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CHICAGO, IL, United States

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 207.05K | Year: 2008

DESCRIPTION (provided by applicant): The long-term objective of this research is to develop a non-invasive approach for early assessment of de novo 3MH production in cancer patients as a way of assessing which patients are at high risk for future developme nt of skeletal muscle atrophy. The approach is based on the known increase in the rate constant for de novo production of 3-methylhistidine (3MH) in this sub-set of cancer patients as a consequence of their unique tumor-host interactions. As such, we hypot hesize that the rate constant for the terminal portion of the isotope decay curve following ingestion of a single oral dose of deuterated-3-methylhistidine (D-3MH) provides an accurate measure of this increased risk and that this rate constant can be measu red non-invasively from timed spot urine samples obtained during this period. Furthermore, we hypothesize that consumption of 3MH- containing meals up to the time of dosing will not adversely affect the results making the entire procedure clinically releva nt. During Phase I, we will establish the feasibility of our over all approach by testing the following hypotheses: (i) isotope enrichment in spot urine samples is identical with the corresponding plasma samples, and (ii) meat intake up to and including th e time of dosing does not influence the slope of the terminal portion of the isotope decay curve. Testing the validity of these two hypotheses is the central focus of the Phase-I research and is crucial to the development of an approach that is both scient ifically sound as well as non-invasive and clinically relevant. We will test the feasibility of our approach in ten healthy older adult male volunteers. If Phase-I testing is successful, we propose, with Phase-II funding, to conduct a statistically powerfu l prospective investigation to demonstrate that this test conducted in newly diagnosed lung and gastrointestinal cancer patients predicts future development of muscle wasting. We expect the outcome of the combined Phase-I and Phase-II research to lead to t he manufacture and marketing of a suitable Test Kit for early identification of increased muscle proteolysis in at-risk cancer patients so that medical intervention can take place and prevent future muscle atrophy. Project Narrative: Skeletal mus cle loss is an important, but unpredictable, occurrence in patients with different types of cancer. Clinically significant skeletal muscle loss cannot be reversed and has poor prognostic implications. Its early assessment is important because it would perm it selection of cancer patients for preventive strategies. The purpose of this project is to develop a non-invasive method for early assessment of increased skeletal muscle degradation in patients with cancer. Our approach is based on development of a (non -radioactive) stable isotope tracer approach to permit accurate quantitative measurement of skeletal muscle degradation early in the course of muscle loss by monitoring spot urine samples for the ratio of labeled/unlabeled 3-methylhistidine the morning aft er consuming a small amount of labeled 3-methylhistidine along with dinner.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 204.34K | Year: 2008

DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to develop an inexpensive, totally non-invasive surrogate test for the 2-h oral glucose tolerance test (2-h OGTT) for the purpose of identifying individuals with pre-diabete s for preventive purposes. We believe that such a test can be developed based on oral administration of a 75-g 13C-labeled glucose solution administered according to the current American Diabetes Association protocol followed by the measurement of the area under the curve (AUC) for breath CO2 isotopic enrichment. Because this test measures the combined effects of impairments in both glucose and lipid oxidation during an OGTT protocol, it: (i) is more sensitive than the current 2-h OGTT, and (ii) correlates strongly with the 2-h OGTT blood glucose. And because it relies solely on collecting breath samples, it is totally non-invasive and thus ideal for screening purposes involving large numbers of individuals. Our preliminary data demonstrate that this is a go od surrogate test for the 2-h OGTT, but in order to proceed further we need to first establish its intra- and inter-individual variability as a function of worsening glucose tolerance. During Phase-I funding cycle (the current application), we will conduct a protocol in 20 men and women whose glycemia ranges from normoglycemic to diabetic according to standard 2-h OGTT blood glucose for the purpose of establishing intra- and inter-individual variability of the proposed test at different values of 2-h OGTT. During a subsequent Phase-II funding cycle, we plan to conduct appropriate protocols in order to: (i) establish the strength of the correlation between this surrogate test and the 2-h OGTT, and (ii) investigate whether this approach can be used to predict development of impaired glucose tolerance for preventive purposes. During Phase-III and with non-SBIR funds, we will: (i) establish a central facility to manufacture the relevant test kits, and (ii) develop collaborative relations with selected diabetes re search centers in order to demonstrate its applications and make the test available to the community. PUBLIC HEALTH RELEVANCE: Type 2 diabetes mellitus (T2DM) is a serious chronic disease affecting millions of people globally. Prevention/delay of onset of diabetes is considered an important issue in diabetes management and requires the ability to select individuals early in the course of progression (pre-diabetes) before onset of clinical symptoms. Current diagnosis of pre-diabetes is based on either fasti ng plasma glucose or 2-hour plasma glucose after administration of an oral glucose tolerance test (OGTT). These two methods identify different subsets of pre-diabetics and are both necessary for selection of at-risk individuals. Use of oral glucose toleran ce test has been discouraged by the American Diabetes Association because of its limitations related to cost, convenience, and repeatability. We propose to develop a totally non-invasive surrogate test for the 2-h OGTT based on breath sampling after admini stration of a standard dose of glucose labeled with the non- radioactive stable isotope 13C6-glucose.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 901.96K | Year: 2002

DESCRIPTION (provided by the applicant): The long-term objectives of this proposed project are to develop a "Test Kit" for quantitative assessment of steatorrhea in infants without the need for control of dietary fat intake and quantitative collections of stools for several days as is the case with the current "Gold Standard," viz, the 72-hour fecal fat method. Our proposed "Test Kit" is based on administering a feeding of infant formula containing a suitably labeled 13C-triglyceride (TG), a trace amount of the nonabsorbable marker dysprosium chloride (DyC1-3) and the visual marker Brilliant Blue followed by laboratory analysis of Dy and 13C-Excess in one or more sample(s) of stool containing the visual marker. The research conducted during Phase-I of this grant has led to the selection of 1,3-(13C-2) dipalmitoyl, 2-lauryl glycerol (P*LP*) as the most suitable TG* for applications in infants. During Phase II of the project, we propose to conduct clinical protocols with cystic fibrosis and healthy infants in order to: (1) define the parameters of the expected linear correlation between fecal excretion of P*LP* and fecal fat, (2) demonstrate the significance of this novel method in medical management of infants with steatorrhea, and (3) obtain research data necessary for the manufacture of a safe and noninvasive "Test Kit" for accurate assessment of steatorrhea in infants. The "Test Kit" has widespread applications in clinical management of infants with a wide range of disorders leading to steatorrhea.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 198.62K | Year: 2005

DESCRIPTION (provided by applicant): Iron deficiency anemia (IDA) is a major problem among adults and elderly. In men and postmenopausal women, IDA is currently thought to result from gastrointestinal (GI) blood loss. Despite thorough GI tract evaluation, a significant number of patients are found to be negative for fecal occult blood (FOB) and >30% do not have lesions consistent with chronic blood loss, suggesting that iron (Fe) malabsorption plays an important role. Currently, however, there is neither a suitable test to measure Fe absorption nor a role in the present scheme of GI examination for its evaluation. We propose to modify the current protocol for FOB testing to permit concurrent evaluation of both FOB and Fe absorption in a noninvasive test. The modification involves ingesting a gelatin capsule at bedtime that contains small quantities of Fe labeled with a non-radioactive (stable) isotope (Fe ), the recently developed nonabsorbable marker DyCl3, and the food colorant (visual stool marker) FD&C Blue No. 1.This is followed by laboratory analysis of a small sample of the visually marked stool for blood (the current practice) and the ratio Fe*/Dy; the latter provides accurate information on presence of iron malabsorption. During Phase-I, we will test the feasibility of this method by establishing the expectedly high value of iron absorption in healthy pre-menopausal women who are iron deficient without involvement of the GI tract. During Phase-II, we will evaluate the range of iron malabsorption that exists in IDA patients with suspected malabsorption (e.g celiac disease, H. pylori gastritis, or IDA patients refractory to iron supplementation, etc.) and in appropriate "controls" (IDA patients without malabsorption). During Phase-Ill, we will manufacture a "Test Kit', obtain FDA approval and work with the GI community to develop applications for measurement of iron malabsorption in the evaluation of IDA patients using private funds.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 860.52K | Year: 2009

DESCRIPTION (provided by applicant): The overall objective of this grant is to develop a non-invasive method for assessment of insulin resistance and impaired glucose tolerance (IGT) as a measure of pre-diabetes suitable for application to large-scale screening studies and to individualized preventive strategies in patients at risk for development of diabetes. This new approach is based on the known alterations in the mix of whole-body fuel utilization that occurs during progression from normal glucose tolerance to impaired glucose tolerance to diabetes. It involves administration of a standard oral glucose tolerance test solution that contains, in addition, a small quantity of the non-radioactive (stable isotope) 13C6-glucose, followed by measurement of breath 13CO2 isotope enrichment. During Phase-I of this project, we have established the proof-of-concept and feasibility of this approach. We have demonstrated that the correlation of the said method with the common indices of insulin resistance possesses similar statistical strength compared with those published for these indices and the currently accepted gold standard, i.e. the glucose-clamp. We have also demonstrated that inter-individual reproducibility of the breath test as a measure of IGT is acceptably low and its correlation with OGTT sufficiently high to permit its development as a non-invasive test of IGT. During Phase-II, we will conduct a number of clinical investigations to: 1) evaluate the intra- and inter-individual variability of our method compared to the glucose-clamp, the three common indices (HOMA-IR, QUICKI, and WBISI), and the standard OGTT; and 2) to evaluate the correlation between our proposed breath test, the glucose-clamp, common indices, and OGTT in individuals whose glycemia ranges from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to diabetes and whose body mass index (BMI) covers the range from lean to obese. We anticipate that successful completion of the Phase-II research will lead to the development of a routine method for assessment of insulin resistance and a non-invasive test of IGT for application to screening and individualized preventive studies. After successful completion of Phase-II research and with non-SBIR funding, we will establish a central facility to produce and market appropriate test kit(s) along with the necessary analytical expertise - making the method available to all interested parties for clinical or research purposes. PUBLIC HEALTH RELEVANCE: Insulin resistance and impaired glucose tolerance are early manifestations of serious chronic disorders of major concern to public health: diabetes, chronic heart disease, obesity, hypertension, etc. Their early recognition is important for preventive purposes. Currently, the Gold Standard for assessing insulin resistance is the so-called glucose-clamp, which is not suitable for general-purpose clinical management of patients. The surrogate methods available currently, the so-called Common indices show large inter- individual variability's for any given value of their corresponding glucose-clamp and, thus, are not suitable for individualized preventive purposes. During Phase-I of this SBIR program, we have demonstrated that a non- invasive Breath Test has the potential to be a suitable surrogate test for the glucose-clamp and as a non- invasive measure of impaired glucose tolerance (pre-diabetes). During Phase-II, we propose to develop this test and to demonstrate its high linear correlation with both the glucose-clamp and oral glucose tolerance test.

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