Annual Report on the Rare Diseases and Conditions Research Activities of the National Institutes of Health FY 2000
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National Institute on Drug Abuse (NIDA)
Overview of NIDA Rare Diseases Research Activities With respect to the prevention of drug abuse and treatment of drug abusers, NIDA provides national leadership, conducting and supporting biomedical and behavioral research, health services research, research training, and health information dissemination. NIDA plans, conducts, fosters, and supports a comprehensive program of research and research training relating to the causes, prevention, treatment, patterns, and consequences of drug abuse and addiction, through research performed in its own laboratories and through contracts and grants to scientific institutions and individuals. NIDA supports training in fundamental sciences and clinical disciplines relating to drug abuse by making individual and institutional research training awards, and coordinates with other research institutes and Federal agencies on activities relevant to drug abuse and addiction. NIDA also conducts and fosters health information dissemination activities, including the collection and dissemination of research findings and related educational materials for health professionals, educators, and the lay public. In addition, NIDA coordinates with institutions and professional associations and with international, national, state, and voluntary agencies working in these areas, including collaboration with the Substance Abuse and Mental Health Services Administration (SAMHSA) on services research issues and other programmatic issues. History of NIDA Rare Diseases Research Four drug abuse treatment medications have received orphan product designation: levomethadyl acetate hydrochloride, naltrexone, buprenorphine, and naloxone. Levomethadyl acetate hydrochloride (trade name ORLAAM), an alternative to methadone used for opiate maintenance therapy, received New Drug Application (NDA) approval in 1993. Naltrexone, an opiate antagonist for use in detoxified patients, was approved in 1985 and no longer enjoys orphan exclusivity. The opiate partial agonist buprenorphine and a combination of buprenorphine plus naloxone have also received orphan designation but do not currently have approved NDAs. Incidence and prevalence figures for dependence on controlled substances (other than alcohol or nicotine) are always difficult to estimate, as they vary from type of drug, community, and supply availability (generally a function of supply interdiction/law enforcement). Unlike other disease conditions, illicit marketers have a reason (profit) to introduce and infect the population with abusable and/or dependenceproducing substances. Illicit drugs utilized in some communities are not always available or in vogue in other communities. Thus, there may be various drug dependence indications that, in and of themselves, may affect fewer than 200,000 persons in the United States. It is very clear, however, that abuse of opiates (heroin and other narcotics) and stimulants (such as cocaine and "crack cocaine") are endemic in the United States. Even the lowest estimates put dependence levels of these substances at figures well above the 200,000 threshold generally used for defining orphan products. The total disease burden of drug abuse in the United States has been estimated to exceed $110 billion per year. Injection drug use and sexual contact among users is a highly correlated vector in the spread of HIV, hepatitis, and tuberculosis, creating a public health problem of enormous magnitude while at the same time receiving treatment as an orphan disease by the pharmaceutical industry. Despite the enormous public health burden of this disease state, there exists little or no incentive for pharmaceutical companies to pursue research and development of new treatment medications for drug abusers. Although the total numbers of persons afflicted may seem sufficient in the aggregate, unlike other disease states, many drug abusers are not seeking treatment at the same time. Therefore, the actual population who may be a potential market for medications is only a fraction of the total number who could benefit. Additionally, many of these persons will be treated in publicly funded clinics where reimbursement is perceived by companies as modest or inadequate and subject to artificial control. Some treatment agents may themselves be abusable and will be strictly controlled. An example of these agents is methadone, classified as a Schedule II controlled substance for use in opiate maintenance therapy. Some 900 U.S. clinics are licensed to dispense methadone and serve approximately 190,000 persons per year with a pharmaceutical market value of approximately $30 million per year. This is simply not an attractive market to most manufacturers based on projected return on investment when compared to nearly any other indication they could pursue. Each of these points is well-documented in the recent Institute of Medicine Report on the Development of Medications for the Treatment of Opiate and Cocaine Addiction , 1995, and are well-known to the pharmaceutical and market research industries. Pharmacological treatment of drug-dependent populations is not the dominant treatment modality in the United States. Most therapeutic regimens are non-pharmacologically based. Because no medications have as yet demonstrated efficacy for the treatment of cocaine dependence, NIDA's orphan product experience to date has focused on medications to treat opiate dependence. While opiate and cocaine dependence do not fit the "numerical" definition of orphan products, de facto they certainly do. As an instructive example, consider the development and approval of the methadone alternative levomethadyl acetate hydrochloride (trade name ORLAAM). Despite the facts that human data on 6,000 subjects from government-sponsored studies were available for levomethadyl acetate hydrochloride, the compound was off-patent, and that the government had a large supply of the compound available for anyone interested in obtaining an NDA, no private-sector entity attempted to finish the development of this compound until NIDA paid a contractor to do so. Similarly, the development of naltrexone was largely a NIDA-funded effort. Therefore, these products should be viewed as entirely "orphan-like" insofar as their ability to attract private-sector sponsors; until recently, this was also persuasive to FDA. In the case of pharmacological treatment for opiate dependence, the population in treatment cannot at present exceed 190,000 per year. Given these facts, historically orphan designation was permitted for two products substantially developed by NIDA (naltrexone, 1985, and ORLAAM, 1993) as treatments for opiate dependence. ORLAAM received orphan designation on the basis that it could be used to transfer patients from methadone (and there were fewer than 200,000 receiving methadone), and naltrexone received designation on the basis that there were fewer than 200,000 detoxified addicts at any given time. In the more recent designation of buprenorphine (1994), FDA appeared to be taking a more restrictive view via application of their more recently promulgated regulations. Although the issue was not definitively answered in the case of buprenorphine, FDA expressed the view that orphan designation where the population in question exceeded 200,000 would be difficult unless there was a medical/biological reason why 200,000 persons could not utilize the product. In other words, treatment capacity or the number of persons seeking treatment might not suffice for orphan designation. In the case of buprenorphine, this did not prove to be an insurmountable burden because that product's sponsor could prove to FDA that based on historic, current, and projected expenditures, it would not recoup its investment during 7 years of exclusive marketing in the United States. Thus, a unique situation exists where the preclinical efforts are completed, NIDA is supporting clinical trials, and the sponsor has the expertise to manufacture new formulations. Buprenorphine became the first product to receive an orphan designation based on an economic, rather than a population-based, rationale. The sponsor selected this route beacuse there was less certainty that FDA would continue to allow orphan designation based on the capacity of the treatment system as opposed to the actual incidence and prevalence of opiate dependence. Recent Scientific Advances in Rare Diseases Research The discovery of opiate receptors by NIDA-funded scientists in the 1970s opened a new era of neurobiological research that continues today. Scientists continue to map brain receptor system types and subtypes, continuously gaining understanding of their structure and function. This information will allow the design of interventions (behavioral, chemical, and genetic) that may be useful in the treatment of a huge number of human disorders, all of which are mediated in the brain. A generation of research has shown that drug addiction is a complex biomedical and behavioral disease that has its roots in those parts of the brain that underlie, mediate, and allow us to have the emotions that make us human. Just as we have learned that depression is a brain disease that can be treated with medicine, so too have we learned that drug addiction is a brain disease that can and should be treated with medicine. There is a critical distinction between drug abuse and drug addiction. Drug abuse is a voluntary behavior; the casual user makes a free and conscious decision to break the law and use an illicit, mind-altering substance. Drug addiction is a disease of the brain, resulting from repeated and prolonged self-administration of such a substance. Addiction is brought on by drug-taking behavior in much the same sense that lung cancer is brought on by cigarette smoking and heart disease is brought on by excessive fat intake. Once the disease is established, however—be it in the brain, the lung, or the heart—the physiological dysfunction must be corrected to restore health. The role of a medication is to re-establish normality to brain function and behavior so that the addicted patient has the opportunity for rehabilitation through counseling, psychotherapy, vocational training, and other therapeutic services. While the mechanisms of many central nervous system disorders have not been elucidated, scientists working in the field of drug abuse have now identified and cloned the putative site of action in the brain for every major drug of abuse. Thus, the potential to develop new treatments is enormous. For example, having cloned the dopamine transporter mechanism where cocaine exerts its action, NIDA scientists are now designing molecules that will block cocaine's effects at this site without disrupting the essential neurotransmitter functions of dopamine. NIDA and other scientists have developed pharmacological agents for the treatment of opiate dependence in various functional categories. For example, methadone and ORLAAM are mu agonist medications currently approved for opiate treatment. Naltrexone is an opiate antagonist approved for treatment, and naloxone is approved for use in the treatment of opiate overdose. NIDA is currently working on a partial mu agonist (buprenorphine) that will further contribute to the arsenal of agents available for treatment. Rare Diseases Research Initiatives As described in the history section above, NIDA considers medications for the treatment of dependence on controlled substances to be de facto orphans. The development of medications for the treatment of these conditions may well be considered rare disease research within the context of an urgent public health need with a wholly inadequate private-sector response. Therefore, NIDA's medications development program effort may (until facts prove otherwise) be considered as part of a rare disease research initiative. In 1990 the NIDA Medications Development Division (MDD) was established. In 1999, MDD became part of the Division of Treatment Research and Development (DTR&D). The functions of DTR&D are as follows:
DTR&D operates within the larger context of a NIDA-wide Medications Development Program that incorporates basic research discoveries from other divisions (intramural and extramural) in the quest to develop new pharmacological treatments. Application of research results from the intramural and extramural community allows the Division to have access to the latest theoretical bases and an opportunity to test new hypotheses in controlled clinical settings. Recognizing that physicians will soon have a choice of five different FDA-approved products for treating opiate addiction (methadone, ORLAAM, buprenorphine, buprenorphine/naloxone, and naltrexone) and no FDA-approved products for treating addictions to stimulants (e.g., cocaine or methamphetamine), NIDA's efforts are currently shifting toward a greater emphasis on discovery and development of medications for treating stimulant dependence. While initial clinical trials in this area have focused on medications that are already marketed for other indications, substantial efforts are also being devoted to the discovery and development of novel compounds that may specifically address the problem of stimulant dependence. It is worth noting that within the pharmaceutical industry approximately, $75 million are devoted to biological screening and pharmacological testing for each successful new medication that reaches the market. NIDA is willing to make such an investment in medications discovery and is working to establish collaborations with pharmaceutical companies that will allow NIDA to screen chemical libraries at biochemical targets (e.g., dopamine D-1 receptors) implicated as potential sites of action for effective medications. Efforts are also directed toward supporting synthesis of novel compounds for screening and pharmacological testing through grants and contracts. Significant areas of research and development are summarized below. Opiate Addiction Treatment Buprenorphine/Buprenorphine-Naloxone Combination A 16-week, 735-patient, 12-center trial of buprenorphine, an opiate partial agonist medication for the treatment of heroin dependence, has been completed. Data from this study and other previous and ongoing studies have been analyzed. These data demonstrate the effectiveness of buprenorphine in reducing illicit opiate abuse and in retaining patients in treatment (Ling et al., Addiction, 1998). Under development is a combination dosage of buprenorphine plus naloxone, which would be useful as a potential "non-narcotic" or "take-home" treatment medication. Testing is currently under way to determine the abuse potential of buprenorphine plus naloxone. A tablet form of buprenorphine and of buprenorphine plus naloxone is also under development, and commercial sponsorship for these products has been negotiated. A 12-site, 52-week trial of the tablet products was completed in September 1998. An NDA for buprenorphine was submitted in 1997. The NDA for buprenorphine combined with naloxone was submitted and reviewed in 1999. FDA has deemed both submissions fiapprovable,fl and it is hoped that actual approval may occur in the fall of 2001. Given that buprenorphine combined with naloxone received an "approvable" status by FDA in calendar year 1999, plans are under way to enhance the introduction of this new front-line product to the American treatment system. The hope is that pharmacological treatment with buprenorphine products will enable it to be used in a wider variety of settings than is currently the case for methadone and ORLAAM. To test the viability of this approach, NIDA and the Department of Veterans Affairs (VA) began a study in 1999 designed to assess the use of a buprenorphine/naloxone sublingual tablet formulation in nonclinic-based settings for the treatment of opiate addiction. The study will also evaluate the administration of buprenorphine to adolescents (ages 15-21 years). A total of 583 patients have been enrolled. Data from this study will be used to expand labeling and will be considered in developing guidelines for the administration of the buprenorphine/naloxone sublingual tablet in office-based settings. As an immediate goal, this protocol will be implemented in multiple settings (e.g., university-based or affiliated clinics, community mental health clinics, or private physicians' offices), with buprenorphine prescribed and supplemented with relapse prevention therapy delivered by an appropriately trained medical assistant. A collaborative arrangement of this protocol allows physicians practicing in one of the above settings to participate in this study provided they agree to adhere to the requirements of the protocol. The study will be specifically aimed at answering the following critical treatment expansion issues:
Depot Naltrexone Naltrexone, a marketed, long-acting, orally effective opioid antagonist, was approved in 1985 for the indication of blocking the pharmacological effects of exogenously administered opiates. It is an adjunct to the maintenance of the opioid-free state in detoxified, formerly opioid-dependent individuals. One of the major obstacles to the success of naltrexone has been patient compliance with therapy. Naltrexone must be taken at least three times per week and has no effect other than to block the effects of heroin, a drug that the patient is not supposed to use. Because of this, many patients forget to take or stop taking their medication. Therefore, the greatest success with naltrexone has been in the limited population of highly motivated formerly opiate-dependent patients. Via a Small Business Innovative Research (SBIR) contract, NIDA completed the production and preclinical testing of a batch of 120 doses of depot naltrexone in 1999. These doses were designed to provide a sustained level of naltrexone for 30 days when administered subcutaneously in humans and to produce a blood level of about 2-3 ng/ml. This product has been shown to block challenges in primates, and a similar preparation has been shown to block some of the effects of morphine challenges in humans. This preparation was tested in an inpatient clinical study to assess its ability to block specific responses to heroin challenges between 12 and 25 mg. Based on the promising results of this study, an outpatient double-blind study was designed to test the product. The outpatient study began in the summer of 2000. Approximately 8 of 60 subjects planned have been completed. Additionally, a small positron emission tomography (PET) study to assess the receptor occupancy of naltrexone during a challenge protocol is planned. Naltrexone was approved in 1994 for the treatment of alcohol abuse. The depot preparation may also be of value for the treatment of that disease. Dextromethorphan A revolutionary advance in our understanding of one of the basic neurochemical mechanisms underlying opiate addiction has resulted from recent animal investigations of the role of N-methyl-D-asparate (NMDA) receptor antagonists in opiate addiction. Drugs that antagonize the NMDA receptor complex are capable of inhibiting opiate withdrawal and tolerance and, in some cases, of reversing tolerance. As a first step, NIDA plans to assess the toxicity of NMDA receptor antagonists and to evaluate their effects on conditioned cues and drug abuse. It is hypothesized that this class of drugs has a unique pharmacological effect in decreasing the conditioned cues that appear to perpetuate opiate-seeking behavior. Furthermore, we anticipate that these compounds will not have the abuse liability associated with other opiate treatments, such as methadone and buprenorphine. Medication Systems for Neonatal Treatment NIDA has expressed an interest in the development of medications and formulations to treat withdrawal symptoms in babies born to opiate-dependent mothers. Although many scientists are interested in novel drug-delivery systems, very few have considered the treatment of neonates. NIDA plans to focus specifically on narcotic skin patches for the treatment of neonates born to addicted mothers. Infants born to mothers who abuse opiates or who are on methadone maintenance can go through withdrawal periods lasting for 3 or more weeks. Currently, there are no FDA-approved medications for the treatment of these neonates, although paregoric (opium solution) has been used. A transdermal delivery system (patches) for opiate agonists such as fentanyl or buprenorphine offers advantages over oral or injectable dosage forms because of its convenience for use in neonates. This technology is available, is currently in use, and could be readily adapted for use in neonates undergoing withdrawal. Clinical trials will require careful planning, and both FDA approval and regulations concerning use in treatment may present unique problems not anticipated by the Narcotic Addict Treatment Act. Opioid Peptides as Medications The three major types of opioid receptors in the brain are mu, delta, and kappa. Morphine, heroin, methadone, and ORLAAM bind to the mu receptor with high affinity. The naturally occurring ligand for the kappa opioid receptor is dynorphin A. Animal studies indicate that dynorphin A alleviates opiate withdrawal and that this peptide also decreases tolerance to chronically administered mu opioid receptor agonists (e.g., morphine). Indeed, kappa opioid abnormalities in the central nervous system may underlie the drug-seeking behavior of heroin addicts. The effects of dynorphin on opiate withdrawal are currently being investigated by NIDA-funded scientists in opiate-dependent subjects. Cocaine Addiction Treatment Compounds in Advanced Clinical Testing Several small studies of potential cocaine addiction treatment agents have been completed and are in various stages of data analysis. Clinically significant findings will be followed up in larger controlled trials as warranted. The development of anticocaine medications has proven to be a daunting task, and to date only one potential medication has been identified that justifies a phase III trial. A retrospective analysis of a phase II trial of selegiline in cocaine addicts indicated a differential outcome in favor of selegiline versus placebo. This finding needs to be replicated in a larger and more statistically powerful clinical trial. The DTR&D will conduct a phase III multicenter trial of selegiline beginning in the spring of 2001. Additionally, there is a growing body of evidence generated by NIDA grantees concerning the potential use of disulfiram in the treatment of cocaine dependence. Disulfiram (Antabuse), marketed as aversive therapy for treating alcoholism, is also showing promise in the treatment of cocaine dependence. Several NIDA-sponsored studies conducted at Yale University documented interaction of disulfiram with cocaine in humans. Pharmacokinetics studies showed that disulfiram increases plasma concentrations of cocaine and potentiates physiological-cardiovascular responses to cocaine. Three efficacy trials conducted with different populations of cocaine-dependent individuals suggest that disulfiram in combination with each of three different therapeutic interventions (cognitive behavioral treatment, 12- step facilitation, or clinical management) is effective in treating cocaine dependence. In cocaine-alcohol abusers, disulfiram treatment showed sustained effect on reduced cocaine and alcohol use 1 year after cessation of the therapy. Disulfiram treatment of cocaine-abusing opioid-dependent patients maintained on methadone resulted in significant decrease of the amount and frequency of cocaine use. A preliminary study showed that disulfiram also decreases cocaine use in cocaine-opioidŒdependent addicts maintained on buprenorphine. NIDA is currently sponsoring three large outpatient clinical trials with disulfiram as the treatment for cocaine dependence:
All these studies include some form of behavioral or cognitive therapy and drug counseling. They are monitoring not only cocaine use, but also opiate or alcohol use. Finally, NIDA is planning a clinical pharmacology/safety study of the interactions between disulfiram and IV-administered cocaine prior to launching a large-scale phase III multicenter trial with this medication. CRADA with NeuroSearch, AG In late 1997, NIDA entered a CRADA with Danish company NeuroSearch, AG, to perform research on NeuroSearch's proprietary compound NS2359, which is targeted exclusively as a potential treatment for cocaine dependence. As part of this agreement, NeuroSearch has conducted the first of many safety trials on this product. Assuming that analysis of the data generated from this trial is supportive of its safety, NIDA will undertake the necessary safety and efficacy trials required by FDA to further develop NS2359. GBR 12909 Major neurochemical effects of cocaine include release of dopamine (DA), serotonin, and noradrenaline via a transporter-mediated exchange mechanism. There is considerable evidence that the initiation and continuation of cocaine use is associated with the effects of the drug on the dopaminergic, serotonergic, and noradrenergic modulation of the central nervous system (CNS) function. Animal studies suggest that the mesocorticolimbic dopaminergic pathways are important mediators of cocaine's reinforcing and addictive properties. Cocaine binds to these transporters and blocks the removal of these neurotransmitters from the synaptic gap. The neurobiological mechanisms underlying the effects of cocaine are not well-understood. Preclinical studies indicate that cocaine's blockade of the DA transporter plays a key role in producing cocaine's addictive and reinforcing effects. Primate and non-primate studies have shown that GBR 12909 has a strong affinity for the DA transporter. GBR 12909 is a high-affinity, selective, and long-acting inhibitor of DA uptake that produces a persistent and non-competitive blockade of DA transporters and substantially reduces cocaine-induced increases in extracellular mesolimbic DA. In addition, GBR 12909 has a higher affinity than cocaine for the DA transporter. Ongoing research is searching for a dopamine sparing cocaine antagonist that might be developed as a pharmacological treatment to block cocaine from acting at the transporter level to produce its reinforcing effects. GBR has been postulated to act by binding only to precise sites on the dopamine transporter that are required for cocaine binding and making available the sites where DA binds to the transporter. A phase I clinical study was conducted in support of an IND application filed by NIDA. The main objectives of this study were to determine the safety, tolerance, and pharmacokinetics of multiple escalating dosages of oral GBR 12909 in healthy volunteers. In addition, PET scans measuring the occupancy of the DA transporter by GBR 12909 were obtained. The occupancy scan results will be correlated with the safety data to determine an optimal oral dose of GBR 12909. The current study has completed all four dosage levels. Unexpected adverse events included insomnia and increased libido, and disinhibition of aggressive feelings. The data are being analyzed. Dopamine Agonists The activation of the dopaminergic reward system in the brain appears to be the principal neurochemical mechanism involved in the addiction to stimulants such as cocaine and amphetamine. Chronic abuse of these drugs results in DA deficiency in the brain, which has been hypothesized to lead to craving for stimulants, depression, anhedonia, and dysphoria. Several clinical reports, such as that reported for amantadine, suggest that DA agonists decrease cocaine use. NIDA proposes to clinically test several approved medications that would increase dopaminergic tone in the brain and to study novel compounds. Examples of these agents are: 1) direct dopamine agonists and partial agonists, 2) dopamine precursors, 3) reversible monoamine oxidase inhibitors, and 4) drugs that inhibit dopamine, serotonin, and noradrenaline neuronal re-uptake (mimicking cocaine but that have a slower onset of action and are presumably less addictive). Most recently, studies in rodents, and to a lesser extent in monkeys, have differentiated the roles of D1 and D3 receptors with regard to cocaine. The D1 system may inhibit the effects of cocaine, while the D3 system may provide a cocaine substitute of lesser dependence potential. Compounds that affect both systems are under study. Kappa Opioids Recent studies have shown that kappa opioid compounds exhibit effects opposite to those of cocaine in terms of dopamine release and neuron-firing patterns. In animal studies, kappa opioids block drug discrimination and self-administration of cocaine and also prevent context-independent sensitization to cocaine. NIDA and NIDA grantees are testing compounds of this class in clinical studies. Glucocorticoid Antagonists Studies have shown that cocaine causes the release of stress hormones known as glucocorticoids in rats and humans. There is some evidence from rat studies that glucocorticoid antagonists and corticotropinreleasing factor (CRF) antagonists reduce cocaine self-administration in a dose-related manner. NIDA will follow up on these basic research findings with additional studies aimed at developing a potential treatment for cocaine addiction. DTR&D is pursuing CRF antagonist projects with a pharmaceutical company supplier. Immunology Researchers funded by NIDA's DTR&D reported that they have successfully immunized rats against many of the stimulant effects of cocaine. Cocaine was prevented from entering the brain when rats were "vaccinated" with a substance that triggers the body to produce antibodies to cocaine. These antibodies then acted as biological "sponges" to which cocaine binds, thereby reducing the amount available in the blood to reach the brain. The results of this research are presented in "Suppression of Psychoactive Effects of Cocaine by Active Immunization" in the December 14, 1995, issue of Nature . Researchers Kim Janda, Ph.D., Rocio Carrera, M.A., George Koob, Ph.D., and colleagues at The Scripps Research Institute demonstrated a greater than 70% reduction in cocaine uptake in the brains of rats inoculated with the antibody-producing compound as compared to a group that was not inoculated. Researchers designed the compound so that the antibodies produced would respond specifically to the cocaine molecule yet not affect normal brain chemistry. In the study, Dr. Janda and colleagues used an "active immunization" approach by developing a substance that when administered to rats would trigger the immune system to produce antibodies that are specific for the cocaine molecule. The researchers inoculated the rats over a 35-day period and then tested their responses to cocaine. The immunized animals showed significantly lower responses to the stimulant effects of cocaine than control animals because the immunization prevented much of the cocaine from getting to the brain. Cocaine concentrations in the brain tissue of the immunized animals were found to be dramatically less than the concentrations of cocaine in brain tissue of controls. Other immunotherapy research for drug abuse treatment has explored the use of catalytic antibodies and other external agents that can be used to treat cocaine dependence. The research reported in Nature differs by inducing the production of antibodies that remain in the bloodstream for an extended period of time and block cocaine's effects after it is used. The biotechnology company ImmuLogic Pharmaceutical Corporation (Waltham, Massachusetts) also recently announced development of a cocaine vaccine. Dr. Barbara S. Fox of ImmuLogic discussed some of the company's findings in Chemistry and Engineering News , December 18, 1995, and at a January 18, 1996, meeting of the Maryland Bioscience Alliance at the request of NIDA. ImmuLogic had previously received phase I SBIR funding from NIDA. In 1996, NIDA awarded a $700,000 SBIR award to ImmuLogic to complete preclinical development of a vaccine to treat cocaine dependence. Results of ImmuLogic's early vaccine work in animals have received attention in national and trade press, were presented at the College on Problems of Drug Dependence, and were published in Nature Medicine 2, 1129-1132: 1996. The vaccine links a protein to cocaine, resulting in a molecule that induces antibody formulation. Once titers reach a certain level, cocaine's ability to cross the blood-brain barrier is impeded. The award expedited completion of preclinical design and early testing of the vaccine. A phase I (dosing and tolerability trial) was successfully completed in 1999. ImmuLogic is no longer in business and sold the rights to the vaccine to Cantab, Ltd., a British company specializing in vaccine development. NIDA has supported this research via a Strategic Program for Innovative Research on Cocaine Addiction Pharmacotherapy (SPIRCAP) and SBIR grant. Thirty-four subjects completed the initial phase I study in the United States. Specific antibody titers for cocaine were developed in the vaccine-challenged subjects. Under the SPIRCAP award, two additional studies are planned to convene this year: an inpatient study examining the extent to which the antibody can block the effects of administered cocaine, and an outpatient study. To date, no adverse events have been reported, and the company plans to continue development of the vaccine. Serotonin Antagonists Cocaine increases extracellular levels of serotonin, dopamine, and noradrenalin in the brain. Serotonin is an extremely versatile neurotransmitter that activates numerous subreceptors. Studies of two subtypes of receptors (5HT-2 and 5HT-3) suggest that these structures are involved, directly and indirectly through an effect on dopamine, in the rewarding and, possibly, the mood-elevating effects of cocaine. Antagonists of these receptors, which decrease dopamine release, may reduce cocaine craving and use. Therefore, NIDA plans to test serotonin antagonists as potential medications for cocaine addiction. Serotonin Re-uptake Inhibitors A major symptom of cocaine addiction is anhedonia, which is clinically very similar to depression. It has been postulated that cocaine addiction is a form of self-medication for chronic depression. Initial results of studies of the potent serotonin re-uptake blocker fluoxetine (an antidepressant) have yielded mixed results in attempting to answer the suggestion that it may be efficacious in facilitating abstinence from cocaine use. Evaluation of serotonin re-uptake inhibitors as potential medications will continue. One such compound, the currently marketed antidepressant Venlafaxine, a serotonin and norepinephrine uptake inhibitor, is being studied by two NIDA grantees. Nootropic Drugs and Cocaine Dependence Abuse of stimulants such as cocaine and amphetamines is associated with some degree of neurological damage, resulting in cognitive impairments, brain perfusion deficits, strokes, intracranial hemorrhages, and development of early symptoms of movement disorders. NIDA-sponsored studies are under way to test several nootropic medications as potential treatments for cocaine-induced neurological deficits. Cocaine "Receptor": Imaging Studies In addition to the categories of compounds being tested as described above, a new and potentially useful technology is being investigated as to its value for predicting efficacy of potential cocaine treatment medications. Research in the field of structure-activity relationships have revealed highly selective and potent binding ligands for the dopamine transporter. NIDA intramural researchers have identified three "generations" of such compounds, with each succeeding generation being more selective and potent than the previous one. RTI-55, the first potent compound, was shown to be an effective in vivo labeling agent in animal studies and was subsequently examined in human imaging studies by single-photon emission computed tomography (SPECT). A second compound, RTI-121, was found to be more selective for the dopamine transporter but had a higher apparent lipid solubility and exhibited lower specific to nonspecific binding in vivo. NIDA researchers are testing new compounds and are also utilizing some older compounds (e.g., WIN-35,428) in brain imaging studies. Procedures have been developed for estimating the occupancy of transporter sites in vivo. Dopamine transporter imaging studies of cocaine abusers have been completed (see section on GBR 12909). This technology may make it possible to estimate the effectiveness of a potential treatment compound or regimen by correlating receptor occupancy (as shown in imaging studies) with actual clinical results. NIDA will continue to follow this line of research. Methamphetamine Treatment Discovery Efforts and Program Activities Methamphetamine is a potent psychomotor stimulant that has gone through episodic periods of widespread use and abuse in the United Sates. Cocaine abuse and addiction surpassed use of methamphetamine in the 1970s and 1980s, but methamphetamine abuse and addiction has been reappearing in some regions of the United States and is widespread in western U.S. cities such as San Francisco, Denver, Phoenix, and Los Angeles. According to the National Household Survey on Drug Abuse, an estimated 3.8 million people had tried methamphetamine by 1994, and by 1999 the total number had increased to 9.4 million. The epidemic is spreading to rural areas, and nationwide there were approximately 11,000 acute hospital admissions related to amphetamine toxicity in 1999. There are no accepted treatment medications for methamphetamine addiction or abuse. As a result, NIDA has developed a Medication Discovery Program for methamphetamine and is funding a number of extramural and intramural studies to develop medications to treat methamphetamine abuse. Preclinical Methamphetamine Program Methamphetamine abuse has become a substantial drug problem in certain parts of the American Southwest, and data suggest that its use is increasing and spreading to other parts of the United States. Methamphetamine is a powerful stimulant that shares some similarities with cocaine, but also differs from cocaine in certain ways. A January 10, 2000, Methamphetamine Think Tank meeting was held in order to gather a group of consultants to consider the direction of a methamphetamine treatment development program. Based upon recommendations of these consultants, several types of methamphetamine-specific screening assays are being developed to evaluate and characterize compounds for their potential usefulness in the treatment of methamphetamine dependence. Some of the assays recommended are similar to those used in the Cocaine Treatment Discovery Program, and there will be substantial overlap between the two programs. Existing contract protocols will be used to test compounds for their interactions with dopamine transporters, but additional assays will be utilized to measure dopamine release in vitro, which is an effect of methamphetamine that is not shared by cocaine. In addition, behavioral assays are being set up to assess a compound's ability to block the locomotor stimulant effects of methamphetamine, block the discriminative stimulus effects of methamphetamine, and determine effects on methamphetamine self-administration. In addition, assays to measure effects of potential treatment compounds on the cardiovascular system, both alone and in combination with methamphetamine, are being developed. Methods for assessing the neurotoxic effects of methamphetamine are under development, and these assays may be useful in assessment of potential treatment medications. Clinical Methamphetamine Program Since January 2000, NIDA has been working on choosing sites for a new methamphetamine clinical trials network and has identified four sites (Des Moines, Los Angeles, San Diego, and Honolulu) with high concentrations of methamphetamine users. Plans are under way to visit these sites and begin developing a protocol for Bupropion as the first medication trial for this network. NIDA hopes to start a multisite Bupropion study after the prerequisite interaction studies are completed. Four clinical pharmacology studies are also being developed in Los Angeles and San Francisco to study safety interactions of methamphetamine and selegiline as a potential treatment. Phencyclidine (PCP) Treatment Dr. Michael Owens at the University of Arkansas for Medical Sciences in Little Rock receives NIDA funding to develop a new generation of monoclonal antibody-based medications for treating drug abuse ("Immuno-Therapy for Drug Abuse," R01 DA07610, and "Antibody-Based Therapy for Methamphetamine Abuse," R01 DA11560). This research is focused on treatments for methamphetamine, methylenedioxymethamphetamine (MDMA, also known as ecstasy), and PCP abuse. These medications function as pharmacokinetic antagonists and are designed to reverse the effects of drug overdose and/or help blunt the reinforcing effects of drugs of abuse. Because of the unique pharmacological profile of these new medications, they would be well-suited for use with other, more conventional, chemically based medications and treatments such as behavioral modification to aid in the long-term recovery from drug addiction. If successful in humans, these treatments will not only provide a rapid reversal of drug effects in an emergency room setting, but also reduce or prevent the long-term medical problems associated with stimulant drugs of abuse (i.e., neurotoxicity and addiction). Dr. Owens' studies of treating PCP effects are the most advanced and are providing the model system for development of antibody-based therapies for other classes of drugs and toxins. To this end, Dr. Owens has successfully developed an anti-PCP monoclonal antibody that removes PCP from the CNS of rodents in minutes. The group is presently focused on completing the preclinical animal studies necessary for the filing of an IND application and on refining previously developed scale-up methodology for the production of the monoclonal antibody fragments. In other studies, Dr. Owens has shown that a single administration of an anti-PCP monoclonal IgG antibody can significantly reduce PCP's behavioral effects and CNS concentrations for at least 2 weeks, even when PCP is repeatedly administered in large doses to the animals over the entire 2-week period. This is important because a 2-week time period in animals would be equivalent to about 1 to 2 months of protection in humans. Dr. Owens' preliminary studies of antibody-based treatments for methamphetamine are showing the same type of long-term neuroprotective effects. In collaboration with Dr. Brooks Gentry, a clinician/scientist at the University of Arkansas ("Mechanisms of Onset and Offset of Rapid Stimulant Effects," K08 DA00339), Dr. Owens is studying the fundamental medical consequences of rapid input of drugs of abuse into the CNS. These experimental data from animal models of human drug abuse will help in understanding why drug abusers usually prefer rapid routes of drug administration (intravenous and smoking) over slower modes of administration (oral). Finally, these pharmacokinetic and pharmacodynamic studies are being used to aid in the development of novel therapeutic approaches to the treatment of stimulant drugs of abuse. |
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