EXPIRED
CHEMISTRY, PHARMACOLOGY, AND TOXICOLOGY OF SMOKED DRUGS OF ABUSE RELEASE DATE: April 3, 2002 PA NUMBER: PA-02-095 EXPIRATION DATE: April 20, 2005, unless reissued. National Institute on Drug Abuse (NIDA) (www.nida.nih.gov) THIS PROGRAM ANNOUNCEMENT (PA) CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The National Institute on Drug Abuse (NIDA) encourages research that will further the understanding of the chemical composition of smoked drugs of abuse, and the resulting pharmacological and toxicological effects associated with such exposure. This PA solicits nonclinical basic research efforts aimed at chemical isolation/identification, metabolic studies, pharmacokinetics, and in vitro cellular and in vivo animal pharmacology/toxicology studies of condensates or extracts of volatile materials and particulates produced in a smoking process. The drugs of abuse of interest include marijuana, tobacco, crack cocaine, heroin, PCP, and methamphetamine hydrochloride. RESEARCH OBJECTIVES Background According to the Substance Abuse and Mental Health Services Administration (SAMHSA) Household Survey on Drug Abuse (2000), it is estimated that approximately fifty-five million Americans use cigarettes with varying frequency, while marijuana remained the most commonly used illicit drug in the United States among adults and adolescents, followed by crack cocaine and methamphetamine, and to a lesser extent, heroin and PCP. Smoking is the preferred route of administration for many abused substances, including tobacco, marijuana, and crack cocaine. Other abused agents are smoked to avoid intravenous injection. Marijuana, PCP, cocaine, and methamphetamine are often consumed in addition to tobacco products, or mixed together with tobacco in cigars ("blunts"). The complexity and number of products present in the particulate phase of smoke resulting from the burning/pyrolysis of tobacco, marijuana, and to a lesser extent, cocaine and PCP, have been examined to some degree and discussed in the scientific literature. These products include, for example, tobacco-specific N-nitrosamines, aldehydes, phenols, polycyclic aromatic hydrocarbons, and specific products of cannabinoid and cocaine pyrolysis. Some constituents of smoked drugs have been studied and characterized. For example, the carcinogenicity of some tobacco smoke products has been established, however, more research is needed. Some of the products of marijuana smoke have shown mutagenic activity when activated by enzymes. The products from PCP, cocaine, or methamphetamine smoke have been less thoroughly studied for their carcinogenic potential. Clearly, however, additional research is needed in this area. Finally, it has also been recognized that many of these agents have a health risk potential because of their effects on respiratory system responsiveness and function, including exacerbation of asthma, pulmonary edema, dyspnea, bronchoconstriction, and release of proinflammatory mediators. This PA will encourage research aimed at: (1) determining the chemical composition of smoked drugs of abuse, (2) understanding the biological consequences resulting from exposure to these chemicals, and (3) determining the mechanism(s) of action of volatilized compounds using in vivo and in vitro models. The research approaches that would be appropriate to address these issues are varied. The following is just a partial list of possible strategies, approaches, and questions that need to be addressed in this area: (1) Methods to identify chemical components o Develop procedures to obtain and isolate materials from the smoking process, such as vapor phase condensation and chromatographic fractionation, and the extraction of residues, particulates, filters, and solvent/buffer systems. o Design of aerobic/anaerobic pyrolysis systems, smoking devices, and flow systems to expose cells or whole animals to vapor phases. o Develop methods for identification and analytical characterization of individual components of the smoking process, particularly new compounds not previously reported, that may have potential carcinogenic, immunological, medicinal, or other biological effects. Of particular interest are compounds produced when various drugs are mixed or volatilized with tobacco, such as can occur with a mixture of methamphetamine and tobacco. o Evaluate the effect of pyrolysis/burning temperature on chemical composition, including mechanism of compound formation and decomposition. o Conduct chemical characterization of bulk materials and delivery devices such as processed tobacco leaf, bulk marijuana, cigars, and marijuana and tobacco cigarettes from domestic and foreign sources. (2) Biological consequences of smoked substances o Determine inhalation toxicity of volatilized substances during and following acute/subacute animal exposure, including pathological/histopathological findings. o Determine the effects of exposure of bronchial/lung epithelial cells (primary cells and cell lines) to smoke or materials condensed from smoke, which could include genotoxicity and cytotoxicity assays, measures of DNA adduct formation, changes in cellular enzymes, proteins, or receptor expression. o Conduct mutagenicity testing of condensates or the extracts of smoke particulates (3) Mechanisms of action o Conduct pharmacokinetic studies of individual compounds found in smoked substances that have putative or potential biological, toxicological, or addictive properties. o Conduct metabolic studies to determine the metabolites of individual compounds associated with the smoking process. o Identify new biomarkers for detecting inflammatory and malignant or premalignant processes in bronchial/lung cells and tissues. o Conduct studies that examine, identify, and determine the role of enzymes that activate or detoxify smoked compounds, such as cytochrome P450s, peroxidases, and sulfotransferases. MECHANISMS OF SUPPORT This PA will use the NIH research project (R01), small grant (R03), and exploratory/developmental grant (R21) award mechanisms. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Refer to the guidelines for the specific eligibility requirements for the small grant program (R03) at http://grants.nih.gov/grants/guide/pa-files/PAR-00-059.html, and the exploratory/developmental grant program (R21) at http://grants.nih.gov/grants/guide/pa-files/PA-01-012.html. This PA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non- modular research grant applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign 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. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research, and financial or grants management issues: o Direct your questions about scientific/research issues to: Paul Hillery, Ph.D. Division of Neuroscience and Behavioral Research National Institute on Drug Abuse 6001 Executive Boulevard, Room 4282 MSC 9555 Bethesda, MD 20892-9555 Telephone: (301) 443-6275 Email: [email protected] o Direct your questions about financial or grants management matters to: Gary Fleming, J.D., M.A. Grants Management Branch, OPRM National Institute on Drug Abuse 6001 Executive Boulevard, Room 3131 MSC 9541 Bethesda, MD 20892-9541 Telephone: (301) 443-6710 Email: [email protected] 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. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: [email protected]. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs 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. Applicants request direct costs in $25,000 modules. Section C 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 modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study, 2) Obtain agreement from NIDA staff that NIDA will accept your application for consideration for award, and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five 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) APPLICATION PROCESSING: Applications must be received by or mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA 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 a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications 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: o Significance o Approach o Innovation o Investigator o 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. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: 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. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended 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 REQUIRED FEDERAL CITATIONS 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 PA 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. 93.279, 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 see http://grants.nih.gov/grants/guide/pa-files/PA-02-015.html.
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