Dr. David Eisenberg
Laboratory of Structural Biology and Molecular Medicine
Box 951570
Los Angeles, CA 90095-1570
Phone: 310-825-3754
Fax: 310-206-3914
E-mail: david@pauling.mbi.ucla.edu
Number of Human Subjects projects reported: 6
"Dopamine Transport and Storage Measured with DOPA"
Principal Investigator: Dr. Gary W. Small, University of California, Los Angeles
Project started in: 1992
This project ended in fiscal year 2001.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: UCLA1-92-640
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of California, Los Angeles
Most recent approval: 01/31/00
IRB approval number: 92-11-640-13
Explanation of IRB approval:
Research under the DOE Cooperative Agreement was re-focused this year away from human subjects to basic sciences. All human subject projects were removed from DOE funding and closed.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2001
Type(s) of Human Subjects Involvement:
Dopamine is a major neurotransmitter in the central nervous system that is involved in mediating thoughts, emotions and motor behaviors. L-DOPA, which we have labeled with 18F, is a precursor in the synthesis of dopamine. By injecting trace amounts of 18F-L-DOPA in subjects and using PET technologies, we are able to measure the rates at which the dopamine neurons synthesize and excrete dopamine. MRI scans and drawing blood samples for genetic analysis has been added to the protocol this past year. If genetic links can be found, it may be possible to diagnose a brain disorder before symptoms develop.
Cocaine produces its euphoric effects, at least in part, through its effects on the dopamine neuron. Other substances of abuse, such as alcohol and opiates, may have dopamine mechanisms too. In Parkinson's disease, the dopamine neurons are slowly destroyed. With continued cocaine or amphetamine use in animals, there is evidence for damage of the dopamine secreting neurons. Our PET studies so far in humans and monkeys have also shown this. Drug abusers trying to synthesize narcotics in Northern California a number of years ago accidentally made a compound (referred to as MPTP) that induced Parkinson's disease.
We are doing fluorodopa PET scans of Parkinson's disease patients, cocaine abusers, amphetamine abusers, opiate abusers with and without MPTP exposure, alcoholics, and normal controls to better understand the effects of these drugs on the presynaptic dopamine neuron. Damage that these patients sustained to their dopamine system may explain their difficulty in getting off of drugs. Subjects undergo fluorodopa scanning after first stopping the drug, and then after at least 6 months abstinence, to see if there is any recovery. We correlate the findings with their symptoms. We are doing parallel studies in monkeys where drug use and amounts can be controlled to better understand this problem. Drug abusers come from UCLA Neuropsychiatric Hospital and populations. MPTP exposed individuals are sometimes referred by Dr. William Langston in San Jose. Patients who are not UCLA outpatients come into the Clinical Research Center (CRC) in San Jose under an approved CRC protocol.
Risks include: from exposure to radiation, the dose received from this study is well below the levels that are thought to result in a significant risk of harmful effects; from injection of radiopharmaceutical, side effects in some people including muscle stiffness, involuntary movements of the eyes, or restlessness; from blood sampling, slight discomfort from the needle, lightheadedness, fainting, soreness and discoloration; from arterial blood samples, shortness of breath, allergic reaction and low blood pressure from the local anesthetic agent, arterial spasm causing cold or painful hands, tenderness at site of the tube insertion; from the MRI, anxiety and attraction of certain metals to the magnetism of the machine.
The identity of the participants in this research study will remain confidential. Any identifying information will be securely locked in a file cabinet, and only personnel related to the study will have access to these records. No information that identifies any participant will be released without that subject's separate consent, except as specifically required by law.
"Measurement of Myocardial Blood Flow with N-13 Ammonia"
Principal Investigator: Dr. Heinrich R. Schelbert, University of California, Los Angeles
Project started in: 1995
This project ended in fiscal year 2001.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: UCLA1-95-117
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of California, Los Angeles
Most recent approval: 09/22/00
IRB approval number: 95-03-117-12
Explanation of IRB approval:
Research under the DOE Cooperative Agreement was re-focused this year away from human subjects to basic sciences. All human subject projects were removed from DOE funding and closed.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 83
Reporting period for number of human subjects:
Fiscal Year 2001
Type(s) of Human Subjects Involvement:
Co-investigator is Johannes Czernin, MD.
The aim of this study is to determine, noninvasively, coronary artery disease in healthy subjects, individuals at risk, and patients with the disease, using Positron Emission Tomography (PET). PET can assess these problems noninvasively and can identify individuals with early abnormalities in coronary vasomotion or endothelial function. This is of importance because lifestyle modifications, such as smoking cessation or a low lipid diet, might reverse the course of the disease.
All subjects will undergo PET imaging of the heart at rest and during cold pressor stress under baseline conditions and during intravenous L-arginine. L-arginine, a physiologically occurring amino acid, is a precursor of nitric oxide and might induce a small increase in the blood flow to the heart. L-arginine is used clinically to test the pituitary function.
The cold pressor test will be performed by immersing the patient's hand in ice water for about 2 minutes. Cold pressor testing induces a modest increase in heart rate and systolic blood pressure, and is, therefore, considered a very mild stressor.
On the first day, radioisotope N-13 ammonia will be injected when the subject is at rest, and then again during cold pressor testing.
On the second day, the radioisotope N-13 ammonia will be injected when the subject is at rest with the simultaneous application of intravenous L-arginine.
On the third day, the radioisotope N-13 ammonia will be injected during cold pressor testing with the simultaneous application of intravenous L-arginine.
Patients aged 18 years or older, males and nonpregnant females after giving written consent and proving to be within the study criteria will be accepted in the study.
Normal control subjects ages 18 years and older, male and nonpregnant females will be given a normal resting electrocardiogram after giving written consent and proving to be within the study criteria will be accepted in the study.
Twenty normal controls and 40 patient volunteers will be studied.
This is an open trial.
Johannes Czernin, MD., Assistant Professor Nuclear Medicine and H.R. Schelbert, MD., Professor Pharmacology/Nuclear Medicine will be responsible for this research. The research will be conducted in the PET Center, AR-115, CHS, UCLA.
Participants will be exposed to risks from venous blood sampling (slight discomfort); the administration of N-13 ammonia (discomfort, lightheadedness, fainting, bruising, or none of these); exposure to a small amount of radiation (well below the levels that result in risks of harmful effects); the cold pressor test (may cause mild to severe pain of the hand which quickly subsides or coronary spasm in rare cases, slow heart rate which can be reversed by intravenous administration of atropine); dipyridamole (flushed feeling, mild headache, nausea, shortness of breath, irregular heart beat, hypotension or dizziness for a short while). People who suffer from bronchial asthma cannot participate in this study because asthma is a contra-indication for intravenous administration of dipyridamole.
The identity of the participants in this research study will remain confidential. Any identifying information will be securely locked in a file cabinet, and only personnel related to the study will have access to these records. No information that identifies any participant will be released without the participant's separate consent, except as specifically required by law.
"Response of Coronary Vasomotion to Intravenous L-Arginine"
Principal Investigator: Dr. Heinrich Schelbert, University of California, Los Angeles
Project started in: 1996
This project ended in fiscal year 2001.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: UCLA1-96-426
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of California, Los Angeles
Most recent approval: 05/30/00
IRB approval number: 95-09-426-11
Explanation of IRB approval:
Research under the DOE Cooperative Agreement was re-focused this year away from human subjects to basic sciences. All human subject projects were removed from DOE funding and closed.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2001
Type(s) of Human Subjects Involvement:
This three day study protocol will be performed using N-13 ammonia PET at rest (baseline), during Cold Pressor testing, during baseline and intravenous application of L-arginine and during Cold Pressor testing and intravenous L-arginine. This study is aimed at identifying early abnormalities in myocardial blood flow and their potential reversibility by intravenous application of L-arginine. Early identification of individuals with abnormal coronary vasomotion is important because these abnormalities have been shown to precede the development of coronary artery disease.
N-13 ammonia, diluted in saline, is a radiolabeled compound which will be administered intravenously. There are no known side effects of N-13 ammonia. However, the participants will be aware that a small amount of radioactivity will be involved in this study which is comparable to less than 1% of what California law deems an acceptable amount of exposure during the course of one year for a radiology technologist. Women of child bearing age will only be enrolled if they undergo a pregnancy test. Women who are or have been on contraceptive medication until 4 weeks prior to the study will be excluded from the study because estrogen might alter the baseline measurements of myocardial blood flow. However, women using a barrier method such as an intrauterine device or women who agree to take birth control pills for three months following the study will be able to participate in this study.
The cold pressor test involves the immersion of one hand in ice water for 90-120 seconds. This evokes the release of local and adrenal catecholamines resulting in a modest, about 20-30% increase in cardiac work as evidenced by modest increases in the rate pressure product (heart rate x systolic blood pressure). The most common adverse effect of cold is local pain. Other side effects occur rarely. However, episodes of low heart rate and low blood pressure have been observed. This was ascribed to increases in parasympathetic nerve activity. The side effects can be reversed promptly by the intravenous application of atropine, a drug that blocks parasympathetic activity. Cold might induce coronary vasospasm. However, the risk for vasospasm to occur is very small and not greater than induced by cold weather. Some patients with coronary artery disease might develop chest pain. If this occurs, oral nitroglycerine will be administered.
L-arginine is a physiologically occurring amino-acid. It is a known precursor of nitric oxide, a strong physiologic coronary vasodilator. It has been used to test human pituitary function. Few side effects are known. For instance, mild allergic reactions such as flushing, vomiting, headache, or numbness might occur and will pass. Other possible side effects are skin rash, swelling of the hands and the face which will be treated by anti-histamines.
Both N-13 ammonia and L-arginine will be administered intravenously. Therefore, a intravenous line (butterfly) will be placed on day I and day II and III of the study. This might be associated with local pain and a blue discoloration of the skin (hematoma).
Twenty patients with known coronary artery disease will be recruited through the division of Cardiology/Department of Medicine at UCLA. Both, the attending physician and the home officer will need to agree in writing to the participation in this study.
Twenty healthy individuals, matched in age to the patients will be recruited through advertising the study in local newspapers.
Twenty individuals with elevated total or LDL cholesterol will also be enrolled. They will be recruited through the Division of Cardiology/Department of Medicine at UCLA. Both the attending physician and the home officer will need to agree in writing to the participation of their patients in this study.
All participants will be paid $25/hour. They also will be compensated for travelling time and parking.
The Principal Investigator (Johannes Czernin, MD) will obtain the informed consent in the presence of a consent monitor provided by the volunteer office at UCLA. He will also be present throughout the entire study.
Participants will be exposed to risks from venous blood sampling (slight discomfort); the administration of N-13 ammonia (discomfort, lightheadedness, fainting, bruising, or none of these); exposure to a small amount of radiation (well below the levels that result in risks of harmful effects); the cold pressor test (may cause mild to severe pain of the hand which quickly subsides or coronary spasm in rare cases, slow heart rate which can be reversed by intravenous administration of atropine); dipyridamole (flushed feeling, mild headache, nausea, shortness of breath, irregular heart beat, hypotension or dizziness for a short while). People who suffer from bronchial asthma cannot participate in this study because asthma is a contra-indication for intravenous administration of dipyridamole.
The identity of the participants in this research study will remain confidential. Any identifying information will be securely locked in a file cabinet, and only personnel related to the study will have access to these records. No information that identifies any participant will be released without the participant's separate consent, except as specifically required by law.
"Human Subject Research Under Structural Biology & Molecular Medicine Research Program"
Principal Investigator: Dr. David Eisenberg, University of California, Los Angeles
Project started in: 1998
This project ended in fiscal year 2001.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: UCLA1-98-021
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of California, Los Angeles
Most recent approval: 11/06/00
IRB approval number: 97-10-021-04
Explanation of IRB approval:
Research under the DOE Cooperative Agreement was re-focused this year away from human subjects to basic sciences. All human subject projects were removed from DOE funding and closed.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2001
Type(s) of Human Subjects Involvement:
Abstract:
This approval represents the administrative approval for human subject related research projects through the UCLA-DOE Laboratory of Structural Biology and Molecular Medicine under DOE Cooperative Agreement DE-FC03-87ER60615. The various projects represented by this approval have been listed separately in the database with their individual identifiers since this administrative approval was not put in place until FY1998.
"Beta-Amyloid Probes of Alzheimer's Disease"
Principal Investigator: Dr. Gary W. Small, University of California, Los Angeles
Project started in: 1998
This project ended in fiscal year 2001.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: UCLA1-98-039
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of California, Los Angeles
Most recent approval: 09/22/00
IRB approval number: 97-07-039-04A
Explanation of IRB approval:
Research under the DOE Cooperative Agreement was re-focused this year away from human subjects to basic sciences. All human subject projects were removed from DOE funding and closed.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 22
Reporting period for number of human subjects:
Fiscal Year 2001
Type(s) of Human Subjects Involvement:
Current methods of imaging brain function can show patterns of brain activity that are characteristic of Alzheimer's disease, including decreased brain activity in areas known to be involved in memory function. These approaches may show such abnormalities early in the course of the disease. However, the current methods provide measures of general brain function rather than measures specific to the disease process. In order to develop disease-specific brain measures, we measure the concentration of a neuropathological hallmark of the disease, the amyloid plaque. Small molecules labeled with fluorine-18, which can be measured using positron emission tomography (PET) imaging, will be used in the study. After determining the safety of these small molecules, we will inject a small amount into a subject's blood stream and then use PET imaging to determine the molecule's concentration in different regions of the brain. Patients with Alzheimer's disease will be compared with age-matched persons without cognitive impairment. This approach may facilitate a brain imaging test that shows specific patterns that predict the development of Alzheimer's disease, making it useful in identifying persons who would be candidates for new anti-dementia treatments.
The data will be collected by a PET scanning device. Image data will be stored on optical disks. Patient charts with personal identifiers will be kept in a securely locked file cabinet in a locked room to which only the investigators have access.
No severe substantial risks are anticipated. The examination will expose the subjects to a very small amount of radiation, which is not expected to cause any adverse effects. The procedure is associated with the placement of a small IV line. Placing this line might cause some discomfort, dizziness, fainting. In rare instances, infection or bleeding might occur. However, this is unlikely since sterile and standard medical practices will be used, and the discomforts are no different from those encountered during a routine blood test or blood donation.
The identity of the participants in this research study will remain confidential. Any identifying information will be securely locked in a file cabinet, and only personnel related to the study will have access to these records. No information that identifies any participant will be released without the participant's separate consent, except as specifically required by law.
"Repeat Measurements of Myocardial Blood Flow with N-13 Ammonia and PET During Cold Pressor Testing"
Principal Investigator: Dr. Heinrich R. Schelbert, University of California, Los Angeles
Project started in: 1999
This project ended in fiscal year 2001.
Funding for Human Subjects Research:
This project does not involve the use of multiple protocols/subprojects.
Identifier or number: UCLA1-98-061
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of California, Los Angeles
Most recent approval: 09/28/00
IRB approval number: 98-08-061-03
Explanation of IRB approval:
Research under the DOE Cooperative Agreement has moved away from human subject studies to basic sciences. Accordingly, all human subject studies were discontinued or revised and moved out of the DOE Laboratory at the time of the IRB renewal.
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2001
Type(s) of Human Subjects Involvement:
The objective of this study is to evaluate the reproducibility of cold pressor test in healthy individuals, as a non-invasive means to assess early coronary artery disease.
Background: In previous studies we have demonstrated the possibility to identify individuals with early coronary artery disease (CAD). Importantly, disease at this very early stage can be reversed or its progression be halted by changes in lifestyle and newly available medications. Individuals with evidence of early disease typically have coronary risk factors like cigarette smoking, hypertension, diabetes, high cholesterol or obesity. These "coronary risk factors" are usually responsible for the development of early CAD. Therefore, it is of interest to identify these individuals and then, to prevent future manifestations of heart disease.
Identification of early disease required until recently use of highly invasive techniques as for example coronary arteriography or intracoronary ultrasound. However, such evaluation is now possible noninvasively through measurements of myocardial blood flow with positron emission tomography (PET) and cold pressor testing (CPT). Blood flow responses to CPT can be abnormal in patients with coronary artery disease, so that this test will be useful for the detection of early CAD. Several medications are now available for the treatment of early CAD. In order to study the effects of these medications on the coronary artery, repeat measurements of blood flow are needed. Therefore, it will be important to define whether the cold pressor test when used in the same individual produces always the same change. This will be especially important for testing whether newly available medication does in fact normalize blood flow responses to cold and, by implication, reverse the very early stage of coronary artery disease.
Protocol: We will have one study group: healthy young individuals without any coronary risk factors or symptoms of CAD. We will measure myocardial blood flow with PET and a radioactive indicator (N-13 ammonia) at baseline and during CPT when the volunteer immerses the left hand in ice cold water for 90-120 seconds; this will be done on two separate days. It will give us an answer about the reproducibility of this methodology. In addition, in order to rule out the presence of fully developed CAD, we will perform one measurement of myocardial blood flow during adenosine infusion (a standard clinical test to evaluate presence of CAD) only on the first study session. By helping to identify the reproducibility of CPT, this research will provide insight into a potential new strategy for detecting early CAD in humans. Furthermore, it is anticipated to become useful for monitoring "reversal" of early coronary disease in response to treatment.
Forty healthy volunteers will be recruited for this study.
Risks: The overall risk classification of the research is minimal. Participants will be exposed to risks from venous blood sampling (slight discomfort); the administration of N-13 ammonia (discomfort, lightheadedness, fainting, bruising, or none of these); exposure to a small amount of radiation (well below the levels that result in risks of harmful effects); the cold pressor test (mild to severe pain of the hand which quickly subsides, or no pain, coronary spasm in rare cases, slow heart rate which can be reversed by intraveous administration of atropine or no effect); adenosine (flushed feeling, mild headache, nausea, dizziness, abnormal heart rhythms, palpitations, shortness of breath, fainting spells, chest pressure or chest pain for a short while after the injection, or none of these).
Confidentiality: The identity of the participants in this research study will remain confidential. Any identifying information will be securely locked in a file cabinet and only personnel related to the study will have access to these records. No information that identifies any participant will be released without the participant's separate consent, except as specifically required by law.