DEVELOPMENT OF IMMUNOLOGICAL AND MOLECULAR BIOLOGICAL APPROACHES TOEFFECT REDUCTION OF COCAINE USE NIH GUIDE, Volume 21, Number 34, September 25, 1992 PA NUMBER: PA-92-109 P.T. 34 Keywords: Drugs/Drug Abuse Biology, Molecular Immunology Disease Prevention+ Receptors National Institute on Drug Abuse PURPOSE The National Institute on Drug Abuse (NIDA) invites research grant applications for studies on the discovery/development of antibodies, enzymes, or catalytic antibody substances as potential treatments to reduce cocaine use. The proposed medication would provide either active or passive protection against the pharmacodynamic/neurotoxicological action of cocaine. It is anticipated that the proposed medication could function by rapidly reducing the concentration of the cocaine in plasma or serving as a novel antagonist. Within this general field of research, special emphasis should be placed on (1) using a novel protein to block receptor sites through competitive inhibition, (2) using catalytic antibodies to rapidly react with the abused substance and convert the substance into a nonactive species, (3) using anti-idiotype based vaccines to produce antibodies that bind with cocaine and reduce its free plasma concentration, (4) using monoclonal antibodies to bind with the abused substance and reduce its effective concentration in the plasma, and/or (5) enhancing the body's own natural ability to eliminate cocaine. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Program Announcement (PA), Development of Immunological and Molecular Biological Approaches to Effect Reduction of Cocaine Use, is related to the priority of health promotion (alcohol and other drugs). Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473- 1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20492-9325, telephone 202-738-3238. ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, non-profit and for-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, research institutions, units of State and local governments, and eligible agencies of the Federal government. Applications from minority individuals and women are encouraged. Foreign applicants are not eligible for First Independent Researsch Support and Transition (FIRST) Awards (R29). MECHANISM OF SUPPORT Support mechanisms include Research Projects (R01), the small grant (R03), and the FIRST Award (R29). Most investigator-initiated research is supported by research grants. Research grants are awarded to institutions on behalf of Principal Investigators who have designed and will direct a specific project or set of projects. For information on the special requirements of the FIRST awards (R29), and small grants (R03), please contact the program staff listed under INQUIRIES. RESEARCH OBJECTIVES Background Drug abuse, including the use of cocaine, is an addictive disorder that continues to be a burden on societies throughout the world. It is directly associated with crime and the spread of infectious diseases, notably venereal disease and especially AIDS. The existing psycho-pharmacological medications used to treat disorders such as depression and mania have not been wholly successful in treating drug abuse disorders. It is generally believed that there is much room for advancement in the treatment of addictive disorders. A large portion of the addicted population have not been reached and are not enrolled in drug treatment programs. Further, the retention of patients in these programs, particularly for cocaine use is very low. Most cocaine addicts do not actively seek help. The development of an effective treatment for cocaine use is a top priority of the NIDA. The conventional method to discover and develop pharmacotherapeutic agents for substance abuse is to find a receptor site for the abused substance and to screen many compounds for activity at the receptor. For opiates, this approach has been successfully demonstrated; currently, there are two drugs, methadone and naltrexone, approved by the FDA for the treatment of opiate addiction. Methadone, an agonist, serves as a maintenance drug while naltrexone, an antagonist, serves to block opiate effects. Medications presently under clinical evaluation for the treatment of opiate addiction include buprenorphine, a partial agonist; acetylmethadol, a long-acting agonist; and nalmefene, an antagonist. Research is actively being encouraged for the development of other agonist, antagonist, and opiate peptides as potential candidates for the treatment of narcotic addiction. In contrast to the success that has been achieved in the treatment of opiate abuse, no medication has yet been approved for the treatment of cocaine addiction. Clinical studies are currently underway for the evaluation of the efficacy of a number of drugs, such as buprenorphine, carbamazepine, desipramine, mazindol, flupenthixol, nifedipine, and amantadine for the treatment of cocaine addiction. These studies have been open label or conducted in less than 200 subjects. It may be concluded from these clinical trials that research to develop a treatment agent for cocaine addiction must continue. Recent advances in the field of molecular biology, particularly in the area of catalytic antibodies and the development of anti-idiotype based vaccines, suggest that now is the time to apply this technology to developing new, biologically-based medications for cocaine use. Cocaine is a diester and is hydrolyzed to less active metabolites; the metabolites are water soluble and are excreted from the body. The thrust of the approach would be to develop biological systems that either rapidly bind with plasma cocaine (as antibodies) or that rapidly hydrolyze cocaine to a water soluble metabolite (as a catalytic antibody). The result would be to effect a lower (unbound) plasma level of cocaine and/or a shorter duration of cocaine in the body. In addition, it would be appropriate to consider a means of extending the duration of the therapy for reasons of patient compliance and for reasons of relapse prevention. Development of an "anticocaine vaccine," that would be triggered only when the abused drug was taken, would be ideal. Developing a means of stimulating the intrinsic capacity to hydrolyze cocaine is considered an interesting approach which is consistent with diminishing the adverse pharmacological and toxicological effects of a given dose of cocaine. In the applications, programmatic emphasis should be placed on innovation in design and development. To qualify for this program, applications should embody unique and/or innovative theoretical constructs with an experimental approach leading to a new system of drug abuse therapy. The application must detail how these constructs and approaches are consistent with developing a treatment for cocaine use. Areas of Interest The areas of research interest that may be funded include those that are innovative, that develop new methods of drug discovery for cocaine use pharmacotherapies, and that will advance the development of a new medication for the treatment of cocaine use. In general, these may include: o Using antibodies to bind with the abused substance. o Using antibodies or enzymes to increase the natural rate of metabolism of the abused drug. o Developing techniques for blocking the receptor site through competitive inhibition. The approach should be based on molecular biology in order to be compatible with this program. o Developing procedures that enhance the intrinsic capacity to eliminate the abused substance. These areas of research interest are not intended to be all-inclusive and alternate or similar areas will be considered. However, experimental models to develop therapeutic interventions for cocaine use are extremely limited at the present time. Therefore, a major research effort is required to design innovative approaches to expand the current methods and models to those that have not been explored. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in Sections 1-4 of the Research Plan AND summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, the NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) and will be accepted at the standard application receipt dates indicated in the application kit. Application kits are available at most institutional business offices and may be obtained from the Office of Grants Inquires, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/496-7441. The title and number of the announcement must be typed in item 2a on the face page of the application. FIRST Award applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The completed original application and five legible copies must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** REVIEW CONSIDERATIONS The Division of Research Grants serves as a central point of receipt of applications for most discretionary PHS grant programs. Applications received under this announcement will be assigned to an Initial Review Group (IRG) in accordance with established PHS Referral Guidelines. The IRG, consisting primarily of non-Federal scientific and technical experts, will review the applications for scientific and technical merit. Notification of the review recommendations will be sent to the applicant after this initial review. Applications will receive a second-level review by an appropriate National Advisory Council whose review may be based on policy considerations as well as scientific merit. Only applications recommended for further consideration by the Council may be considered for funding. Review Criteria Applications will be assigned on the basis of established PHS referral guidelines. Applications will be reviewed for scientific and technical merit by an initial review group in accordance with the standard NIH peer review procedures. Following scientific-technical review, the applications will receive a second-level review by the appropriate National Advisory Council. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: o Availability of funds o Quality of the proposed project as determined by peer review o Program balance among research areas of the announcement INQUIRIES Written and telephone inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is encouraged. Direct inquiries regarding programmatic issues to: James B. Terrill, Ph.D. Medications Development Division National Institute on Drug Abuse 5600 Fishers Lane, Room 11A-55 Rockville, MD 20857 Telephone: (301) 443-6270 Direct inquiries regarding fiscal matters to: Mrs. Shirley A. Denney Chief, Grants Management Branch National Institute on Drug Abuse 5600 Fishers Lane, Room 8A-55 Rockville, MD 20857 Telephone: (301) 443-6710 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.279. Awards are made under authorization of the Public Health Service Act, sections 301 and 515 (42 USC 241 and 290cc) and administered under PHS grants policies and Federal Regulations 42 CFR 92 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .
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