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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 next article > | View Table of Contents Key: - Free content - New Content - Subscribed Content - Free Trial Content 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: 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 Advertisement Advertise Here Related Stories Substance Abuse As A Chronic Disease C&EN, June 19, 2006 Drugs Of Abuse, Drugs Of Assistance C&EN, June 19, 2006 Chemical Intolerance C&EN, Oct. 10, 2006 Design Of An Antismoking Pill C&EN, Jun. 6, 2005 Email this article to a friend Print this article E-mail the editor Articles By Topic Latest News Business Government & Policy Science / Technology Career & Employment ACS News View All Topics 2003, 63:4 > Vaccines Against Drugs of Abuse:... < Previous | Next > ARTICLE LINKS: Fulltext | PDF (269 K) 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 Journal Content View or print article as PDF (49 KB) Guidelines Editorial Board Aims and Scope Subscriptions 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 Key Words Abstract Rationale Mechanism of Action Questions Regarding the Potential Clinical Use of Vaccination Potential Clinical Applications Acknowledgment References Author Contacts Article Information Publication Details Drug Dosage / Copyright Key Words 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: Research Support, U.S. Gov't, P.H.S. MeSH Terms: 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: 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. Related Articles, Links Cocaine vaccines: antibody protection against relapse in a rat model. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6202-6. PMID: 10823960 [PubMed - indexed for MEDLINE] 7: Sparenborg S, Vocci F, Zukin S. Related Articles, Links Peripheral cocaine-blocking agents: new medications for cocaine dependence. An introduction to immunological and enzymatic approaches to treating cocaine dependence reported by Fox, Gorelick and Cohen in the immediately succeeding articles (see pages 153-174). Drug Alcohol Depend. 1997 Dec 15;48(3):149-51. No abstract available. PMID: 9449012 [PubMed - indexed for MEDLINE] 8: Kantak KM. Related Articles, Links Anti-cocaine vaccines: antibody protection against relapse. Expert Opin Pharmacother. 2003 Feb;4(2):213-8. Review. PMID: 12562311 [PubMed - indexed for MEDLINE] 9: 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, Related Articles, Links Gardner EL. Related Articles, Links The novel dopamine D3 receptor antagonist NGB 2904 inhibits cocaine's rewarding effects and cocaine-induced reinstatement of drug-seeking behavior in rats. Neuropsychopharmacology. 2006 Jul;31(7):1393-405. Epub 2005 Oct 5. PMID: 16205781 [PubMed - indexed for MEDLINE] 11: Milivojevic N, Krisch I, Sket D, Zivin M. Related Articles, Links The dopamine D1 receptor agonist and D2 receptor antagonist LEK-8829 attenuates 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. Related Articles, Links 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. Related Articles, Links 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] Related Articles, Links 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] Related Links Human therapeutic cocaine vaccine: safety and immunogenicity. [Vaccine. 2002] Immunization with trivalent inactivated influenza vaccine in partially immunized toddlers. [Pediatrics. 2006] An open-label, nonrandomized, single-center, prospective extension, clinical trial of booster dose schedules to assess the safety profile and immunogenicity of recombinant outer-surface protein A (OspA) Lyme disease vaccine. [Clin 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. 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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. 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