapy against drugs of abuse. [Curr Drug
Discov Technol. 2004]
Therapeutic vaccines for substance dependence. [Expert Rev Vaccines. 2004]
Ethical issues in using a cocaine vaccine to treat and prevent cocaine abuse and
dependence. [J Med Ethics. 2004]
See all Related Articles...
27:
Koetzner L, Deng S, Sumpter TL, Weisslitz M, Abner RT, Landry DW, Woods JH.
Related Articles, Links
Titer-dependent antagonism of cocaine following active immunization in rhesus monkeys.
J Pharmacol Exp Ther. 2001 Mar;296(3):789-96.
PMID: 11181908 [PubMed - indexed for MEDLINE]
28:
Landry DW, Yang GX.
Related Articles, Links
Anti-cocaine catalytic antibodies--a novel approach to the problem of addiction.
J Addict Dis. 1997;16(3):1-17. Review.
PMID: 9243335 [PubMed - indexed for MEDLINE]
29:
Stromberg MF, Mackler SA, Volpicelli JR, O'Brien CP, Dewey SL.
Related Articles, Links
The effect of gamma-vinyl-GABA on the consumption of concurrently available oral cocaine and
ethanol in the rat.
Pharmacol Biochem Behav. 2001 Feb;68(2):291-9.
PMID: 11267634 [PubMed - indexed for MEDLINE]
30:
Howell LL, Wilcox KM.
Related Articles, Links
The dopamine transporter and cocaine medication development: drug self-administration in
nonhuman primates.
J Pharmacol Exp Ther. 2001 Jul;298(1):1-6. Review.
PMID: 11408518 [PubMed - indexed for MEDLINE]
31:
Schenk S, Partridge B, Shippenberg TS.
Related Articles, Links
U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaineproduced drug-seeking.
Psychopharmacology (Berl). 1999 Jun;144(4):339-46.
PMID: 10435406 [PubMed - indexed for MEDLINE]
32:
Gorelick DA.
Related Articles, Links
Enhancing cocaine metabolism with butyrylcholinesterase as a treatment strategy.
Drug Alcohol Depend. 1997 Dec 15;48(3):159-65. Review.
PMID: 9449014 [PubMed - indexed for MEDLINE]
33:
Schenk S, Partridge B, Shippenberg TS.
Related Articles, Links
Effects of the kappa-opioid receptor agonist, U69593, on the development of sensitization and
on the maintenance of cocaine self-administration.
Neuropsychopharmacology. 2001 Apr;24(4):441-50.
PMID: 11182539 [PubMed - indexed for MEDLINE]
34:
Bagasra O, Forman LJ, Howeedy A, Whittle P.
Related Articles, Links
A potential vaccine for cocaine abuse prophylaxis.
Immunopharmacology. 1992 May-Jun;23(3):173-9.
PMID: 1500284 [PubMed - indexed for MEDLINE]
35:
Maayan R, Lotan S, Doron R, Shabat-Simon M, Gispan-Herman I, Weizman A,
Yadid G.
Related Articles, Links
Dehydroepiandrosterone (DHEA) attenuates cocaine-seeking behavior in the self-administration
model in rats.
Eur Neuropsychopharmacol. 2006 Jul;16(5):329-39. Epub 2005 Nov 23.
PMID: 16309898 [PubMed - indexed for MEDLINE]
36:
Sofuoglu M, Kosten TR.
Related Articles, Links
Emerging pharmacological strategies in the fight against cocaine addiction.
Expert Opin Emerg Drugs. 2006 Mar;11(1):91-8. Review.
PMID: 16503828 [PubMed - indexed for MEDLINE]
1: Expert Opin Emerg Drugs. 2006 Mar;11(1):91-8.
Links
Emerging pharmacological strategies in the fight
against cocaine addiction.
Sofuoglu M, Kosten TR.
Department of Psychiatry, VA Connecticut Healthcare System, Yale University,
School of Medicine, West Haven, CT 06516, USA. [email protected]
Cocaine addiction continues to be an important public health problem worldwide.
At present, there are no proven pharmacotherapies for cocaine addiction. The
studies reviewed here revealed a number of emerging targets for cocaine
pharmacotherapy. First, disulfiram, a medication with dopaminergic effects,
reduced cocaine use in a number of clinical trials. Second, GABA medications,
tiagabine and topiramate, were found promising in clinical trials. Third, a betaadrenergic blocker, propranolol, may be effective especially among cocaineaddicted individuals with high withdrawal severity. Fourth, treatment with a
stimulant medication, modafinil, has reduced cocaine use. Last, a cocaine vaccine
that slows entry of cocaine into the brain holds promise. These promising
findings need to be further tested in controlled clinical trials.
PMID: 16503828 [PubMed - indexed for MEDLINE]
Related Links





Novel approaches to the treatment of cocaine addiction. [CNS Drugs. 2005]
Agents in development for the management of cocaine abuse. [Drugs. 2004]
Behavioral effects of cocaine and dopaminergic strategies for preclinical
medication development. [Psychopharmacology (Berl). 2002]
Glutamatergic agents for cocaine dependence. [Ann N Y Acad Sci. 2003]
A novel strategy for the treatment of cocaine addiction. [Synapse. 1998]
See all Related Articles...
37:
Deroche-Gamonet V, Sillaber I, Aouizerate B, Izawa R, Jaber M, Ghozland S,
Kellendonk C, Le Moal M, Spanagel R, Schutz G, Tronche F, Piazza PV.
Related Articles,
Links
The glucocorticoid receptor as a potential target to reduce cocaine abuse.
J Neurosci. 2003 Jun 1;23(11):4785-90.
PMID: 12805318 [PubMed - indexed for MEDLINE]
38:
Weiss F, Ciccocioppo R, Parsons LH, Katner S, Liu X, Zorrilla EP, Valdez GR, BenShahar O, Angeletti S, Richter RR.
Related Articles,
Links
Compulsive drug-seeking behavior and relapse. Neuroadaptation, stress, and conditioning
factors.
Ann N Y Acad Sci. 2001 Jun;937:1-26. Review.
PMID: 11458532 [PubMed - indexed for MEDLINE]
39:
Rothman RB, Elmer GI, Shippenberg TS, Rea W, Baumann MH.
Related Articles, Links
Phentermine and fenfluramine. Preclinical studies in animal models of cocaine addiction.
Ann N Y Acad Sci. 1998 May 30;844:59-74.
PMID: 9668665 [PubMed - indexed for MEDLINE]
40:
Self DW, Karanian DA, Spencer JJ.
Related Articles, Links
Effects of the novel D1 dopamine receptor agonist ABT-431 on cocaine self-administration and
reinstatement.
Ann N Y Acad Sci. 2000;909:133-44.
PMID: 10911927 [PubMed - indexed for MEDLINE]
Items 41 - 60 of 116
41:
Previous Page
3
Orsini C, Izzo E, Koob GF, Pulvirenti L.
of 6 Next
Related Articles, Links
Blockade of nitric oxide synthesis reduces responding for cocaine self-administration during
extinction and reinstatement.
Brain Res. 2002 Jan 25;925(2):133-40.
PMID: 11792361 [PubMed - indexed for MEDLINE]
42:
Dickerson TJ, Janda KD.
Related Articles, Links
Recent advances for the treatment of cocaine abuse: central nervous system
immunopharmacotherapy.
AAPS J. 2005 Oct 19;7(3):E579-86. Review.
PMID: 16353936 [PubMed - indexed for MEDLINE]
1: AAPS J. 2005 Oct 19;7(3):E579-86.
Links
Recent advances for the treatment of cocaine abuse:
central nervous system immunopharmacotherapy.
Dickerson TJ, Janda KD.
The Skaggs Institute for Chemical Biology and Department of Chemistry, The
Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037,
USA.
Cocaine addiction continues to be a major health and societal problem in spite of
governmental efforts devoted toward educating the public of the dangers of illicit
drug use. A variety of pharmacotherapies and psychosocial programs have been
proposed in an effort to provide a method for alleviation of the physical and
psychological symptoms of cocaine abuse. Unfortunately, these methods have
been met with limited success, illustrating a critical need for new effective
approaches for the treatment of cocaine addiction. Recently an alternative cocaine
abuse treatment strategy was proposed using intranasal administration of an
engineered filamentous bacteriophage displaying cocaine-sequestering antibodies
on its surface. These phage particles are an effective vector for CNS penetration
and are capable of binding cocaine, thereby blocking its behavioral effects in a
rodent model. The convergence of phage display and immunopharmacotherapy
has allowed for an investigation of the efficacy of protein-based therapeutics
acting within the CNS on the effects of cocaine in animal models and has
uncovered a new tool in the battle against cocaine addiction.
PMID: 16353936 [PubMed - indexed for MEDLINE]
Related Links


Bacteriophage-mediated protein delivery into the central nervous system and
its application in immunopharmacotherapy. [Expert Opin Biol Ther. 2005]
Treating cocaine addiction with viruses. [Proc Natl Acad Sci U S A. 2004]
1: Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10416-21. Epub 2004 Jun
28.
Links
Comment in:
Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11193-4.
Treating cocaine addiction with viruses.
Carrera MR, Kaufmann GF, Mee JM, Meijler MM, Koob GF, Janda KD.
Department of Chemistry, The Skaggs Institute for Chemical Biology, The
Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037,
USA.
Cocaine addiction continues to be a major health and social problem in the
United States and other countries. Currently used pharmacological agents for
treating cocaine abuse have proved inadequate, leaving few treatment options. An
alternative is to use protein-based therapeutics that can eliminate the load of
cocaine, thereby attenuating its effects. This approach is especially attractive
because the therapeutic agents exert no pharmacodynamic action of their own and
therefore have little potential for side effects. The effectiveness of these agents,
however, is limited by their inability to act directly within the CNS.
Bacteriophage have the capacity to penetrate the CNS when administered
intranasally. Here, a method is presented for engineering filamentous
bacteriophage to display cocaine-binding proteins on its surface that sequester
cocaine in the brain. These antibody-displaying constructs were examined by
using a locomotor activity rodent model to assess the ability of the phagedisplayed proteins to block the psychoactive effects of cocaine. Results presented
demonstrate a strategy in the continuing efforts to find effective treatments for
cocaine addiction and suggest the application of this protein-based treatment for
other drug abuse syndromes.




Development of immunopharmacotherapy against drugs of abuse. [Curr Drug
Discov Technol. 2004]
Cocaine pharmacology and current pharmacotherapies for its abuse. [Bioorg
Med Chem. 2004]
Novel approaches to the treatment of cocaine addiction. [CNS Drugs. 2005]
See all Related Articles...
Expert Opin Biol Ther. 2005 Jun;5(6):773-81.
Links
Bacteriophage-mediated protein delivery into the
central nervous system and its application in
immunopharmacotherapy.
Dickerson TJ, Kaufmann GF, Janda KD.
Department of Chemistry, The Skaggs Institute for Chemical Biology, The
Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037,
USA.
Cocaine addiction continues to be a major health and social problem in spite of
governmental efforts devoted towards educating the public in the dangers of
illicit drug use. A variety of pharmacotherapies and psychosocial programmes
have been proposed in an effort to provide a method for alleviating the physical
and psychological symptoms of cocaine abuse. Unfortunately, these methods
have been met with limited success, illustrating a critical need for new effective
approaches for the treatment of cocaine addiction. The authors have recently
disclosed an alternative cocaine abuse treatment strategy using intranasal
administration of an engineered filamentous bacteriophage displaying cocainesequestering antibodies on its surface. These phage particles are an effective
vector for central nervous system penetration and are capable of binding cocaine,
thereby blocking its behavioural effects in a rodent model.
PMID: 15952908 [PubMed - indexed for MEDLINE]
Related Links





Recent advances for the treatment of cocaine abuse: central nervous system
immunopharmacotherapy. [AAPS J. 2005]
Treating cocaine addiction with viruses. [Proc Natl Acad Sci U S A. 2004]
Cocaine pharmacology and current pharmacotherapies for its abuse. [Bioorg
Med Chem. 2004]
Anticocaine catalytic antibodies. [J Immunol Methods. 2002]
Application of artificial enzymes to the problem of cocaine. [Ann N Y Acad Sci.
2000]
See all Related Articles...
43:
Deng SX, de Prada P, Landry DW.
Related Articles, Links
Anticocaine catalytic antibodies.
J Immunol Methods. 2002 Nov 1;269(1-2):299-310. Review.
PMID: 12379369 [PubMed - indexed for MEDLINE]
44:
Liu Y, Roberts DC, Morgan D.
Related Articles, Links
Sensitization of the reinforcing effects of self-administered cocaine in rats: effects of dose and
intravenous injection speed.
Eur J Neurosci. 2005 Jul;22(1):195-200.
PMID: 16029209 [PubMed - indexed for MEDLINE]
45:
Xi ZX, Gilbert JG, Pak AC, Ashby CR Jr, Heidbreder CA, Gardner EL.
Related Articles, Links
Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement
as assessed by progressive-ratio and variable-cost-variable-payoff fixed-ratio cocaine selfadministration in rats.
Eur J Neurosci. 2005 Jun;21(12):3427-38.
PMID: 16026480 [PubMed - indexed for MEDLINE]
46:
Nader MA, Czoty PW.
Related Articles, Links
PET imaging of dopamine D2 receptors in monkey models of cocaine abuse: genetic
predisposition versus environmental modulation.
Am J Psychiatry. 2005 Aug;162(8):1473-82. Review.
PMID: 16055768 [PubMed - indexed for MEDLINE]
47:
Kosten TR, Rosen M, Bond J, Settles M, Roberts JS, Shields J, Jack L, Fox B.
Related Articles, Links
Human therapeutic cocaine vaccine: safety and immunogenicity.
Vaccine. 2002 Jan 15;20(7-8):1196-204.
PMID: 11803082 [PubMed - indexed for MEDLINE]
48:
Dewey SL, Morgan AE, Ashby CR Jr, Horan B, Kushner SA, Logan J, Volkow ND,
Fowler JS, Gardner EL, Brodie JD.
Related Articles,
Links
A novel strategy for the treatment of cocaine addiction.
Synapse. 1998 Oct;30(2):119-29.
PMID: 9723781 [PubMed - indexed for MEDLINE]
49:
Davidson C, Lee TH, Xiong Z, Ellinwood EH.
Related Articles, Links
Ondansetron given in the acute withdrawal from a repeated cocaine sensitization dosing
regimen reverses the expression of sensitization and inhibits self-administration.
Neuropsychopharmacology. 2002 Oct;27(4):542-53.
PMID: 12377391 [PubMed - indexed for MEDLINE]
50:
Choi KH, Whisler K, Graham DL, Self DW.
Related Articles, Links
Antisense-induced reduction in nucleus accumbens cyclic AMP response element binding
protein attenuates cocaine reinforcement.
Neuroscience. 2006;137(2):373-83. Epub 2005 Dec 15.
PMID: 16359811 [PubMed - indexed for MEDLINE]
51:
Collins SL, Kantak KM.
Related Articles, Links
Neuronal nitric oxide synthase inhibition decreases cocaine self-administration behavior in rats.
Psychopharmacology (Berl). 2002 Feb;159(4):361-9. Epub 2001 Nov 20.
PMID: 11823888 [PubMed - indexed for MEDLINE]
52:
McCracken CB, Hamby SM, Patel KM, Morgan D, Vrana KE, Roberts DC.
Related Articles, Links
Extended cocaine self-administration and deprivation produces region-specific and timedependent changes in connexin36 expression in rat brain.
Synapse. 2005 Dec 1;58(3):141-50.
PMID: 16138316 [PubMed - indexed for MEDLINE]
53:
De Prada P, Winger G, Landry DW.
Related Articles, Links
Application of artificial enzymes to the problem of cocaine.
Ann N Y Acad Sci. 2000;909:159-69. Review.
PMID: 10911929 [PubMed - indexed for MEDLINE]
54:
Raje S, Cornish J, Newman AH, Cao J, Katz JL, Eddington ND.
Related Articles, Links
Investigation of the potential pharmacokinetic and pharmaco-dynamic drug interaction
between AHN 1-055, a potent benztropine analog used for cocaine abuse, and cocaine after
dosing in rats using intracerebral microdialysis.
Biopharm Drug Dispos. 2006 Jul;27(5):229-40.
PMID: 16586462 [PubMed - indexed for MEDLINE]
55:
Kuhar MJ, Carroll FI, Bharat N, Landry DW.
Related Articles, Links
Anticocaine catalytic antibodies have no affinity for RTI compounds: implications for treatment.
Synapse. 2001 Aug;41(2):176-8.
PMID: 11400184 [PubMed - indexed for MEDLINE]
56:
Kiyatkin EA, Brown PL.
Related Articles, Links
Brain temperature fluctuations during passive vs. active cocaine administration: clues for
understanding the pharmacological determination of drug-taking behavior.
Brain Res. 2004 Apr 16;1005(1-2):101-16.
PMID: 15044070 [PubMed - indexed for MEDLINE]
57:
Mantsch JR, Yuferov V, Mathieu-Kia AM, Ho A, Kreek MJ.
Related Articles, Links
Effects of extended access to high versus low cocaine doses on self-administration, cocaineinduced reinstatement and brain mRNA levels in rats.
Psychopharmacology (Berl). 2004 Aug;175(1):26-36. Epub 2004 Mar 20.
PMID: 15042275 [PubMed - indexed for MEDLINE]
58:
Carrera MR, Ashley JA, Wirsching P, Koob GF, Janda KD.
Related Articles, Links
A second-generation vaccine protects against the psychoactive effects of cocaine.
Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1988-92. Epub 2001 Feb 6.
PMID: 11172063 [PubMed - indexed for MEDLINE]
59:
McCance-Katz E, Sevarino K, Gottschalk PC, Kosten T.
Related Articles, Links
Pharmacotherapy of stimulant dependence: one of Japan's greatest public health challenges.
Nihon Shinkei Seishin Yakurigaku Zasshi. 1999 Oct;19(4):159-86. Review.
PMID: 10637824 [PubMed - indexed for MEDLINE]
60:
Garcia-Ladona FJ, Cox BF.
Related Articles, Links
BP 897, a selective dopamine D3 receptor ligand with therapeutic potential for the treatment of
cocaine-addiction.
CNS Drug Rev. 2003 Summer;9(2):141-58. Review.
PMID: 12847556 [PubMed - indexed for MEDLINE]
Items 61 - 80 of 116
61:
Previous Page
4
of 6 Next
Klein M.
Related Articles, Links
Research issues related to development of medications for treatment of cocaine addiction.
Ann N Y Acad Sci. 1998 May 30;844:75-91. Review.
PMID: 9668666 [PubMed - indexed for MEDLINE]
62:
Leri F, Tremblay A, Sorge RE, Stewart J.
Related Articles, Links
Methadone maintenance reduces heroin- and cocaine-induced relapse without affecting stressinduced relapse in a rodent model of poly-drug use.
Neuropsychopharmacology. 2004 Jul;29(7):1312-20.
PMID: 15039768 [PubMed - indexed for MEDLINE]
63:
Fattore L, Martellotta MC, Cossu G, Mascia MS, Fratta W.
Related Articles, Links
CB1 cannabinoid receptor agonist WIN 55,212-2 decreases intravenous cocaine selfadministration in rats.
Behav Brain Res. 1999 Oct;104(1-2):141-6.
PMID: 11125733 [PubMed - indexed for MEDLINE]
64:
Roberts DC.
Related Articles, Links
Preclinical evidence for GABAB agonists as a pharmacotherapy for cocaine addiction.
Physiol Behav. 2005 Sep 15;86(1-2):18-20. Review.
PMID: 16061264 [PubMed - indexed for MEDLINE]
65:
Mets B, Winger G, Cabrera C, Seo S, Jamdar S, Yang G, Zhao K, Briscoe RJ, Almonte
R, Woods JH, Landry DW.
Related Articles,
A catalytic antibody against cocaine prevents cocaine's reinforcing and toxic effects in rats.
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10176-81.
Links
PMID: 9707620 [PubMed - indexed for MEDLINE]
66:
Sarnyai Z.
Related Articles, Links
Oxytocin and neuroadaptation to cocaine.
Prog Brain Res. 1998;119:449-66. Review.
PMID: 10074806 [PubMed - indexed for MEDLINE]
67:
Soria G, Castane A, Ledent C, Parmentier M, Maldonado R, Valverde O.
Related Articles, Links
The lack of A2A adenosine receptors diminishes the reinforcing efficacy of cocaine.
Neuropsychopharmacology. 2006 May;31(5):978-87.
PMID: 16123743 [PubMed - indexed for MEDLINE]
68:
Le Foll B, Schwartz JC, Sokoloff P.
Related Articles, Links
Dopamine D3 receptor agents as potential new medications for drug addiction.
Eur Psychiatry. 2000 Mar;15(2):140-6.
PMID: 10881212 [PubMed - indexed for MEDLINE]
69:
Rocha BA, Goulding EH, O'Dell LE, Mead AN, Coufal NG, Parsons LH, Tecott
LH.
Related Articles, Links
Enhanced locomotor, reinforcing, and neurochemical effects of cocaine in serotonin 5hydroxytryptamine 2C receptor mutant mice.
J Neurosci. 2002 Nov 15;22(22):10039-45.
PMID: 12427861 [PubMed - indexed for MEDLINE]
70:
Self DW, Genova LM, Hope BT, Barnhart WJ, Spencer JJ, Nestler EJ.
Related Articles, Links
Involvement of cAMP-dependent protein kinase in the nucleus accumbens in cocaine selfadministration and relapse of cocaine-seeking behavior.
J Neurosci. 1998 Mar 1;18(5):1848-59.
PMID: 9465009 [PubMed - indexed for MEDLINE]
71:
Campiani G, Butini S, Trotta F, Fattorusso C, Catalanotti B, Aiello F, Gemma S, Nacci
Related Articles,
Links
V, Novellino E, Stark JA, Cagnotto A, Fumagalli E, Carnovali F, Cervo L, Mennini T.
Synthesis and pharmacological evaluation of potent and highly selective D3 receptor ligands:
inhibition of cocaine-seeking behavior and the role of dopamine D3/D2 receptors.
J Med Chem. 2003 Aug 28;46(18):3822-39.
PMID: 12930145 [PubMed - indexed for MEDLINE]
72:
Matsushita M, Hoffman TZ, Ashley JA, Zhou B, Wirsching P, Janda KD.
Related Articles, Links
Cocaine catalytic antibodies: the primary importance of linker effects.
Bioorg Med Chem Lett. 2001 Jan 22;11(2):87-90.
PMID: 11206477 [PubMed - indexed for MEDLINE]
73:
Koeltzow TE, Vezina P.
Related Articles, Links
Locomotor activity and cocaine-seeking behavior during acquisition and reinstatement of
operant self-administration behavior in rats.
Behav Brain Res. 2005 May 28;160(2):250-9. Epub 2005 Jan 12.
PMID: 15863221 [PubMed - indexed for MEDLINE]
74:
Kantak KM.
Related Articles, Links
Vaccines against drugs of abuse: a viable treatment option?
Drugs. 2003;63(4):341-52. Review.
PMID: 12558457 [PubMed - indexed for MEDLINE]
75:
Lasaro MO, Luiz WB, Sbrogio-Almeida ME, Ferreira LC.
Related Articles, Links
Prime-boost vaccine regimen confers protective immunity to human-derived enterotoxigenic
Escherichia coli.
Vaccine. 2005 Mar 31;23(19):2430-8.
PMID: 15752829 [PubMed - indexed for MEDLINE]
76:
Maurice T, Martin-Fardon R, Romieu P, Matsumoto RR.
Related Articles, Links
Sigma(1) (sigma(1)) receptor antagonists represent a new strategy against cocaine addiction
and toxicity.
Neurosci Biobehav Rev. 2002 Jun;26(4):499-527. Review.
PMID: 12204195 [PubMed - indexed for MEDLINE]
77:
Dickerson TJ, Kaufmann GF, Janda KD.
Related Articles, Links
Bacteriophage-mediated protein delivery into the central nervous system and its application in
immunopharmacotherapy.
Expert Opin Biol Ther. 2005 Jun;5(6):773-81. Review.
PMID: 15952908 [PubMed - indexed for MEDLINE]
78:
Sofuoglu M, Kosten TR.
Related Articles, Links
Novel approaches to the treatment of cocaine addiction.
CNS Drugs. 2005;19(1):13-25. Review.
PMID: 15651902 [PubMed - indexed for MEDLINE]
79:
Samaha AN, Mallet N, Ferguson SM, Gonon F, Robinson TE.
Related Articles, Links
The rate of cocaine administration alters gene regulation and behavioral plasticity: implications
for addiction.
J Neurosci. 2004 Jul 14;24(28):6362-70.
PMID: 15254092 [PubMed - indexed for MEDLINE]
80:
Chambers RA, Self DW.
Related Articles, Links
Motivational responses to natural and drug rewards in rats with neonatal ventral hippocampal
lesions: an animal model of dual diagnosis schizophrenia.
Neuropsychopharmacology. 2002 Dec;27(6):889-905.
PMID: 12464446 [PubMed - indexed for MEDLINE]
Items 81 - 100 of 116
81:
Previous Page
5
of 6 Next
Deroche-Gamonet V, Darnaudery M, Bruins-Slot L, Piat F, Le Moal M, Piazza PV.
Related Articles, Links
Study of the addictive potential of modafinil in naive and cocaine-experienced rats.
Psychopharmacology (Berl). 2002 Jun;161(4):387-95. Epub 2002 Apr 20.
PMID: 12073166 [PubMed - indexed for MEDLINE]
82:
Karila L, Ferreri M, Coscas S, Cottencin O, Benyamina A, Reynaud M.
Related Articles, Links
Self-mutilation induced by cocaine abuse: the pleasure of bleeding.
Presse Med. 2007 Feb;36(2 Pt 1):235-7. Epub 2006 Dec 20.
PMID: 17259032 [PubMed - indexed for MEDLINE]
83:
O'Brien CP.
Related Articles, Links
Anticraving medications for relapse prevention: a possible new class of psychoactive
medications.
Am J Psychiatry. 2005 Aug;162(8):1423-31. Review.
PMID: 16055763 [PubMed - indexed for MEDLINE]
84:
Haney M, Kosten TR.
Related Articles, Links
Therapeutic vaccines for substance dependence.
Expert Rev Vaccines. 2004 Feb;3(1):11-8. Review.
PMID: 14761239 [PubMed - indexed for MEDLINE]
85:
Haile CN, During MJ, Jatlow PI, Kosten TR, Kosten TA.
Related Articles, Links
Disulfiram facilitates the development and expression of locomotor sensitization to cocaine in
rats.
Biol Psychiatry. 2003 Nov 1;54(9):915-21.
PMID: 14573319 [PubMed - indexed for MEDLINE]
86:
Bechtholt AJ, Mark GP.
Related Articles, Links
Enhancement of cocaine-seeking behavior by repeated nicotine exposure in rats.
Psychopharmacology (Berl). 2002 Jul;162(2):178-85. Epub 2002 May 1.
PMID: 12110995 [PubMed - indexed for MEDLINE]
87:
Homberg JR, Arends B, Wardeh G, Raaso HS, Schoffelmeer AN, de Vries TJ.
Related Articles, Links
Individual differences in the effects of serotonergic anxiolytic drugs on the motivation to selfadminister cocaine.
Neuroscience. 2004;128(1):121-30.
PMID: 15450359 [PubMed - indexed for MEDLINE]
88:
Carrera MR, Kaufmann GF, Mee JM, Meijler MM, Koob GF, Janda KD.
Related Articles, Links
Treating cocaine addiction with viruses.
Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10416-21. Epub 2004 Jun 28.
PMID: 15226496 [PubMed - indexed for MEDLINE]
89:
Glick SD, Visker KE, Maisonneuve IM.
Related Articles, Links
Effects of cyclazocine on cocaine self-administration in rats.
Eur J Pharmacol. 1998 Sep 11;357(1):9-14.
PMID: 9788768 [PubMed - indexed for MEDLINE]
90:
Smith MA, Yancey DL, Morgan D, Liu Y, Froestl W, Roberts DC.
Related Articles, Links
Effects of positive allosteric modulators of the GABAB receptor on cocaine self-administration in
rats.
Psychopharmacology (Berl). 2004 Apr;173(1-2):105-11. Epub 2004 Jan 8.
PMID: 14712341 [PubMed - indexed for MEDLINE]
91:
Morgan D, Smith MA, Roberts DC.
Related Articles, Links
Binge self-administration and deprivation produces sensitization to the reinforcing effects of
cocaine in rats.
Psychopharmacology (Berl). 2005 Mar;178(2-3):309-16. Epub 2004 Aug 19.
PMID: 15322729 [PubMed - indexed for MEDLINE]
92:
Anton B, Leff P.
Related Articles, Links
A novel bivalent morphine/heroin vaccine that prevents relapse to heroin addiction in rodents.
Vaccine. 2006 Apr 12;24(16):3232-40. Epub 2006 Feb 8.
PMID: 16494974 [PubMed - indexed for MEDLINE]
93:
Baker DA, Tran-Nguyen TL, Fuchs RA, Neisewander JL.
Related Articles, Links
Influence of individual differences and chronic fluoxetine treatment on cocaine-seeking
behavior in rats.
Psychopharmacology (Berl). 2001 Apr;155(1):18-26.
PMID: 11374332 [PubMed - indexed for MEDLINE]
94:
Colby CR, Whisler K, Steffen C, Nestler EJ, Self DW.
Related Articles, Links
Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine.
J Neurosci. 2003 Mar 15;23(6):2488-93.
PMID: 12657709 [PubMed - indexed for MEDLINE]
95:
LeSage MG, Keyler DE, Hieda Y, Collins G, Burroughs D, Le C, Pentel PR.
Related Articles, Links
Effects of a nicotine conjugate vaccine on the acquisition and maintenance of nicotine selfadministration in rats.
Psychopharmacology (Berl). 2006 Mar;184(3-4):409-16. Epub 2005 Jul 1.
PMID: 15991003 [PubMed - indexed for MEDLINE]
96:
McCarthy LE, Mannelli P, Niculescu M, Gingrich K, Unterwald EM, Ehrlich ME.
Related Articles, Links
The distribution of cocaine in mice differs by age and strain.
Neurotoxicol Teratol. 2004 Nov-Dec;26(6):839-48.
PMID: 15451047 [PubMed - indexed for MEDLINE]
97:
Cornish JL, Kalivas PW.
Related Articles, Links
Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction.
J Neurosci. 2000 Aug 1;20(15):RC89.
PMID: 10899176 [PubMed - indexed for MEDLINE]
98:
Caine SB, Negus SS, Mello NK, Patel S, Bristow L, Kulagowski J, Vallone D, Saiardi
A, Borrelli E.
Related Articles, Links
Role of dopamine D2-like receptors in cocaine self-administration: studies with D2 receptor
mutant mice and novel D2 receptor antagonists.
J Neurosci. 2002 Apr 1;22(7):2977-88.
PMID: 11923462 [PubMed - indexed for MEDLINE]
99:
Sutton MA, Karanian DA, Self DW.
Related Articles, Links
Factors that determine a propensity for cocaine-seeking behavior during abstinence in rats.
Neuropsychopharmacology. 2000 Jun;22(6):626-41.
PMID: 10788762 [PubMed - indexed for MEDLINE]
100:
Placenza FM, Vaccarino FJ, Fletcher PJ, Erb S.
Related Articles, Links
Activation of central neurokinin-1 receptors induces reinstatement of cocaine-seeking
behavior.
Neurosci Lett. 2005 Dec 16;390(1):42-7.
PMID: 16125318 [PubMed - indexed for MEDLINE]
Items 101 - 116 of 116
101:
Previous Page
6
Wickelgren I.
of 6
Related Articles, Links
Teaching the brain to take drugs.
Science. 1998 Jun 26;280(5372):2045-6. No abstract available.
PMID: 9669958 [PubMed - indexed for MEDLINE]
102:
Bowers MS, McFarland K, Lake RW, Peterson YK, Lapish CC, Gregory ML, Lanier
SM, Kalivas PW.
Related Articles,
Links
Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking.
Neuron. 2004 Apr 22;42(2):269-81.
PMID: 15091342 [PubMed - indexed for MEDLINE]
103:
Shalev U, Grimm JW, Shaham Y.
Neurobiology of relapse to heroin and cocaine seeking: a review.
Pharmacol Rev. 2002 Mar;54(1):1-42. Review.
Related Articles, Links
PMID: 11870259 [PubMed - indexed for MEDLINE]
104:
Samaha AN, Li Y, Robinson TE.
Related Articles, Links
The rate of intravenous cocaine administration determines susceptibility to sensitization.
J Neurosci. 2002 Apr 15;22(8):3244-50.
PMID: 11943825 [PubMed - indexed for MEDLINE]
105:
Kruzich PJ, Grimm JW, Rustay NR, Parks CD, See RE.
Related Articles, Links
Predicting relapse to cocaine-seeking behavior: a multiple regression approach.
Behav Pharmacol. 1999 Sep;10(5):513-21.
PMID: 10780257 [PubMed - indexed for MEDLINE]
106:
Ettinger RH, Ettinger WF, Harless WE.
Related Articles, Links
Active immunization with cocaine-protein conjugate attenuates cocaine effects.
Pharmacol Biochem Behav. 1997 Sep;58(1):215-20.
PMID: 9264094 [PubMed - indexed for MEDLINE]
107:
Kreek MJ.
Related Articles, Links
Opiate and cocaine addictions: challenge for pharmacotherapies.
Pharmacol Biochem Behav. 1997 Jul;57(3):551-69. Review.
PMID: 9218280 [PubMed - indexed for MEDLINE]
108:
Carrera MR, Ashley JA, Parsons LH, Wirsching P, Koob GF, Janda KD.
Related Articles, Links
Suppression of psychoactive effects of cocaine by active immunization.
Nature. 1995 Dec 14;378(6558):727-30.
PMID: 7501020 [PubMed - indexed for MEDLINE]
109:
Wiesbeck G, Dursteler-MacFarland K.
[New developments in the pharmacotherapy of cocaine dependence]
Nervenarzt. 2006 Sep;77(9):1064, 1066-70. Review. German.
Related Articles, Links
PMID: 16425053 [PubMed - indexed for MEDLINE]
110:
Gallacher G.
Related Articles, Links
A potential vaccine for cocaine abuse prophylaxis?
Immunopharmacology. 1994 Jan-Feb;27(1):79-84.
PMID: 8206756 [PubMed - indexed for MEDLINE]
111:
Brower KJ.
Related Articles, Links
Self-medication of migraine headaches with freebase cocaine.
J Subst Abuse Treat. 1988;5(1):23-6.
PMID: 3361623 [PubMed - indexed for MEDLINE]
112:
Slusher BS, Jackson PF.
Related Articles, Links
A shot in the arm for cocaine addiction.
Nat Med. 1996 Jan;2(1):26-7. Review.
PMID: 8564829 [PubMed - indexed for MEDLINE]
113:
[No authors listed]
Related Articles, Links
Addictions. Can an anti-seizure drug assist recovery from cocaine and crystal meth addiction?
TreatmentUpdate. 2005 Mar;17(2):5-6. No abstract available.
PMID: 17228465 [PubMed - indexed for MEDLINE]
114:
Landry DW.
Related Articles, Links
Immunotherapy for cocaine addiction.
Sci Am. 1997 Feb;276(2):42-5. No abstract available.
PMID: 9000762 [PubMed - indexed for MEDLINE]
115:
Self DW.
Drug addiction. Cocaine abuse takes a shot.
Nature. 1995 Dec 14;378(6558):666-7. No abstract available.
Related Articles, Links
PMID: 7501009 [PubMed - indexed for MEDLINE]
116:
Intini C, Casazza AM.
Related Articles, Links
Experimental studies on the activity of a new antitrachoma vaccine in mice.
Rev Int Trach. 1968;45(1):58-63. No abstract available.
PMID: 5709711 [PubMed - indexed for MEDLINE]