MEDICATIONS DEVELOPMENT TO TREAT ALCOHOLISM AND ALCOHOL-RELATED DISEASES
(SBIR/STTR)
RELEASE DATE: October 7, 2002
RFA NUMBER: AA-03-005
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
(http://www.niaaa.nih.gov)
LETTER OF INTENT RECEIPT DATE: December 23, 2002
APPLICATION RECEIPT DATE: January 23, 2003
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Mechanism Objectives
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations
o References
PURPOSE
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is
seeking research grant applications on the development of medications
for alcohol abuse/dependence and alcohol-related diseases.
Investigations 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. Applications are also encouraged
to develop and test agents for the treatment of acute alcohol
withdrawal and alcohol intoxication. Evaluations of pharmacological
agents to treat alcohol-induced diseases, such as alcoholic liver
diseases, are encouraged as well.
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 (NPY), cannabinoid, and hypothalamic-
pituitary-adrenal (HPA) systems (Litten et al., 1996; Roberts and Koob,
1997; Johnson and Ait-Daoud, 2000; Lallemand et al., 2001). 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; Monti et al.,
2001). Nonetheless, naltrexone may not be effective for all alcoholics
(Kranzler et al., 2000; Krystal et al, 2001). 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 have
been 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); FG 5974 (and
its analogues), a 5-HT1A agonist/5-HT2A antagonist (Roberts et al.,
1998), and agents with selective affinity to GABAA alpha1 or GABAA alpha5
receptor subunits (June et al., 2001, Harvey et al., 2002).
A spectrum of neurotransmitter systems (e.g., GABA, NMDA, 5-HT,
dopamine), neuropeptide systems (neuropeptide Y, leptin), signal
transduction pathways (PKA, PKC), and gene transcription factors (delta
fosB) have been implicated in alcohol dependence and craving. New
therapeutic compounds may emerge from further research on known ethanol
targets, or may occur by identifying possible therapeutic targets and
prototype drug candidates through research on systems and mechanisms
not yet examined in relation to alcohol. As basic research reveals
promising targets relevant to alcohol abuse and its consequences,
analogs acquired from existing libraries, or newly-synthesized analogs
developed through computational and combinatorial chemistry can be
screened in vitro or in standardized behavioral assays for potential
therapeutic efficacy.
Advances in molecular genetics (e.g., microarray analysis, targeted
mutations, and proteomics) offer a powerful approach for broad-spectrum
scanning of participants in the adaptive process. Individual gene
clusters or functionally-related proteins can be identified in specific
brain regions in temporal relation to alcohol exposure. Such studies
may identify biochemical pathways and brain circuits which are
preferentially recruited as alcohol dependence develops. Receptors or
pathways involved in alcohol drinking and other alcohol effects can be
disabled selectively with targeted knockout strategies. An unanswered
question facing medical treatment concerns potential targets for
modifying neurological changes underlying craving and alcohol-seeking
after periods of prolonged abstinence.
For pharmacological management of acute alcohol withdrawal,
benzodiazepines have been the most widely used medication over the past
two decades. They have consistently been demonstrated to assuage many
symptoms of withdrawal (Mayo-Smith, 1997). Recent studies have focused
on benzodiazepine dosing strategies. For example, a "loading dose"
technique in which benzodiazepines are given every 1 or 2 hours until
withdrawal symptoms subside, appears effective in preventing over- and
under-dosing of medication (Wartenberg et al., 1990; Sullivan et al.,
1991; Saitz et al., 1994). Yet in spite of their benefits,
benzodiazepines have adverse effects including memory impairment,
drowsiness, lethargy, and cognitive problems.
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 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.
- Agents to treat acute alcohol withdrawal.
- Agents to induce sobriety in intoxicated individuals
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 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, NPY, cannabinoid,
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 the severity of protracted symptoms.
- 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.
- 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.
- Use of proteomic approaches to identify molecular targets for
medications development for alcohol abuse susceptibility, alcohol
dependence, alcohol consumption, withdrawal, and relapse, and alcohol-
associated medical conditions.
- Synthesis of new compounds based on the molecular structure of
receptors, ion channels, and sites of cellular signal transduction
mechanisms involved in alcohol's actions on the nervous system.
- Screening of existing "off the shelf" compounds for properties
associated with therapuetic efficacy for treating alcohol abuse and
alcohol related conditions.
- Identification of factors influencing clinical efficacy of
medications 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.
- Development of alternative medications to treat acute alcohol
withdrawal. Also, assuming the "kindling" effect (the severity of
withdrawal symptoms increases after repeated withdrawal episodes) has
clinical relevance (Becker, 1998), can kindling be effectively curbed
by medications to treat withdrawal?
MECHANISM OF SUPPORT PHASE I
Phase I applications in response to this RFA will be funded as Phase I
SBIR grants (R43) or STTR grants (R41) with modifications as described
below. Responsibility for the planning, direction, and execution of the
proposed research will be solely that of the applicant. Applications
for Phase I grants should be prepared using the PHS 398 instructions
and forms: http://grants.nih.gov/grants/funding/phs398/phs398.html.
Please refer to Chapter VI of the PHS 398 instructions prior to
preparing an SBIR application. PHS 398 forms specific to SBIR
applications are available. See
http://grants.nih.gov/grants/funding/phs398/398_SBIRSTTRforms.doc.
Project Period and Amount of Award
The NIAAA intends to commit approximately $1,000,000 in FY 2003 to fund
5 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
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.
Consultant and Contractual Costs
The total amount of all consultant costs and contractual costs normally
may not exceed 33% of the total costs requested for Phase I SBIR
applications. Phase I grant applications submitted under this PA may
exceed this limit if the resources required for developing an alcohol
sensor and data analysis system are relatively scarce, highly
specialized, and multidisciplinary. Deviations must be appropriate and
fully justified.
Page Limitations
The specified page limitations for Phase I applications applies (see
SBIR/STTR Omnibus Grant Solicitation at
http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf).
MECHANISM OF SUPPORT - PHASE II
Phase II applications in response to this RFA will be awarded as Phase
II SBIR grants (R44) or STTR grants. Phase II applications in response
to this RFA will only be accepted as competing continuations of
previously funded NIH Phase I SBIR awards. The previously funded Phase
I award need not have been awarded under this RFA but the Phase II
proposal must be a logical extension of the Phase I research.
Applications for Phase II awards should be prepared using the PHS 398
instructions and forms:
http://grants.nih.gov/grants/funding/phs398/phs398.html. Please refer
to Chapter VI of the PHS 398 instructions prior to preparing an SBIR
application. PHS 398 forms specific to SBIR applications are available.
See
http://grants.nih.gov/grants/funding/phs398/398_SBIRSTTRforms.doc.
Project Period and Amount of Award
Phase II applications under this RFA will be considered with a project
period up to two years and a budget not to exceed a total cost of
$750,000. Any deviations from these limitations must be appropriate
and fully justified.
Consultant and Contractual Costs
The total amount of all consultant costs and contractual costs normally
may not exceed 50% of the total costs requested for Phase II SBIR
applications.
The Fast-Track initiative can be utilized under this RFA.
This RFA uses just-in-time concepts. It also uses the modular budgeting
format. (see
http://grants.nih.gov/grants/funding/phs398/instructions2/p1_SBIRSTTR
_general_instructions.htm. Specifically, if you are submitting an application
budget of $100,000 total costs or less, use the modular format.
PROGRAM OBJECTIVES
The SBIR program consists of the following three phases:
Phase I
The objective of Phase I is to establish the technical merit and
feasibility of the proposed research, or research and development
efforts, and to determine the quality of performance of the small
business grantee organization prior to providing further federal
support in Phase II.
Phase II
The objective of this phase is to continue the research or research and
development efforts initiated in Phase I.
Phase III
The objective of this phase, where appropriate, is for the small
business concern to pursue the commercialization of the results of the
research or research and development funded in Phases I and II. Phase
III occurs without SBIR funding.
FUNDS AVAILABLE
The participating IC(s) intends to commit approximately $1,000,000 in
FY 2003 to fund 5 to 10 new SBIR grants in response to this RFA.
Because the nature and scope of the proposed research will vary from
application to application, it is anticipated that the size and
duration 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.
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your business has any of the
following characteristics:
o Independently owned and operated, is not dominant in the field of
operation in which it is proposing, has its principal place of business
located in the United States, and is organized for profit.
o At least 51% owned, or in the case of a publicly owned business, at
least 51% of its voting stock is owned by United States citizens or
lawfully admitted permanent resident aliens.
o Must not have, including its affiliates, more than 500 employees and
meets the other regulatory requirements found in 13 CFR Part 121.
o Business concerns include, but are not limited to, any individual
(sole proprietorship), partnership, corporation, joint venture,
association, or cooperative.
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to
carry out the proposed research is invited to work with their
organization to develop an application for support. Individuals from
underrepresented racial and ethnic groups as well as individuals with
disabilities are always encouraged to apply for NIH programs. The
primary employment of the PI must be with the small business concern at
the time of award and during the conduct of the proposed project.
Primary employment means that more than one half of the PI's time is
spent in the employ of the small business concern. Primary employment
with a small business concern precludes full-time employment at another
organization.
WHERE TO SEND INQUIRIES
We encourage your inquiries concerning this PA and welcome the
opportunity answer questions from potential applicants.
- Direct your questions about scientific/research issues to:
Joanne B. Fertig, Ph.D.
Division of Clinical and Prevention Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulvard, Suite 505 MSC 7003
Bethesda, MD 20892-7003
For express mail use:
Rockville, MD 20852)
Telephone: (301) 443-0635
Fax: (301) 443-8774
Email: jfertig@niaaa.nih.gov
Mark Egli, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402
Bethesda, MD 20892-7003 [for express mail, use Rockville, MD 20852]
Tel. 301-594-6382
FAX 301-594-0673
Email: megli@willco.niaaa.nih.gov
- Direct your questions about financial or grants management matters
to:
Judy Fox Simons
Chief, Grants Management Branch
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 504
6000 Executive Boulevard, MSC 7003
Bethesda, MD 20892-7003
(301) 443-4704 (telephone)
(301) 443-3891 (fax)
email: jsimons@willco.niaaa.nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent by that
includes the following information:
o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
Although a letter of intent is not required, is not binding, and does
not affect 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 by the date listed at the beginning
of this document. The letter of intent should be sent to:
RFA-AA-03-005
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
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant
application instructions and forms (rev. 5/2001). The PHS 398 is
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in
an interactive format. Please refer to Chapter VI of the PHS 398
instructions prior to preparing a SBIR application. PHS 398 forms
specific to SBIR applications are available:
http://grants.nih.gov/grants/funding/phs398/398_SBIRSTTRforms.doc.
For further assistance contact GrantsInfo, Telephone (301) 710-0267,
Email: GrantsInfo@nih.gov.
Specific Instructions for Modular Grant Applications
SBIR applications requesting up to $100,000 per year in total costs
(direct costs, indirect costs and fee) must be submitted in a modular
grant format. The modular grant format simplifies the preparation of
the budget in these applications by limiting the level of budgetary
detail. Section VI of the research grant application instructions for
the PHS 398 (rev. 5/2001) at
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants. Additional information
on SBIR modular grants is available at
http://grants.nih.gov/grants/funding/phs398/instructions2/p1_SBIRSTTR
_general_instructions.htm.
Using the RFA Label
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/labels.doc (MS Word) or
http://grants.nih.gov/grants/funding/phs398/labels.pdf (PDF).
Sending an Application to the NIH
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
Office of Scientific Affairs
Attn: RFA-AA-03-005
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Blvd., Suite 409
Bethesda, 20892-7003
Telephone: (301) 443-4375
Fax: (301) 443-6077
Application Processing
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.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR
and responsiveness by the NIAAA. Incomplete and/or non-responsive
applications will be returned to the applicant without further
consideration.
An appropriate peer review group convened by NIAAA in accordance with
the review criteria stated below will evaluate applications that are
complete and responsive to the RFA for scientific and technical merit.
As part of the initial merit review, all applications will:
o Receive a written critique
o Undergo a selection process in which only those applications deemed
to have the highest scientific merit, generally the top half of
applications under review, will be discussed and assigned a priority
score
o Receive a second level review by the appropriate national advisory
council or board
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 your application in order to judge the likelihood
that the proposed research will have a substantial impact on the
pursuit of these goals:
- Significance
- Approach
- Innovation
- Investigator
- Environment
The scientific review group will address and consider each of these
criteria in assigning your application's overall score, weighting them
as appropriate for each application. Your 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,
you may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.
Review criteria for all SBIR/STTR applications:
1. Significance
- Does the proposed project have commercial potential to lead to a
marketable product or process? Does this study address an important
problem?
- What may be the anticipated commercial and societal benefits of the
proposed activity?
- If the aims of the application are achieved, how will scientific
knowledge be advanced?
- Does the proposal lead to enabling technologies (e.g.,
instrumentation, software) for further discoveries?
-Will the technology have a competitive advantage over
existing/alternate technologies that can meet the market needs?
2. Approach
- Are the conceptual framework, design, methods, and analyses adequately
developed, well-integrated, and appropriate to the aims of the project?
- Is the proposed plan a sound approach for establishing technical and
commercial feasibility?
- Does the applicant acknowledge potential problem areas and consider
alternative strategies?
- Are the milestones and evaluation procedures appropriate?
3. Innovation
- Does the project challenge existing paradigms or employ novel
technologies, approaches or methodologies?
- Are the aims original and innovative?
4. Investigators
- Is the Principal Investigator capable of coordinating and managing the
proposed SBIR/STTR?
- Is the work proposed appropriate to the experience level of the
Principal Investigator and other researchers, including consultants and
subcontractors (if any)?
- Are the relationships of the key personnel to the small business and
to other institutions appropriate for the work proposed?
5. Environment
- Is there sufficient access to resources (e.g., equipment, facilities)?
- Does the scientific and technological 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?
Review criteria for Phase II applications:
- How well did the applicant demonstrate progress toward meeting the
Phase I objectives, demonstrating feasibility, and providing a solid
foundation for the proposed Phase II activity?
- Did the applicant submit a concise Product Development Plan that
adequately addresses the four areas described in the Research Plan item
J?
- Does the project carry a high degree of commercial potential, as
described in the Product Development Plan?
Review criteria for Phase I/Phase II Fast Track applications:
- Does the Phase I application specify clear, appropriate, measurable
goals (milestones) that should be achieved prior to initiating Phase II?
- Did the applicant submit a concise Product Development Plan that
adequately addresses the four areas described in the Research Plan, item
J?
- To what extent was the applicant able to obtain letters of interest,
additional funding commitments, and/or resources from the private sector
or non-SBIR/ STTR funding sources that would enhance the likelihood for
commercialization?
- Does the project carry a high degree of commercial potential, as
described in the Product Development Plan?
Phase I and Phase II Fast-Track applications that satisfy all of the
review criteria will receive a single rating. Failure to provide clear,
measurable goals may be sufficient reason for the scientific review
group to exclude the Phase II application from Fast-Track review.
ADDITIONAL REVIEW CRITERIA:
In addition to the above criteria, your application will also be
reviewed with respect to the following:
o PROTECTIONS: 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.
o INCLUSION: The adequacy of plans to include subjects from both
genders, all racial and ethnic groups (and subgroups), and children as
appropriate for the scientific goals of the research. Plans for the
recruitment and retention of subjects will also be evaluated. (See
Inclusion Criteria included in the section on Federal Citations, below)
o DATA SHARING: The adequacy of the proposed plan to share data.
o BUDGET: The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: December 23, 2002
Application Receipt Date: January 23, 2003
Peer Review Date: March-April 2003
Council Review: June 4, 2003
Earliest Anticipated Start Date: July 1, 2003
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
Scientific merit (as determined by peer review)
Availability of funds Programmatic priorities
Commercialization potential
Applications will compete for available funds with all other favorably
recommended SBIR applications. Note that applicants may achieve all
Phase I goals and milestones and still not receive Phase II funding.
REQUIRED FEDERAL CITATIONS
MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research
components involving Phase I and II clinical trials must include
provisions for assessment of patient eligibility and status, rigorous
data management, quality assurance, and auditing procedures. In
addition, it is NIH policy that all clinical trials require data and
safety monitoring, with the method and degree of monitoring being
commensurate with the risks (NIH Policy for Data Safety and Monitoring,
NIH Guide for Grants and Contracts, June 12, 1998:
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research
projects unless a clear and compelling justification is 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 clinical research should read the AMENDMENT
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research - Amended, October, 2001," published in the NIH Guide
for Grants and Contracts on October 9, 2001
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a
complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm
The amended policy incorporates: the use of an NIH definition
of clinical research; updated racial and ethnic categories in
compliance with the new OMB standards; clarification of language
governing NIH-defined Phase III clinical trials consistent with the new
PHS Form 398; and updated roles and responsibilities of NIH staff and
the extramural community. The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or
proposals and/or protocols must 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)
investigators must report annual accrual and progress in conducting
analyses, as appropriate, by sex/gender and/or racial/ethnic group
differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN
SUBJECTS: The NIH maintains a policy 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 is available at
http://grants.nih.gov/grants/funding/children/children.htm.
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. You will find this policy
announcement in the NIH Guide for Grants and Contracts Announcement,
dated June 5, 2000, at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
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 PA 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.
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. Furthermore, we caution reviewers that their
anonymity may be compromised when they directly access an Internet
site.
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 RFA 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.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance No. 93.273, and is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review. 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 described
at http://grants.nih.gov/grants/policy/policy.htm and under Federal
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.
The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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.
Becker, H.C. (1998) Kindling in alcohol withdrawal. Alcohol Health and
Research 22:25-33.
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.
Freedland, C.S., Sharpe, A.L., Samson, H.H., and Porrino, L.J. (2001)
Effects of SR141716A on ethanol and sucrose self-administration.
Alcoholism: Clinical and Experimental Research 25:277-282.
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.
Harvey, S.C., Foster, K.L., McKay, P.F., Carroll, M.R., Seyoum, R.,
Woods J.E., Grey, C., Jones, C.M., McCane, S., Cummings, R., Mason, D.,
Ma, C., Cook, J.M., and June, H.L. (2002). The GABA(A) receptor
alpha1 subtype in the ventral pallidum regulates alcohol seeking
behaviors. Journal of Neuroscience 22:3765-75.
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., Harvey, S.C., Foster, K.L., McKay, P.F., Cummings, R.,
Garcia, M., Mason, D., Grey, C., McCane, S., Williams, L.S., Johnson,
T.B., He, X., Rock, S., and Cook, J.M. (2001) GABA(A) receptors
containing (alpha)5 subunits in the CA1 and CA3 hippocampal fields
regulate ethanol-motivated behaviors: An extended ethanol reward
circuitry. Journal of Neuroscience 21:2166-77.
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.
Kranzler, H.R., Modesto-Lowe, V., and Van Kirk, J. (2000) Naltrexone
vs. nefazodone for treatment of alcohol dependence: A placebo-
controlled trial. Neuropsychopharmacology 22:493-503.
Krystal, J.H., Cramer, J.A., Krol, W.F., Kirk, G.F., and Rosenheck,
R.A. (2001) Naltrexone in the treatment of alcohol dependence. The New
England Journal of Medicine 345:1734-1739.
L ., 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.
Mayo-Smith, M.F. (1997) Pharmacological management of alcohol
withdrawal: A meta-analysis and evidence-based practice guideline.
Journal of the American Medical Association278:144-151.
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.
Monti, P.M., Rohsenow, D.J., Swift, R.M., Gulliver, S.B., Colby, S.M.,
Mueller, T.I., Brown, R.A., Gordon, A., Abrams, D.B., Niaura, R.S., and
Asher, M.K. (2001) Naltrexone and cue exposure with coping
communication skills training for alcoholics: Treatment Process and 1-
year outcomes. Alcoholism: Clinical and Experimental Research 25:1634-
1647.
Morris, P.LP., Hopwood, M., Whelan, G., Gardiner, J., and Drummond, E.
(2001) Naltrexone for alcohol dependence: A randomized controlled
trial. Addiction 96:1565-1573.
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- -naltrexol reduces alcohol consumption in rats. Alcoholism:
Clinical and Experimental Research 24:1593-1596.
Saitz, R., Mayo-Smith, M.F., Roberts, M.S., Redmond, H.A., Bernard,
D.R., and Calkins, D.R. (1994) Individualized treatment for alcohol
withdrawal: A randomized double-blind controlled trial. Journal of the
American Medical Association 272:519-523.
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.
Sullivan, J.T., Swift, R.M., and Lewis, D.C. (1991) Benzodiazepine
requirements during alcohol withdrawal syndrome: Clinical implications
of using a standardized withdrawal scale. Journal of Clinical
Psychopharmacology 11:291-295.
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.
Wartenberg, A.A., Nirenberg, T.D., Liepman, M.R., Sivai, L.Y., Begin,
A.M., and Monti, P.M. (1990) Detoxification of alcoholics: Improving
care by symptom-triggered sdeation. Alocholism: Clinical and
Experimental Research 14:71-75.
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.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
|
|
|
|
Department of Health and Human Services (HHS)
|
|
|
|
NIH... Turning Discovery Into Health®
|