Release Date:  January 27, 1999

RFA:  AA-99-004


National Institute on Alcohol Abuse and Alcoholism

Letter of Intent Receipt Date:  April 2, 1999
Application Receipt Date:  April 28, 1999


The National Institute on Alcohol Abuse and Alcoholism (NIAAA) requests
applications to develop and evaluate potential new medications for eventual
clinical use in the treatment of alcoholism or alcohol-mediated medical
consequences or to further develop and evaluate agents that already show
clinical potential based on preclinical data.  With the rapid advances in
understanding how ethanol acts on the brain and behavior and on other organs
of the body, an unprecedented opportunity exists to develop and evaluate new
medications for eventual use in clinical trials.  There are a number of
alcohol-related phenomena that could be examined, including reduction in
ethanol consumption, craving and relapse, signs and symptoms accompanying
acute and protracted withdrawal, ethanol-induced cognitive dysfunction,
intoxication, and various endpoints of organ damage.


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 Request for Applications (RFA) is
related to the priority area of alcohol abuse and alcoholism. Potential
applicants may obtain a copy of "Healthy People 2000" at


Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and eligible
agencies of the Federal government. Racial/ethnic minority individuals, women,
and persons with disabilities are encouraged to apply as Principal


This RFA will use the National Institutes of Health (NIH) research project
grant (R01) award mechanism. Applicants may also submit Investigator-Initiated
Interactive Research Project Grants (IRPG). Interactive Research Project
Grants require the coordinated submission of related regular research project
grant applications from investigators who wish to collaborate on research, but
do not require extensive shared physical resources.  Responsibility for the
planning, direction, and execution of the proposed project will be solely that
of the applicant.  The total project period for an  application submitted in
response to this RFA may not exceed 5 years.  This RFA is one-time
solicitation.  Future unsolicited competing continuation applications will
compete with all investigator-initiated applications and be reviewed according
to the customary peer review procedures.  The anticipated award date is
September 30, 1999.


The NIAAA intends to commit approximately $2,500,000 in FY 1999 to fund 8 to
10 new grants in response to this RFA. Because the nature and scope of the
research proposed may vary, it is anticipated that the size of each award will
also vary.  Although the financial plans of the NIAAA provide support for this
program, awards pursuant to this RFA are contingent upon the availability of
funds and the receipt of a sufficient number of applications of outstanding
scientific and technical merit.



Neuroscience and behavioral research funded by NIAAA has led to significant
advances in our understanding of how alcohol acts on the brain.  Specific
targets of alcohol in the brain are being characterized, and the adaptive
mechanisms underlying the development of dependence on alcohol are beginning
to be understood.  New findings from several research groups are beginning to
describe the configurations of the proteins of neurotransmitter receptors and
ion channels necessary for alcohol's actions.  In addition, amino acid
sequences that are important in the actions of alcohol are being identified. 
For example, using site-directed mutagenesis, researchers have found sequences
in the GABA receptor important for ethanol's action.  Such studies will help
in the design of new medications or the new use of already approved
medications that can block the effects of alcohol on the brain.  As research
further defines the mechanisms underlying the development of alcohol
dependence or other alcohol-related conditions, more effective pharmacotherapy
can evolve from these findings by helping to identify compounds for possible
clinical trials.  Evidence of the benefits of this research is exemplified by
the approval of naltrexone, the first drug approved by the Food and Drug
Administration (FDA) for alcoholism treatment in almost 50 years.

A similar approach can be used to develop new treatments for alcohol-induced
tissue injury.  For example, in the case of alcoholic liver disease, advances
have been made in understanding some of the factors that contribute to the
disease.  Research has shown that TNF-alpha levels in plasma and liver are
elevated in humans and animals affected with alcoholic liver disease.  In
animal models of alcoholic liver disease, administration of TNF-alpha
antibodies attenuates liver injury and in TNF-alpha receptor-deficient mice,
chronic ethanol feeding fails to elicit liver injury.  Thus, attenuation of
TNF-alpha levels may help to ameliorate alcoholic liver disease in humans.

Potential compounds can arise from a number of sources.  For example,
researchers use many substances to elucidate mechanisms underlying the actions
of alcohol.  Some of them may have clinical potential if properly developed to
the stage for controlled clinical trials.  Prototypes could also come from
existing libraries of compounds or from new ones based on some rational
molecular design.  Possible compounds can include those for use in other
clinical conditions or diseases with potential for treating various aspects of
alcohol-related conditions.  In addition, through serendipitous findings,
substances can reveal clinical potential.  To proceed to clinical trials,
appropriate in vivo efficacy and toxicological studies must be completed to
allow for an application for an Investigational New Drug (IND) that would
permit human testing.

General Principles

Any medication development program should be based on the clinical outcomes to
be obtained from use of a medication.  For example, in treating alcoholism,
the distinction should be made among obtaining total abstinence from alcohol,
decreased consumption, and reduced craving or relapse.  The targeted outcome
will determine the types of models and outcome measures used.  (See below for
areas of interest.)  It is anticipated that the review process will include
consideration of compound(s), appropriateness of the various models to test
efficacy, and specificity and predictiveness of outcome measures.  Validating
the predictive ability of a compound could, when relevant, include the use of
existing drugs for comparison purposes.

Animal Models

The use of animal models has been the hallmark of understanding how alcohol
modifies behavior and biological mechanisms.  These models have examined
alcohol consumption, positive and negative reinforcement, dependence and
withdrawal, craving and relapse and mimic alcohol-induced tissue injury.  In
developing and evaluating compounds of potential clinical value, some of the
same paradigms may be used.  However, rather than being research tools, they
become evaluative tools.  The efficacy of a compound is determined, in part,
by the outcome measures selected.  Appropriate care should be taken in
selecting the appropriate outcome measures, including consideration of
eventual FDA approval of human trials.

Human Testing

Early human screening of potential compounds is a critical element in the drug
development process.  Before embarking on costly Phase III clinical trials, it
is vital to know whether medications that look efficacious and safe in animal
models are also relevant to alcohol-related human behaviors and conditions.
Applications are also sought to develop/enhance the use of a limited number of
humans for early-stage testing of new clinical entities and/or existing
compounds for treatment of alcohol-related behaviors and medical conditions.

The development plan for both animals and humans should include: (1)
specification and rationale for the component(s) of the alcohol-related
phenomena being targeted, e.g., initiation of alcohol consumption, positive
reinforcement, negative reinforcement, relapse reduction, craving for alcohol,
improvement in cognitive deficits caused by excessive drinking.  (2)
Theoretical basis and detailed methodology for laboratory studies.  (3)
Rationale and relevance of surrogate markers/outcome measures to clinical
features of the selected alcohol phenomenon.  (4) Rationale and putative
mechanism of action by which the proposed compound(s) to be evaluated might
alter the targeted alcohol phenomenon.  (5) Clear and definitive strategy for
rejecting/further advancing a compound's development.  In the case of human
studies, full safety and toxicity profiles for proposed compound(s) are needed
to adequately justify introduction of test compounds into human subjects.

Areas Of Interest

Agents that Modulate/Suppress the Desire to Drink

Over the past 5 years, significant progress has been made with medications
that diminish the desire to drink (sometimes referred to as "anticraving"
medications).  This progress has been highlighted by the recent FDA-approval
of the opioid antagonist naltrexone.  In two landmark studies, alcohol-
dependent patients were treated with naltrexone for 3 months and experienced
higher sobriety rates, fewer days drinking, and lower craving for alcohol than
did placebo-treated subjects.  In particular, naltrexone-treated subjects who
sampled alcohol drank less alcohol than those who had received placebo.  With
psychosocial intervention, naltrexone-treated subjects who received a
supportive therapy emphasizing abstinence enjoyed higher rates of sobriety. 
If drinking was initiated, those treated with naltrexone and coping-skill
training were more successful in avoiding a return to heavy drinking.

In addition to opioid antagonists, other types of agents appear promising. 
One of these is acamprosate (calcium acetylhomotaurinate) and has been studied
extensively in Europe and appears efficacious in reducing alcohol consumption
and relapse, with no major adverse effects reported. Although the mechanism
underlying acamprosate's effect is still being investigated, it appears that
acamprosate interacts with the GABA system and excitatory amino acids such as

With the paucity of medications to reduce the desire to drink, a high priority
is for the development of new compounds in this area.

Agents to Treat the Protracted Withdrawal Syndrome

The protracted withdrawal syndrome, also known as protracted abstinence, late
withdrawal, or "dry drunk," is in the very early stages of research. 
Pharmacological treatment has been hampered by the lack of agreement on
distinctive signs and symptoms and the duration of the syndrome. Some of the
purported symptoms include anxiety, irritability, hostility, depression,
insomnia, fatigue, and craving.  Recent research has suggested that the
kindling effect may contribute to symptoms of protracted withdrawal, thereby
leading to alcohol craving and relapse.  Research is needed to determine the
efficacy of medications in preventing kindling and reducing the symptoms
associated with it.  It is likely that some of these medications may overlap
with pharmacological agents described above in reducing the desire to drink.

Agents Used to Treat Acute Alcohol Withdrawal

Acute alcohol withdrawal is characterized by a highly variable range of signs
and symptoms.  These include relatively mild signs and symptoms such as
sweating, tachycardia, hypertension, tremors, and anxiety to more serious
consequences including seizures and delirium tremens.  Its etiology has been
hypothesized to involve perturbation of one or more neuronal and hormonal
systems, including noradrenergic hyperactivity, alterations in gamma-
aminobutyric acid (GABA)-benzodiazepine receptors, elevated activity of the
hypothalamic-pituitary-adrenal axis, and changes in the N-methyl-D-aspartate
(NMDA) glutamate receptors.

For more than two decades, benzodiazepines have been the most widely used
medication for pharmacological management of alcohol withdrawal.  They are
effective in preventing delirium tremens and have consistently been
demonstrated to assuage many signs and symptoms of withdrawal.  Although the
most recent studies have focused on benzodiazepine dosing strategies,
benzodiazepines still have adverse effects including acute memory
difficulties, drowsiness, lethargy, and acute cognitive problems that may
complicate treatment and recovery.  Carbamazepine has also been shown to be
effective for treating alcohol withdrawal.

Other medications are being explored in the management of withdrawal symptoms,
including GABAergic agents, NMDA antagonists, dopaminergic agents, calcium
channel antagonists, and nitrous oxide.  Their effectiveness in the clinic has
not been established.

Another research topic under active investigation is alcohol withdrawal
"kindling" or sensitization.  Kindling studies suggest that the severity of
withdrawal symptoms increases as a function of the number of previous alcohol
withdrawals, an observation that has been reported in both animals and humans. 
If kindling plays an important role in the intensity of withdrawal symptoms,
especially after repeated withdrawals, new therapeutic strategies may be

Agents to Improve Cognitive Dysfunction

There is a very significant need to develop treatments for the prevention and
amelioration of the cognitive disturbances and structural brain damage
associated with alcohol consumption.  Among excessive drinkers, there is a
wide spectrum of cognitive disturbances associated with chronic ethanol
consumption, ranging from mild cognitive disturbances such as reduced
attentional and visuospatial abilities to severe amnesia, dementia and
psychosis.  Thus, medications to improve cognitive function in alcoholics,
particularly in alcoholic dementia and Korsakoff's psychosis, would lead to
enrichment in quality of life of alcoholics as well as reduction in costs of
long-term institutionalization.

Recent studies have suggested some medications can improve memory to a
clinically meaningful degree in some patients with alcohol-induced amnesia. 
Unfortunately, very little research has been conducted on developing
pharmacological cognitive enhancers or neuroprotective agents, a topic of
major concern.

Agents Used to Induce Sobriety in Intoxicated Individuals

The search for a single effective amethystic agent (alcohol antagonist) has
to-date been unsuccessful, perhaps due to alcohol's diverse effects on body
systems.  Continued research in this area is important since a significant
number of people die each year from alcohol overdose.  Development of
medications to induce sobriety quickly and safely is particularly needed to
assist treatment in emergency room settings.  Since death often comes from
respiratory arrest, medications blocking the effects of alcohol on respiration
should be emphasized.

Agents Used to Treat Alcohol-Induced Organ/Tissue Damage

Organ/tissue damage is a major medical consequence of chronic alcohol abuse. 
Medications are needed to prevent, alleviate, or counteract alcohol-induced
tissue injury.  Diseases include alcohol-induced hepatitis, hypertension,
cardiomyopathy, and pancreatitis.

Several approaches have been taken in the treatment of alcoholic liver
disease.  A major effort is exploring the role of oxidative stress.  To this
end, investigators are testing the effectiveness of the antioxidants vitamin A
and E and precursors of glutathione, and other nutritional supplements, such
as phosphatidylcholine and S-adenosylmethionine. Further studies are required
to test the efficacy of various antioxidants for the treatment and prevention
of alcoholic liver disease.  In addition, research on gene therapy for
alcoholic liver disease is being encouraged.  An example of this approach is
to increase in the liver the amount of superoxide dismutase, an enzyme that
metabolizes free radicals.

Reducing the activity of TNF-alpha in the liver would be another approach to
treating alcoholic liver disease.  Approaches could include developing TNF-
alpha antibodies or antisense nucleotides or reducing other proinflammatory
cytokines such as IL-1 and IL-6.


It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research.  This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research," which was published in the Federal Register of March 28, 1994 (FR
59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994, available on the web at:


It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in
Research Involving Human Subjects that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.


Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the proposed research, the name, address, and telephone
number of the Principal Investigator, the identities of other key personnel
and participating institutions, and the number and title of the RFA in
response to which the application may be submitted.  Although a letter of
intent is not required, is not binding, and does not enter into the review of
a subsequent application, the information that it contains allows NIAAA staff
to estimate the potential review workload and avoid conflict of interest in
the review.

The letter of intent is to be sent to the program staff listed under INQUIRIES
by the letter of intent receipt date listed in the heading of this RFA.


The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants.  These forms are available at most institutional
offices of sponsored research and from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email:

The RFA label available in the PHS 398 (rev. 4/98) application form must be
affixed to the bottom of the face page of the application.  Failure to use
this label could result in delayed processing of the application such that it
may not reach the review committee in time for review.  In addition, the RFA
title and number must be typed on line 2 of the face page of the application
form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed, photocopies, in one package to:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must be
sent to:

Chief, Extramural Project Review Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 409, MSC 7003
Bethesda, MD  20892-7003
Rockville, MD  20852 (for express/courier service)

Applications must be received by the application receipt date listed in the
heading of this RFA.  If an application is received after that date, it will
be returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The
CSR will not accept any application that is essentially the same as one
already reviewed. This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications must include
an introduction addressing the previous critique.


Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NIAAA. If the application is not responsive to the RFA,
CSR staff may contact the applicant to determine whether to return the
application to the applicant or submit it for review in competition with
unsolicited applications at the next review cycle.

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the NIAAA in accordance with the review criteria stated below.  As part of the
initial merit review, a process may be used by the initial review group in
which applications receive a written critique and undergo a process in which
only those applications deemed to have the highest scientific merit, generally
the top half of the applications under review, will be discussed, assigned a
priority score, and receive a second level review by the National Advisory
Council on Alcohol Abuse and Alcoholism.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In
the written comments reviewers will be asked to discuss the following aspects
of the application in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered in assigning the overall score,
weighting them as appropriate for each application.  Note that the application
does not need to be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high priority score.  For example, an
investigator may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.

(1) Significance:  Does this study address an important problem, e.g. clinical
outcome? If the aims of the application are achieved, how will scientific
knowledge be advanced?  What will be the effect of these studies on the
concepts or methods that drive this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?  Are the compounds, the models, and the relevance of the
outcome measures appropriately justified?

(3) Innovation:  Does the project employ novel concepts, approaches or method?
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements?  Is there evidence of institutional

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the
research.  Plans for the recruitment and retention of subjects will also be

o  The reasonableness of the proposed budget and duration in relation to the
proposed research

o  The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project 
proposed in the application.


Letter of Intent Receipt Date:    April 2, 1999
Application Receipt Date:         April 28, 1999
Peer Review Date:                 July 1999
Council Review:                   September 1999
Earliest Anticipated Start Date:  September 30, 1999


Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review);
o  availability of funds; and
o  programmatic priorities.


Inquiries concerning this RFA are encouraged.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues involving animal studies to:

Walter A. Hunt, Ph.D.
Division of Basic Research 
National Institute of Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD  20892
Telephone:  (301) 443-4225
FAX:  (301) 594-0673

Direct inquiries regarding programmatic issues involving human studies to:

Joanne Fertig, Ph.D.
Division of Clinical and Prevention Research
National Institute of Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 505, MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-0635
FAX: (301) 443-8774

Direct inquiries regarding fiscal matters to:

Linda Hilley
Grants Management Branch
National Institute of Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 504, MSC-7003
Bethesda, MD  20892-7003
Telephone: (301) 443-4704
FAX:  (301) 443-3891

Applications from small businesses under the SBIR Program are also encouraged
under the Small Business Innovative Research (SBIR) Program announcement. SBIR
grant application guidelines and application receipt deadline dates can be
found at


This program is described in the Catalog of Federal Domestic Assistance No.
93.273. Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC
241 and 285) and administered under NIH grant policies and Federal Regulations
42 CFR 52 and 45 CFR Part 74 or Part 92, as applicable. This program is not
subject to the intergovernmental review requirements of Executive Order 12372
or Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-use of all tobacco products.  In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care, or early childhood
development services are provided to children.  This is consistent with the
PHS mission to protect and advance the physical and mental health of the
American people.

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