MEDICATIONS TO TREAT ALCOHOL DEPENDENCE AND ALCOHOL-RELATED DISEASES

Release Date:  October 1, 2001

RFA:  RFA-AA-02-005

National Institute on Alcohol Abuse and Alcoholism
 (http://www.niaaa.nih.gov/)

Letter of Intent Receipt Date:  January 13, 2002
Application Receipt Date:       February 13, 2002

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  MODULAR 
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS UP TO $250,000 PER 
YEAR. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 
(REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

PURPOSE

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking 
research grant applications on the clinical use of medications for alcohol 
abuse/dependence and alcohol-related diseases.  Investigation are needed on 
pharmacological agents that prevent or reduce alcohol intake by decreasing the 
alcohol craving/urge to drink and/or alleviating the negative symptoms 
associated with drinking (e.g., protracted withdrawal syndrome). Evaluations 
of pharmacological agents to clinically treat alcohol-induced diseases, such 
as alcoholic liver diseases, are also encouraged.  In addition, applications 
can include the utilization of human laboratory paradigms to screen potential 
medications for subsequent Phase 2 and 3 trials as well as to determine the 
actions of the medications.  All applications submitted in response to this 
RFA should be conducted in humans.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of "Healthy People 2010," a PHS-led national 
activity for setting priority areas.  This Request for Applications (RFA), 
Medications to Clinically Treat Alcohol Dependence and Alcohol-Related 
Disease, is related to one or more of the priority areas.  Potential 
applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

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 
Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project 
grant (R01) and the NIAAA exploratory/developmental (R21) award mechanism.  
Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  The total project period for a 
research project grant (R01) application submitted in response to this RFA may 
not exceed 5 years.  Exploratory/developmental grants (R21) are limited to 3 
years for up to $100,000/year for direct costs. (See Program Announcement PA- 
99-131, “NIAAA Exploratory/Developmental Grant Program,” 
http://grants.nih.gov/grants/guide/pa-files/PA-99-131.html, for a complete 
description of the R21 mechanism.) This RFA is a 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 2002.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH. Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001).  
Additional information on Modular Grants can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm

FUNDS AVAILABLE

The NIAAA intends to commit approximately $2,000,000 in FY 2002 to fund 6 to 
10 new and/or competitive continuation 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 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 
meritorious applications. At this time, it is not known if this RFA will be 
reissued.

RESEARCH OBJECTIVES

Background

During the past decade advances have been made in medications development to 
treat alcoholism (see comprehensive reviews by Garbutt et al., 1999; Swift, 
1999; and Kranzler, 2000).  The fruits of these efforts have been highlighted 
by the FDA approval of naltrexone, the first medication approved for 
alcoholism in the 50 years since the introduction of disulfiram.  Advances 
have also been made in understanding the biological mechanisms underlying 
alcohol drinking behavior.  For example, it is now known that multiple 
neurotransmitter, neuromodulator, and hormonal systems can alter alcohol 
intake and are either directly or indirectly involved in problematic drinking. 
These include opioid, serotonin, dopamine, gamma-aminobutyric acid (GABA), 
glutamate, neuropeptide Y, and hypothalamic-pituitary-adrenal (HPA) systems 
(Litten et al., 1996; Roberts and Koob, 1997; Johnson and Ait-Daoud, 2000).  
This recent knowledge has led to many biological targets for testing novel 
pharmacological agents.

To date, the two most promising and successful medications are naltrexone and 
acamprosate.  Two important clinical trials of naltrexone (Volpicelli et al., 
1992 and O’Malley et al., 1992) first demonstrated efficacy of naltrexone in 
alcohol dependent patients and contributed significantly to FDA approval of 
naltrexone.  Although naltrexone is not a “magic bullet” for alcoholism 
treatment, it appears to have a moderate effect in reducing drinking, 
particularly reducing relapse to heavy drinking (Volpicelli et al., 1997; 
Anton et al., 1999; Morris et al., 2001; Heinala et al., 2001).   Recent 
studies have suggested that patient compliance plays a significant role in the 
efficacy of naltrexone (Volpicelli et al., 1997; Chick et al., 2000).  Several 
studies are currently being funded to address many issues surrounding the 
clinical use of naltrexone such as how long should patients receive 
naltrexone; what is the optimal dose; what types of alcoholics respond best; 
what is the optimal combination with behavioral/psychosocial interventions; 
and can the efficacy of naltrexone be improved by combining it with other 
medications.  Finally, nalmefene, another opioid antagonist, has also 
demonstrated effectiveness in preventing relapse to heavy drinking in alcohol-
dependent patients (Mason et al., 1999).

Acamprosate has been studied extensively in Europe and is currently approved 
for alcoholism treatment in 37 countries. Sixteen controlled clinical trials 
have been conducted across 11 European countries involving more than 4,600 
alcohol dependent patients.  The studies have consistently shown that 
individuals treated with acamprosate are more likely to complete treatment, 
have longer times to their first drink, have greater abstinence rates, and 
demonstrate longer cumulative abstinence durations than placebo-treated 
patients (Mason and Ownby, 2000). A 21-site trial of acamprosate has recently 
been completed in the US with 601 alcohol dependent patients. Results of this 
trial will be submitted to the FDA as part of a New Drug Application to obtain 
US approval.  Acamprosate’s mechanism of action has yet to be definitively 
identified, although several studies suggest that it may modulate activity of 
the glutamate system (Littleton, 1995; Spanagel and Zieglgansberger, 1997).

The serotonergic system has also been implicated in drinking behavior.  The 
serontonin3 (5-HT3) receptor has been shown to regulate release of dopamine in 
the mesolimbic area, particularly in the nucleus accumbens.  Ondansetron, a 5-
HT3 antagonist, has been demonstrated to reduce desire to drink in humans and 
to augment stimulant and sedative effects of alcohol (Johnson, 1993; Swift et 
al., 1996).  A 12-week dosage trial of ondansetron has recently been completed 
in early onset alcoholics and late onset alcoholics (Johnson et al., 2000b).  
Ondansetron reduced frequency and quantity of alcohol consumption in early 
onset alcoholics, but not in the late onset alcoholics.  Interestingly, a 
preliminary study combining ondansetron and naltrexone showed that the 
combination reduced alcohol craving and enhanced drinking outcome to a greater 
extent than had each demonstrated alone (Johnson et al., 2000a; Ait-Daoud et 
al., 2001).

Results of selective serotonin reuptake inhibitors (SSRIs) in human alcohol 
trials have been inconsistent (Pettinati, 1996, Kranzler, 2000).  Recent data, 
however, suggest that subpopulations of alcohol dependent patients respond 
differentially to the SSRIs.  For example, Kranzler et al. (1996) and 
Pettinati et al. (2000) showed that higher-risk/severity type B alcoholics had 
less favorable treatment outcome to SSRIs than lower-risk/severity type A 
alcoholics.  Cornelius and colleagues (1997) found that fluoxetine reduced 
depressive symptoms and alcohol intake in severe inpatient populations of 
alcoholics with major depression and suicide risk.  In contrast, Pettinati et 
al. (2001) and McGrath (1998) reported that fluoxetine and sertraline were no 
better than placebo in improving depression and reducing drinking in a less 
severe population of depressed alcoholics. 

Since all the medications discussed above produce small to medium effects to 
reduce or prevent drinking, developing and evaluating new and more potent 
medications remain a high priority.  Several promising pharmacological agents 
could lead to clinical testing.  These include, but are not limited to, 
memantine, a non-competitive NMDA antagonist (Holter et al., 1996); kudzu and 
its purified active components (e.g., puerarin) (Keung and Vallee, 1993; Lin 
et al., 1996); corticotropin-releasing factor (CRF) antagonists (Bell et al., 
1998; Le et al., 2000; Richter et al., 2000); opioid subtype receptor 
antagonists such as delta2 antagonist naltriben (June et al., 1999); 6-beta 
naltrexol, an active metabolite of naltrexone (Rukstalis et al., 2000); 
synthetic neurosteroids (Morrow et al., 1999); 1-aminocyclopropanecarboxylic 
acid (ACPC), a NMDA partial agonist (Stromberg et al., 1999); and FG 5974 (and 
its analogues), a 5-HT1A agonist/5-HT2A antagonist (Roberts et al., 1998).

Finally, progress has been made in elucidating the mechanisms of alcohol-
induced organ damage.  In particular, several primary factors underlying the 
pathogensis of alcoholic liver disease have been identified including 
cytokines and reactive oxygen species (ROS) (Tsukamoto and Lu, 2001).  For 
example, the administration of antibodies against the proinflammatory tumor 
necrosis factor (TNF)-? attenuated alcohol-induced liver injury in rats 
(Iimuro et al., 1997).  A later study showed an absence of alcohol liver 
injury in knockout mice missing the TNF receptor 1 (Yin et al., 1999). ROS are 
generated by the metabolism of alcohol and can also cause damage to the liver 
(Tsukamoto and Lu, 2001). ROS are quickly inactivated by antioxidants, such as 
glutathione and vitamins A and E.  Antioxidants, such as S-adenosyl-L-
methionine (SAMe), have also been shown to reduce alcohol-induced liver injury 
in animals.  Potential new treatments of alcoholic liver disease include 
antioxidants, such as SAMe and vitamin E; as well as other types of agents 
including phosphatidylcholine, a phospholipid; pirfenidone, a new broad-
spectrum anti-fibrotic agent; and metformin, an insulin-sensitizing agent 
(Lieber, 2001; Miric et al., 2001; Tsukamoto and Lu, 2001).    

Specific Areas of Interest 

NIAAA is committed to the development and assessment of pharmacological agents 
to treat alcohol use disorders as well as the more prevalent and severe 
medical conditions associated with chronic drinking. Pharmacological agents of 
interest for human laboratory testing and Phase 2, 3, and 4 clinical testing 
can be categorized by function as follows: 

- Agents to decrease craving or urge to drink;

- Agents to attenuate negative symptoms of alcoholism (e.g.,"protracted 
withdrawal" symptoms);

- Agents to diminish drinking by alleviating co-occurring psychiatric 
pathology and other drug use; 

- Agents to treat alcohol-associated liver disease and other end-organ 
diseases, such as pancreatitis, cardiomyopathy, and bone disease. 

Many important clinical priorities and issues exist for these classes of 
pharmacological agents and are identified, but not limited, to the following: 

- New and existing pharmacological agents (already having IND status) and 
combination of those agents, need to be identified and evaluated in 
conjunction with behavioral therapies for alcoholism treatment.  Optimal 
dosing regimens and length of treatment need to be established.  Although 
NIAAA has supported projects on the efficacy of the opioid antagonist 
naltrexone, the therapeutic potential of other pharmacological agents in the 
opioid class is a current research priority.  In addition to opioid 
antagonists, the therapeutic potential of other types of agents needs to be 
assessed.  Among these are agents that interact with the serotonergic, 
dopaminergic, glutamatergic, GABAergic, and HPA systems as well as herbal 
preparations.   

- Development of pharmacological agents to attenuate negative symptoms of 
chronic drinking, sometimes referred to as the "protracted withdrawal" 
syndrome.  Research on potential pharmacological treatment of this phenomenon 
has been quite limited, due to failure to specify cardinal symptoms associated 
with sustained sobriety by alcoholics. Research is needed to establish 
operational definitions of this event as is research on agents to reduce 
relapse. 

- Pharmacological agents need to be identified and their efficacy evaluated in 
special populations previously understudied in medication trials.  Examples of 
such populations of interest are alcohol abusing/dependent individuals in the 
criminal justice system, health professions, adolescents and the elderly.

- Development of pharmacological agents to treat alcoholics with comorbid 
psychopathology such as bipolar disorder, schizophrenia, and anxiety disorders 
including social phobia and post-traumatic stress disorder. The co-occurrence 
of psychiatric problems among alcoholics in treatment is frequent. 
Comorbidity, however, is generally associated with a poorer treatment 
prognosis as well as high dropout rates and poor compliance.  Research needs 
to include assessment of changes in the comorbid psychopathology as well as 
changes in drinking outcomes.

- Development of medications to treat alcoholic liver diseases and other 
alcohol-related, end-organ diseases. These may include agents that inactivate 
excess ROS or alter the production or clearance of cytokines.  In reducing the 
high mortality from alcoholic hepatitis and cirrhosis, potential medications 
that prevent necrosis/inflammation and avert or reverse the progression of 
fibrosis are of high priority.  Other potential agents include those that are 
effective in treating alcohol-induced portal hypertension, pancreatitis, and 
bone disease.

- Factors influencing clinical efficacy of medications to treat alcohol abuse 
and dependence can be identified using human laboratory behavioral 
pharmacology paradigms.  Prior to beginning phase 2 clinical trials potential 
medications can be screened in the laboratory to determine the following: 1) 
the medication’s impact to reduce craving for alcohol and/or to diminish the 
negative symptoms of drinking; 2) likelihood of adverse events, especially in 
the presence of alcohol; 3) pharmacokinetics for medication combinations; and 
4) optimal dosing regimens.  Studies are sought which develop and expand use 
of these human laboratory paradigms.

Supported pharmacological investigations should include use of appropriate 
control groups, adequate sample sizes, and employment of proper statistical 
analyses.  In evaluating the efficacy of all pharmacological agents, it is 
important to identify subtypes of alcoholics particularly amenable to 
pharmacological treatment as well as to explore integration of pharmacotherapy 
with behavioral and verbal therapies. In addition, the experimental treatments 
should be carefully described, and diagnostic and outcome instruments should 
reflect state-of-the-art alcoholism assessment.  While early clinical studies 
may employ highly homogeneous samples in a single setting, it is desirable in 
later-stage research to have greater heterogeneity in samples and sites.  
Efficacy studies also need to measure compliance with the pharmacological 
intervention and adequately verify self-reports. Finally, after completion of 
the active treatment of the clinical trial, it is recommended that subjects be 
followed-up for at least six months.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and 
their sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating 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 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at  
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. 

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.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS

NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

DATA AND SAFETY MONITORING PLAN 

As of the October 2000 receipt date, applicants must supply a general 
description of the Data and Safety Monitoring Plan for ALL clinical trials; 
this must be included in the application 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html
The degree of monitoring should be commensurate with risk. NIH Policy for Data 
and Safety Monitoring requires establishment of formal Data and Safety 
Monitoring Boards for multi-site clinical trials involving interventions that 
entail potential risk to the participants. The absence of this information 
will negatively affect your priority score.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT

The Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) cited 
publicly and officially by a Federal agency in support of an action that has 
the force and effect of law (i.e., a regulation) may be accessed through FOIA.  
It is important for applicants to understand the basic scope of this 
amendment.  NIH has provided guidance at:
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the application. 
In addition, applicants should think about how to structure informed consent 
statements and other human subjects procedures given the potential for wider 
use of data collected under this award.

LETTER OF INTENT

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 plan the review.

The letter of intent is to be sent to:

RFA-AA-02-005
Extramural Project Review Branch 
National Institute on Alcohol Abuse and Alcoholism 
6000 Executive Boulevard, Room 409, MSC 7003 
Bethesda, MD  20892-7003 
Rockville, MD  20852 (for express/courier service) 
Telephone:  (301) 443-4375  FAX:  (301) 443-6077 

by the letter of intent receipt date listed.


APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in 
applying for these grants and will be accepted at the standard application 
deadlines (http://grants.nih.gov/grants/dates.htm) as indicated in the 
application kit.  This version of the PHS 398 is available in an interactive, 
searchable PDF format. The NIH will return applications that are not submitted 
on the 5/2001 version.  For further assistance contact GrantsInfo, Telephone 
301/435-0714, Email: GrantsInfo@nih.gov.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only when 
there is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and NIH staff.  
The research grant application form PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.

The RFA label available in the PHS 398 (rev. 5/2001) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  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. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

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

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
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:

Extramural Project Review Branch
RFA: AA02-005
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Blvd, 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by NIAAA.  Incomplete and/or non-responsive applications will 
be returned to the applicant without further consideration.  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, all applications will 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? 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?

(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 
support?

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 
evaluated.

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

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

o  The adequacy of the proposed plan to share data, if appropriate.


Schedule:

Letter of Intent Receipt Date:    January 13, 2002
Application Receipt Date:         February 13, 2002
Peer Review Date:                 April-May 2002
Council Review:                   August 2002
Earliest Anticipated Start Date:  September 29, 2002

AWARD CRITERIA

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

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

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Joanne B. Fertig, Ph.D.
Division of Clinical and Prevention Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard MSC 7003, Suite 505
Bethesda, MD  20892-7003
Rockville, MD  20852 (for express mail/courier)
Telephone:  (301) 443-0635
FAX:  (301) 443-8774
Email:  jfertig@willco.niaaa.nih.gov


Direct inquiries regarding fiscal matters to:

Judy Fox Simons
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 505
6000 executive Blvd. (MSC-7003)
Bethesda, MD  20892-7003
(For express mail use:  Rockville, MD  20852)
Telephone:  (301) 443-2434
Email:  jsimons@willco.niaaa.nih.gov


AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.273.  Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  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.


REFERENCES

Ait-Daoud, N., Johnson, B.A., Prihoda, T.J., and Hargita, I.D. (2001) 
Combining odansetron and naltrexone reduces craving among biologically 
predisposed alcoholics: Preliminary clinical evidence.  Psychopharmacology 
154:23-27.

Anton, R.F., Moak, D.H., Waid, L.R., Latham, P.K., Malcolm, R.J. and Dias, 
J.K. (1999) Naltrexone and cognitive behavioral therapy for the treatment of 
outpatient alcoholics: Results of a placebo-controlled trial.  American 
Journal of Psychiatry 156:1758-1764.

Bell, S.M., Reynolds, J.G., Thiele, T.E., Gan, J., Figlewicz, D.P., and Woods, 
S.C. (1998) Effects of third intracerebroventricular injections of 
corticotropin-releasing factor (CRF) on ethanol drinking and food intake.  
Psychopharmacology 139:128-135.

Chick, J., Anton, R., Checinski, K., Croop, R., Drummond, D.C., Farmer, R., 
Labriola, D., Marshall, J., Moncrieff, J., Morgan, M.Y., Peters, T., and 
Ritson, B. (2000) A multicentre, randomized, double-blind, placebo-controlled 
trial of naltrexone in the treatment of alcohol dependence or abuse.  The 
Journal of Alcohol and Alcoholism 35:587-593.

Cornelius, J.R., Salloum, I.M., Ehler, J.G., Jarrett, P.J., Cornelius, M.D., 
Perel, J.M., Thase, M.E., and Black, A. (1997) Fluoxetine in depressed 
alcoholics: A double-blind, placebo-controlled trial.  Archives of General 
Psychiatry 54:700-705.

Garbutt, J.C., West, S.L., Carey, T.S., Lohr, K.N., and Crews, F.T. (1999) 
Pharmacological treatment of alcohol dependence: A review of the evidence.  
Journal of the American Medical Association 281:1318-1325.

Heinala, P., Alho, J., Kiianmaa, K., Lonnqvist, J., Kuoppasalmi, K., and 
Sinclair, J.D. (2001) Targeted use of naltrexone without prior detoxification 
in the treatment of alcohol dependence: A factorial double-blind, placebo-
controlled trial.  Journal of Clinical Psychopharmacology 21:287-292.

Holter, S.M., Danysz, W., and Spanagel, R. (1996) Evidence for alcohol anti-
craving properties of memantine.  European Journal of Pharmacology 314:R1-R2.

Iimuro, Y., Gallucci, R.M., Luster, M.I., Kono, H., and Thurman, R.G. (1997) 
Antibodies to tumor necrosis factor alpha attenuate hepatic necrosis and 
inflammation caused by chronic exposure to ethanol in the rat.  Hepatology 26: 
1530-1537. 

Johnson, B.A., Campling, G.M., Griffiths, P., and Cowen, P.J. (1993) 
Attenuation of some alcohol-induced mood changes and the desire to drink by 5-
HT3 receptor blockade: A preliminary study in healthy male volunteers.  
Psychopharmacology 112:142-144.

Johnson, B.A., and Ait-Daoud, N. (2000) Neuropharmacological treatments for 
alcoholism: Scientific basis and clinical findings.  Psychopharmacology 
149:327-344.

Johnson, B.A., Ait-Daoud, N., and Prihoda, T.J. (2000a)  Combining ondansetron 
and naltrexone effectively treats biologically predisposed alcoholics:  From 
hypotheses to preliminary clinical evidence.  Alcoholism:  Clinical and 
Experimental Research 24:737-742.

Johnson, B.A., Roache, J.D., Javors, M.A., DiClemente, C.C., Cloninger, C.R., 
Prihoda, T.J., Bordnick, P.S., Ait-Daoud, N., and Hensler, J. (2000b) 
Odansetron for reduction of drinking among biologically predisposed alcoholic 
patients:  A randomized controlled trial.  Journal of American Medical 
Association 284:963-971.

June, H.L., McCane, S.R., Zink, R.W., Portoghese, P.S., Li, T.K., and 
Froehlich, J.C. (1999) The d2-opioid receptor antagonist naltriben reduces 
motivated responding for ethanol.  Psychopharmacology 147:81-89.

Keung, W-M., and Vallee, B.L. (1993) Daidzin and daidzein suppress free-choice 
ethanol intake by Syrian Golden hamsters.  Proceeding of the National Academy 
of Sciences of the USA 90:10008-10012.

Kranzler, H.R. (2000) Pharmacotherapy of alcoholism: Gaps in knowledge and 
opportunities for research.  Journal of Alcohol and Alcoholism 35:537-547.

Kranzler, H.R., Burleson, J.A., Brown, J., and Babor, T.F. (1996) Fluxoxetine 
treatment seems to reduce the beneficial effects of cognitive-behavioral 
therapy in type B alcoholics.  Alcoholism:  Clinical and Experimental Research 
20:1534-1541.

Lê., A.D., Harding, S., Juzytsch, W., and Watchus, J. (2000) The role of 
corticotrophin-releasing factor in stress-induced relapse to alcohol-seeking 
behavior in rats.  Psychopharmacology 150:317-324.

Lieber, C.S. (2001) Liver diseases by alcohol and hepatitis C: Early detection 
and new insights in pathogenesis lead to improved treatment.  The American 
Journal on Addictions 10(Supplement): 29-50.

Lin, R.C., Guthrie, S., Xie, C-Y., Mai, K., Lee, D.Y., Lumeng, L., and Li, T-
K. (1996) Isoflavonoid compounds extracted from Pueraria labata suppress 
alcohol preference in a pharmacogenetic rat model of alcoholism.  Alcoholism:  
Clinical and Experimental Research 20:659-663.

Litten, R.Z., Allen, J., and Fertig, J. (1996) Pharmacotherapies for alcohol 
problems:  A review of research with focus on developments since 1991. 
Alcoholism:  Clinical and Experimental Research 20:859-876.

Littleton, J. (1995) Acamprosate in alcohol dependence: How does it work?  
Addiction 90:1179-1188.

Mason, B.J., and Ownby, R.L. (2000) Acamprosate for the treatment of alcohol 
dependence:  A review of double-blind, placebo-controlled trials.  CNS 
Spectrums 5:58-69.

Mason, B.J., Salvato, F.R., Williams, L.D., Ritvo, E.C., and Cutler, R.B. 
(1999) A double-blind, placebo-controlled study of oral nalmefene for alcohol 
dependence.  Archives of General Psychiatry 56:719-724.

McGrath, P.J. (1998) Antidepressant treatment outcomes for primary depression 
comorbid with alcoholism.  Presented at the Scientific Meeting of the Research 
Society on Alcoholism, Hilton Head Island, South Carolina.

Miric, G., Dallemagne, C., Endre, Z., Margolin, S., Taylor, S.M., and Brown, 
L. (2001) Reversal of cardiac and renal fibrosis by pirfenidone and 
spironolactone in streptozotocin-diabetic rats. British Journal of 
Pharmacology 133:687-694.

Morris, P.LP., Hopwood, M., Whelan, G., Gardiner, J., and Drummond, E. (2001) 
Naltrexone for alcohol dependence:  A randomized controlled trial.  Journal of 
Alcohol and Alcoholism, in press. 

Morrow, A.L., Janis, G.C., VanDoren, M.J., Matthews, D.B., Samson, H.H., 
Janak, P.H., and Grant, K.A. (1999) Neurosteroids mediate pharmacological 
effects of ethanol: A new mechanism of ethanol action?  Alcoholism:  Clinical 
and Experimental Research 23:1933-1940.

O’Malley, S.S., Jaffe, A.J., Chang, G., Schottenfeld, R.S., Meyer, R.E. and 
Rounsaville, B. (1992) Naltrexone and coping skills therapy for alcohol 
dependence:  A controlled study.  Archives of General Psychiatry 49:881-887.

Pettinati, H.M. (1996) Use of serotonin selective pharmacotherapy in the 
treatment of alcohol dependence.  Alcoholism:  Clinical and Experimental 
Research 20:23A-29A.

Pettinati, H.M., Volpicelli, J.R., Kranzler, H.R., Luck, G., Rukstalis, M.R. 
and Cnaan, A. (2000) Sertraline treatment for alcohol dependence:  Interactive 
effects of medication and alcoholic subtype. Alcoholism:  Clinical and 
Experimental Research 24:1041-1049.

Pettinati, H.M., Volpicelli, J.R., Luck, G., Kranzler, H.R., Rukstalis, M.R. 
and Cnaan, A. (2001) Double-blind clinical trial of sertraline treatment for 
alcohol dependence. Journal of Clinical Psychopharmacology 21:143-153.

Richter, R.M., Zorrilla, E.P., Basso, A.M., Koob, G.F., and Weiss, F. (2000) 
Altered amygdalar CRF release and increased anxiety-like behavior in sardinian 
alcohol-preferring rats:  A microdialysis and behavioral study. Alcoholism:  
Clinical and Experimental Research 24:1765-1772.

Roberts, A.J. and Koob, G.F. (1997) The neurobiology of addiction:  An 
overview. Alcoholism:  Clinical and Experimental Research 21:101-114.

Roberts, A.J., McArthur, R.A., Hull, E.E., Post, C. and Koob, G.F. (1998) 
Effects of amperozide, 8-OH-DPAT, and FG 5974 on operant responding for 
ethanol.  Psychopharmacology 137:25-32.

Rukstalis, M.R., Stromberg, M.F., O’Brien, C.P. and Volpicelli, J.R. (2000) 6-
ß-naltrexol reduces alcohol consumption in rats. Alcoholism:  Clinical and 
Experimental Research 24:1593-1596.

Spanagel, R. and Zieglgansberger, W. (1997) Anti-craving compounds for 
ethanol: New pharmacological tools to study addictive processes.  Trends in 
Pharmacological Sciences 18:54-59.

Stromberg, M.F., Volpicelli, J.R., O’Brien, C.P. and Mackler, S.A. (1999) The 
NMDA receptor partial agonist, 1-aminocyclopropanecarboxylic acid (ACPC), 
reduces ethanol consumption in the rat.  Pharmachology Biochemistry and 
Behavior 64:585-590.

Swift, R.M., Davidson, D., Whelihan, W., and Kuznetsov O. (1996) Ondansetron 
alters human alcohol intoxication.  Biological Psychiatry 40:514-521.

Swift, R.M. (1999) Drug therapy for alcohol dependence.  The New England 
Journal of Medicine 340:1482-1490.

Tsukamoto, H. and Lu, S.C. (2001) Current concepts in the pathogenesis of 
alcoholic liver injury.  FASEB Journal 15: 1335-1349.

Volpicelli, J.R., Alterman, A.I., Hayashida, M. and O’Brien, C.P. (1992) 
Naltrexone in the treatment of alcohol dependence.  Archives of General 
Psychiatry 49:876-880.

Volpicelli, J.R., Rhines, K.C., Rhines, J.S. Volpicelli, J.A., Alterman, A.I 
and O’Brien, C.P. (1997) Naltrexone and alcohol dependence.  Archives of 
General Psychiatry 54:737-742.

Yin, M., Wheeler, M.D., Kono, H., Bradford, B.U., Gallucci, R.M., Luster, 
M.I., and Thurman, R.G. (1999). Essential role of tumor necrosis factor alpha 
in alcohol-induced liver injury in mice.  Gastroenterology 117: 942-952.


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