HEMOGLOBIN-BASED OXYGEN CARRIERS:  MECHANISMS OF TOXICITY

NIH GUIDE, Volume 21, Number 42, November 20, 1992



PA:  PA-93-23



P.T. 34



Keywords:

  Hematology 

  Biochemistry 

  Biology, Cellular 

  Biology, Molecular 

  Pharmacology 

  Pathophysiology 



National Heart, Lung, and Blood Institute



PURPOSE



The National Heart, Lung, and Blood Institute (NHLBI) announces a

Program Announcement (PA) on the above subject.  The purpose of this

initiative is to encourage research aimed at providing an understanding

of the mechanisms of toxicity of hemoglobin-based oxygen carriers.



HEALTHY PEOPLE 2000



The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention objectives of "Healthy People 2000,"

a PHS-led national activity for setting priority areas.  This PA,

Hemoglobin-based Oxygen Carriers:  Mechanisms of Toxicity, is related

to the priority area of food and drug safety.  Potential applicants may

obtain a copy of "Healthy People 2000" (Full Report:  Stock No.

017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.

017-001-00473-1) through the Superintendent of Documents, Government

Printing Office, Washington, DC 20402-9325 (telephone 202-782-3238).



ELIGIBILITY REQUIREMENTS



Applications may be submitted by foreign and domestic, for-profit and

non-profit organizations, public and private, such as universities,

colleges, hospitals, laboratories, units of State and local

governments, and eligible agencies of the Federal Government.

Applications from minority individuals and women are encouraged.

Awards in connection with this announcement will be made to foreign

institutions only for research of very unusual merit, need and promise,

and in accordance with PHS policy governing such awards.  Foreign

institutions are not eligible for First Independent Research Support

and Transition (FIRST) (R29) awards.



MECHANISM OF SUPPORT



This PA will use the National Institutes of Health (NIH) research

project grant (R01) and FIRST (R29) award.  Applicants, who will plan

and execute their own research programs, are requested to furnish their

own estimates of the time required to achieve the objectives of the

proposed research project.  Up to five years of support may be

requested.  Because the nature and scope of the research proposed in

response to this PA may vary, it is anticipated that the size of an

award will also vary.  Those applicants requesting support under the

FIRST (R29) award should be certain that the direct costs requested are

within the guidelines for that award.  Administrative adjustments in

project period and/or amount of support may be required at the time of

the award.  All current policies and requirements that govern the

research grant programs of the NIH will apply to grants awarded in

connection with this PA.



RESEARCH OBJECTIVES



Background



An alternative to red blood cells for transfusion has been sought

unsuccessfully for over one hundred years.  In recent years, the NHLBI

and other government agencies have supported research on the

development of stable oxygen carriers that do not need to be

cross-matched and that can be stored for extended periods of time.

During the past decade, awareness of the dangers inherent in

transfusion of homologous red blood cells has heightened.  These

include transmission of infectious agents such as HIV, hepatitis

viruses and other microorganisms.  Consequently, physicians are

increasingly reluctant to transfuse their patients and patients are

increasingly reluctant to receive blood.  Although testing of units of

blood is becoming more comprehensive and efficient, there is no

question that products that are free of infectious agents that could be

used in place of red cells would have wide clinical application.  In

spite of this promise, studies of hemoglobin-based oxygen carriers have

been disappointing as unpredictable toxicities have thwarted

development of clinically useful products.



Infusion of hemoglobin-based oxygen carriers into the circulation can

result in a variety of outcomes.  Carrier molecules may leave the

circulation by a number of routes including endothelial transcytosis,

phagocytic uptake, and diffusion.  The effects of these materials may

be as diverse as the range of properties of the various tissues they

bathe.  Their interaction with endothelium-derived relaxing factors,

stimulation of other vasoactive materials, and stimulation of mediators

of inflammation may add to the complex biological reactions noted in



research to date.  Furthermore, much of the previous work in this field

is clouded by species differences, so that, at present, there are no

animal or in vitro models that will reliably predict human reactions.



In addition to Federal support, research and development of artificial

oxygen carriers have been carried out by industry.  Indeed, industry

has contributed valuable knowledge in the area of product and quality

control.  Sophisticated high technology systems have been developed to

produce products in large quantities.  However, in recent clinical

trials with hemoglobin-based oxygen carriers, unexpected toxicities

were observed suggesting the need for more basic research to address

fundamental questions concerning interaction with the immune system and

endothelium in particular.



Research Objectives and Experimental Approaches



The purpose of this PA is to encourage research aimed at providing an

understanding of the mechanisms of toxicity of hemoglobin-based oxygen

carriers.  This program encourages research addressing such fundamental

questions as:  (1) what are the mechanisms of vasoactivity of

hemoglobin solutions, (2) how do protein modifications affect

vasoactivity, (3) what are the mechanisms of stimulation of

inflammation mediators by hemoglobin-based oxygen carriers, (4) how can

this stimulation be prevented, (5) what animal or in vitro models are

best used to study toxic effects of oxygen carriers, (6) what are the

long-term (metabolic and pharmacologic) effects of oxygen carriers, and

(7) what models are best to demonstrate efficacy in terms of oxygen

transport to tissue.  Particular encouragement is offered to

investigators possessing modern tools, who are well-trained, and who

are currently pursuing other research interests to devote time and

resources to this area.  It is hoped that interdisciplinary and

collaborative approaches may be developed which will complement the

efforts of workers in the field.  The ultimate goal is to satisfy a

fundamental need in clinical medicine, i.e., development of a safe,

economical and efficacious alternative to homologous human red blood

cells for transfusion.



Examples of promising topics are:



o  Studies of the interaction of hemoglobin with endothelium and

macrophages.

o  Development of animal models that simulate clinical use, such as

trauma, shock, infection, and surgical blood loss.

o  Studies relating the biochemical modification of hemoglobin with its

biological effects.

o  Studies of encapsulation of hemoglobin into artificial vesicles -

biochemical, physical, physiological, and biological effects.

o  Studies of the tissue distribution and metabolic fate of modified

hemoglobins, and artificial vesicles.



These are intended as examples only.  Investigators are encouraged to

consider other innovative approaches.



Applications may address one or several issues, but should retain a

common theme and focus on addressing those issues.  Because issues

involving hematology, biochemistry, physiology, cell biology,

pharmacology or molecular biology may need to be addressed in a

coordinated manner, collaboration among investigators having expertise

in these and other appropriate disciplines is encouraged.  When

individuals are at different institutions, individual R01 applications

may include consortium arrangements.



While the main focus of this PA is on basic or fundamental research

studies to elucidate the mechanisms of toxicity of hemoglobin-based

oxygen carriers, clinical studies, but not clinical trials, are also

appropriate.  Collaborative arrangements with ongoing clinical studies

or trials that provide patient material at little or no cost to the

applicant are also encouraged.  Such arrangements should be clearly

delineated in the application.  The description should include

sufficient information to permit scientific evaluation of the studies

proposed.  Among issues to include are the number and type of

specimens/patients, patient population characteristics (including

gender and minority composition; see STUDY POPULATIONS below), overall

goals of the collaborative project, remaining term of the project, and

IRB approval of the project.  If substantial interactions and costs

with ongoing projects are proposed, a consortium agreement can be

developed and submitted to support this additional research aspect.



If statistical analysis is anticipated, the methodologies and personnel

involved should be described in the application and evident in the

study design.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



NIH policy is that applicants for NIH clinical research grants and

cooperative agreements will be required to include minorities and women

in study populations so that research findings can be of benefit to all

persons at risk of the disease, disorder or condition under study;

special emphasis should be placed on the need for inclusion of

minorities and women in studies of diseases, disorders and conditions

which disproportionately affect them.  This policy is intended to apply

to males and females of all ages.  If women or minorities are excluded

or inadequately represented in clinical research, particularly in

proposed population-based studies, a clear compelling rationale should

be provided.



The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  In addition, gender and

racial/ethnic issues should be addressed in developing a research

design and sample size appropriate for the scientific objectives of the

study.  This information must be included in the form PHS 398 (rev.

9/91) in Sections 1-4 of the Research Plan AND summarized in Section 5,

Human Subjects.  Applicants are urged to assess carefully the

feasibility of including the broadest possible representation of

minority groups.  However, NIH recognizes that it may not be feasible

or appropriate in all research projects to include representation of

the full array of United States racial/ethnic minority populations

(i.e., Native Americans including American Indians or Alaskan Natives,

Asian/Pacific Islanders, Blacks, and Hispanics).  The rationale for

studies on single minority population groups should be provided.



For the purpose of this policy, clinical research includes human

biomedical and behavioral studies of etiology, epidemiology, (and

preventive strategies), diagnosis, or treatment of diseases, disorders

or conditions, including but not limited to clinical trials.



The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the  results of

the study broadly, and this should be addressed by applicants.



For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including

minorities.



If the required information is not contained within the application,

the application will be deferred until the information is provided.



Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.  If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the selected

study population is inadequate, it will be considered a scientific

weakness or deficiency in the study design and will be reflected in

assigning the priority score to the application.



All applications for clinical research submitted to NIH are required to

address these policies.  NIH funding components will not award grants

or cooperative agreements that do not comply with these policies.



APPLICATION PROCEDURES



Applications are to be submitted on the grant application form PHS 398

(rev. 9/91) and will be accepted at the standard application deadlines

as indicated in the application kit.  The receipt dates for

applications for AIDS-related research are found in the PHS 398 (rev.

9/91) instructions.



FIRST award applications must include at least three sealed letters of

reference attached to the face page of the original application.  FIRST

award applications submitted without the required number of reference

letters will be considered incomplete and will be returned without

review.



Application kits are available at most institutional offices of

sponsored research and may be obtained from the Office of Grants

Inquiries, Division of Research Grants, National Institutes of Health,

Westwood Building, Room 449, Bethesda, MD 20892, telephone (301)

496-7441.  Section 2 on the face page of the application must be

completed.  Check "YES" to indicate the application is submitted in

response to a program announcement.  The title and program announcement

number must be typed in Section 2a of the application as follows:

"HEMOGLOBIN-BASED OXYGEN CARRIERS:  MECHANISMS OF TOXICITY" PA-93-23.



The completed original application and five legible copies must be sent

or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



REVIEW CONSIDERATIONS



Although this is an NHLBI PA, the National Institute of Environmental

Health Sciences also has an interest in the subject matter of this PA.

Applications will be assigned to the most appropriate Institute on the

basis of established PHS referral guidelines.  Applications will be

reviewed for scientific and technical merit by study sections of the

Division of Research Grants, NIH, in accordance with the standard peer

review procedures.



Following scientific-technical review, the applications will receive a

second-level review by the appropriate advisory council.



AWARD CRITERIA



Funding decisions will be made on the basis of scientific and technical

merit of the proposed grant as determined by peer review, program

needs, balance among research areas of the announcement, and the

availability of funds.



Awards in response to this PA will be made to foreign institutions only

for research of very unusual merit, need, and promise, and in

accordance with PHS policy governing such awards.



INQUIRIES



Inquiries regarding this program announcement may be directed to:



Dr. George J. Nemo

Division of Blood Diseases and Resources

National Heart, Lung, and Blood Institute

Federal Building, Room 504

Bethesda, MD  20892

Telephone:  (301) 496-1537

FAX:  (301) 496-9940



For fiscal and administrative matters, contact:



Ms. Jane R. Davis

Division of Extramural Affairs

National Heart, Lung, and Blood Institute

Westwood Building, Room 4A15

Bethesda, MD  20892

Telephone:  (301) 496-7257

FAX:  (301) 402-1200



AUTHORITY AND REGULATIONS



The programs of the Division of Blood Diseases and Resources, NHLBI,

are described in the Catalog of Federal Domestic Assistance No. 93.839.

Awards will be made under the authority of the Public Health Service

Act, Section 301 (42 USC 241) and administered under PHS grants

policies and Federal regulations, most specifically 42 CFR Part 52 and

45 CFR Part 74.  This program is not subject to the intergovernmental

review requirements of Executive Order 12372 or to Health Systems

Agency review.



.

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