MEDICATIONS DEVELOPMENT TO TREAT ALCOHOLISM (SBIR/STTR) RELEASE DATE: December 4, 2003 RFA Number: RFA-AA-04-002 (This RFA has been reissued, see RFA-AA-06-006 and RFA-AA-06-007) Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.273 LETTER OF INTENT RECEIPT DATE: March 15, 2004 APPLICATION RECEIPT DATE: April 14, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Project Period and Amount of Award 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 Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations o References NOTICE: This Request for Application (RFA) must be read in conjunction with the current OMNIBUS SOLICITATION OF THE NATIONAL INSTITUTES OF HEALTH, CENTERS FOR DISEASE CONTROL AND PREVENTION, and FOOD AND DRUG ADMINISTRATION FOR SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) GRANT APPLICATIONS. The solicitation (see http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf [PDF] or http://grants.nih.gov/grants/funding/sbirsttr1/index.doc [MS Word]) contains information about the SBIR and STTR programs, regulations governing the programs, and instructional information for submission. All of the instructions within the SBIR/STTR Omnibus Solicitation apply with the following exceptions: o Application Receipt Date April 14, 2004 o Initial review convened by the NIAAA Division of Extramural Activities PURPOSE OF THIS RFA 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 cessation(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. 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;). 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 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). 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 et al., 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 et al. (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 medications discussed above produce small to medium effects in reducing or preventing drinking, development and evaluation of new and more potent medications remains 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 BUT NOT LIMITED TO 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 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 combinations 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 therapeutic efficacy for treating alcohol abuse and alcohol related conditions. - 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? MECHANISMS OF SUPPORT This RFA uses the SBIR and STTR mechanisms, which are set-aside programs. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Future unsolicited, competing- continuation applications based on this project will compete with all SBIR/STTR applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 27, 2004. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW SBIR/STTR applications using the standard receipt dates for NEW applications described in the current SBIR/STTR Omnibus Solicitation. This RFA uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats. Specifically, if you are submitting an application budget of $100,000 total costs (direct, F&A and fee) or less, use the modular budget format. For applications requesting more than $100,000, use the non-modular budget format. Instructions for both are described in the current SBIR/STTR Omnibus Solicitation. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. Except as otherwise stated in this RFA, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement, March 2001, available at http://grants.nih.gov/grants/policy/nihgps_2001. Applications may be submitted for support as Phase I STTR (R41) or Phase I SBIR (R43) grants; Phase II STTR (R42) or Phase II SBIR (R44) grants; or the SBIR/STTR FAST-TRACK option as described in the SBIR/STTR Omnibus Solicitation. Phase II applications in response to this RFA will only be accepted as competing continuations of previously funded NIH Phase I SBIR/STTR awards. The Phase II application must be a logical extension of the Phase I research but not necessarily a Phase I project supported in response to this RFA. Fast Track applications will benefit from expedited evaluation of progress following the Phase I feasibility study for transition to Phase II funding for expanded developmental work. PROJECT PERIOD AND AMOUNT OF AWARD The SBIR/STTR Omnibus Solicitation indicates the statutory guidelines of funding support and project duration periods for SBIR and STTR Phase I and Phase II awards. However, these award levels for time and amount are statutory guidelines, not ceilings. Therefore, applicants are encouraged to propose a reasonable budget and project period that is appropriate for completion of the research project. Deviations from the guidelines are acceptable, but must be well justified. Applicants are encouraged to discuss budgetary deviations with NIH program staff prior to submission of the application. For this RFA, time periods of up to 2 years for Phase I may be requested. Time periods of up to 3 years may be requested for Phase II. Total costs include direct costs, F&A, and fee/profit. FUNDS AVAILABLE NIAAA intends to commit approximately $2,000,000 to fund 5-10 Phase I and/or Phase II applications under the SBIR/STTR set-aside funding mechanism. Although the financial plans of the NIAAA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if competing renewal applications will be accepted and/or if this RFA will be reissued. ELIGIBLE INSTITUTIONS: Eligibility requirements are described in the SBIR/STTR Omnibus Solicitation. Only small business concerns are eligible to submit SBIR/STTR applications. A small business concern is one that, on the date of award for both Phase I and Phase II agreements, meets ALL of the criteria as described in the current SBIR/STTR Omnibus Solicitation. 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 institution 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. On an SBIR application, the principal investigator must have his/her primary employment (more than 50%) with the small business at the time of award and for the duration of the project. The PI on an STTR application may be employed with the small business concern or the participating non- profit research institution as long as s/he has a formal appointment with or commitment to the applicant small business concern, which is characterized by an official relationship between the small business concern and that individual. SPECIAL REQUIREMENTS All applications that list direct costs greater than $500,000 in any year of the proposed research must have a data sharing plan. Information on NIH data sharing policy and procedures can be found at: http://grants.nih.gov/grants/policy/data_sharing/index.htm WHERE TO SEND INQUIRIES We encourage your inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquires may fall into three areas: scientific/research, peer review, and finance or grants management issues. o Direct your questions about scientific/research issues to: NIAAA Program Contacts: Joanne B. Fertig, Ph.D. Division of Treatment and Recovery Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 505 Bethesda, MD 20892-7003 [For express mail use, Rockville, MD 20852] Tel: (301) 443-0635 Fax: (301) 443-8774 Email: jfertig@niaaa.nih.gov Peter B. Silverman, Ph.D., J.D. Division of Neuroscience and Behavior National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402 Bethesda, MD 20892-7003 [for express mail, use Rockville, MD 20852] Tel. 301-402-6966 FAX 301-594-0673 Email: psilverm@mail.nih.gov o Direct your questions about peer review issues to: Eugene G. Hayunga, Ph.D. Chief, Extramural Project Review Branch Office of Scientific Affairs 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 o Direct your questions about financial or grants management matters to: Judy Fox (formerly 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 [for express mail, use Rockville, MD 20852] Tel. (301) 443-4704 Fax (301) 443-3891 email: jsimons@willco.niaaa.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent 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: Extramural Project Review Branch Office of Scientific Affairs ATTN: RFA-AA-04-002 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 The PHS 398 research grant application must be used for all SBIR/STTR Phase I, Phase II and Fast-Track applications (new and revised.) Effective October 1, 2003, applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html. Prepare your application in accordance with the SBIR/STTR Omnibus Solicitation and the PHS 398. The NIH will return applications that are not submitted on the 5/2001 version of the PHS 398. For further assistance contact GrantsInfo, Telephone: (301) 710-0267, Email: GrantsInfo@nih.gov. USING THE RFA LABEL: The RFA label available in the PHS 398 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 or http://grants.nih.gov/grants/funding/phs398/labels.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 (for USPS EXPRESS OR REGULAR MAIL) Bethesda, MD 20817 (for EXPRESS/COURIER NON-USPS 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-04-002 National Institute on Alcohol Abuse and Alcoholism 6000 Executive Blvd., Suite 409 Bethesda, 20892-7003 [for express mail use Rockville, 20852] Telephone: (301) 443-4375 Fax: (301) 443-6077 RECEIPT OF APPLICATIONS. Applications must be received on or before the receipt date listed on the first page of this announcement. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Research (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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIAAA. Incomplete applications will not be reviewed. If the application is not responsive to the RFA, NIH 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 appropriate NIH 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: o 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 and assigned a priority score o Receive a written critique o Receive a second level review by the NIAAA 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 evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals within the context of the SBIR/STTR Program. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score: o Significance o Approach o Innovation o Investigator o Environment 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? PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See additional information and criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 additional information and Inclusion Criteria in the sections on Federal Citations, below). Human Subjects: Protection of Human Subjects from Research Risks - for all studies involving human subjects. See instructions and "Guidance for Preparing the Human Subjects Research Section. If an exemption is claimed, is it appropriate for the work proposed? If no exemption is claimed, are the applicant's responses to the six required points appropriate? Are human subjects placed at risk by the proposed study? If so, are the risks reasonable in relation to the anticipated benefits to the subjects and others? Are the risks reasonable in relation to the importance of the knowledge that reasonably may be expected to be gained? Are the plans proposed for the protection of human subjects adequate? Inclusion of Women Plan - for clinical research only. Does the applicant propose a plan for the inclusion of both genders that will provide their appropriate representation? Does the applicant provide appropriate justification when representation is limited or absent? Does the applicant propose appropriate and acceptable plans for recruitment/outreach and retention of study participants? Inclusion of Minorities Plan - for clinical research only. Does the applicant propose a plan for the inclusion of minorities that will provide their appropriate representation? Does the applicant provide appropriate justification when representation is limited or absent? Does the applicant propose appropriate and acceptable plans for recruitment/outreach and retention of study participants? Inclusion of Children Plan- for all studies involving human subjects. Does the applicant describe an acceptable plan in which the representation of children of all ages (under the age of 21) is scientifically appropriate and recruitment/retention is addressed realistically? If not, does the applicant provide an appropriate justification for their exclusion? Data and Safety Monitoring Plan for clinical trials only. Does the applicant describe a Data and Safety Monitoring Plan that defines the general structure of the monitoring entity and mechanisms for reporting Adverse Events to the NIH and the IRB? CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the required five items described under Vertebrate Animals (section f of the Research Plan instructions) will be assessed. If vertebrate animals are involved, are adequate plans proposed for their care and use? Are the applicant's responses to the five required points appropriate? Will the procedures be limited to those that are unavoidable in the conduct of scientifically sound research? BIOHAZARDS: Is the use of materials or procedures that are potentially hazardous to research personnel and/or the environment proposed? Is the proposed protection adequate? ADDITIONAL REVIEW CONSIDERATIONS: The following items may be also be considered by reviewers but will not be included in the determination of scientific merit. SHARING RESEARCH DATA: Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. Information on NIH data sharing policy and procedures can be found at: http://grants.nih.gov/grants/policy/data_sharing/index.htm BUDGET: The reasonableness of the proposed budget may be considered. For all applications, is the percent effort listed for the PI appropriate for the work proposed? On applications requesting up to $100,000 total costs, is the overall budget realistic and justified in terms of the aims and methods proposed? On applications requesting over $100,000 in total costs, is each budget category realistic and justified in terms of the aims and methods? PERIOD OF SUPPORT: The appropriateness of the requested period of support in relation to the proposed research. PHASE II APPLICATIONS: In addition to the above review criteria: - 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 Commercialization Plan [formerly Product Development Plan] that adequately addresses the seven areas described in the Research Plan item J? - Does the project carry a high degree of commercial potential, as described in the Commercialization Plan? AMENDED APPLICATIONS In addition to the above criteria, the following criteria will be applied to revised applications. - Are the responses to comments from the previous SRG review adequate? - Are the improvements in the revised application appropriate? TYPE 2 PHASE II COMPETING CONTINUATION APPLICATIONS In addition to the above review criteria, the following items will be applied to ALL Type 2 Competing Continuation Phase II applications in the determination of scientific merit and the priority score: o Does the activity as proposed address issues related to Federal regulatory approval processes? o What will be the effect of these studies on the concepts or methods that drive this field? PHASE I/PHASE II FAST-TRACK APPLICATION REVIEW CRITERIA For Phase I/Phase II Fast Track applications, the following criteria also will be applied: - 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 Commercialization Plan [formerly Product Development Plan] that adequately addresses the seven 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 Commercialization 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. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: March 15, 2004 Application Receipt Date: April 14, 2004 Peer Review Date: June/July 2004 Council Review: September 2004 Earliest Anticipated Start Date: September 27, 2004 AWARD CRITERIA Applications submitted in response to an RFA will compete for available funds with all other recommended SBIR and STTR applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities For FAST-TRACK applications, the Phase II portion may not be funded until a Phase I final report and other documents necessary for continuation have been received and assessed by program staff that the Phase I milestones have been successfully achieved. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing. Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. 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 "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. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. 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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the Standards for Privacy of Individually Identifiable Health Information , the Privacy Rule, on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as covered entities ) must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on Am I a covered entity? Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. 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 at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm 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 sedation. 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.subtype. Alcoholism: Clinical and Experimental Research 24:1041-1049.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices



NIH Office of Extramural Research Logo
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy
NIH... Turning Discovery Into Health®



Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.