NIH GUIDE, Volume 21, Number 34, September 25, 1992

PA NUMBER:  PA-92-109

P.T. 34


  Drugs/Drug Abuse 

  Biology, Molecular 


  Disease Prevention+ 


National Institute on Drug Abuse


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.


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.


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).


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.



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


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


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.





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


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


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.


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


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


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**


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.


Applications will compete for available funds with all other approved

applications.  The following will be considered in making funding


o  Availability of funds

o  Quality of the proposed project as determined by peer review

o  Program balance among research areas of the announcement


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


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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