Healthy
Conditions
Keywords
dichloroacetate, tyrosine, maleylacetoacetate, trichloroethylene, leucine, haplotype
Brief summary
This project focuses on the kinetics, metabolism and human toxicology of dichloroacetate (DCA)and tyrosine catabolism. The hypothesis is that tyrosine metabolism will be greatest in subject who harbor the KRT variant for GSTz1/MAAI for which DCA exhibits a high Km.
Detailed description
Specific Aim 4. Quantify the effects of DCA on human tyrosine metabolism and on its own biotransformation in relation to dose and genotype.
Interventions
DRUGDichloroacetate
Healthy men and women with different haplotypes will receive an infusion of leucine and tyrosine. The following day they begin a 5 day course of dichloroacetate (DCA)at a dose of 2.5mcg/kg/day. On day 6 they return and receive another infusion of leucine and tyrosine. After a 30 day washout period the subject returns and again receives an infusion of leucine and tyrosine. Then on day 2 they begin a dose of DCA at 25mg/kg for 5 days and then return for the final infusion of leucine and tyrosine.
GENETICGenotyping
Subjects will have 5 mls of blood drawn for genotyping
OTHERLeucine
Healthy men and women with different haplotypes will receive an infusion of leucine and tyrosine. The following day they begin a 5 day course of dichloroacetate (DCA)at a dose of 2.5mcg/kg/day. On day 6 they return and receive another infusion of leucine and tyrosine. After a 30 day washout period the subject returns and again receives an infusion of leucine and tyrosine. Then on day 2 they begin a dose of DCA at 25mg/kg for 5 days and then return for the final infusion of leucine and tyrosine.
OTHERtyrosine
Healthy men and women with different haplotypes will receive an infusion of leucine and tyrosine. The following day they begin a 5 day course of dichloroacetate (DCA)at a dose of 2.5mcg/kg/day. On day 6 they return and receive another infusion of leucine and tyrosine. After a 30 day washout period the subject returns and again receives an infusion of leucine and tyrosine. Then on day 2 they begin a dose of DCA at 25mg/kg for 5 days and then return for the final infusion of leucine and tyrosine.
Sponsors
University of Florida
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
22 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Adults scheduled for elective surgery for benign liver disease. * Normal EKG and history * Normal baseline labs
Exclusion criteria
* Pregnancy * severe anemia, defined as a hematocrit \< 30%. * diabetes mellitus * renal insufficiency, defined as a serum creatinine \> 1.5 mg/dl or a creatinine clearance \< 60 ml/min * elevated liver enzymes * psychiatric illness requiring medication * primary biliary cirrhosis or any other form of cirrhosis * viral hepatitis or non-viral steatohepatitis * coronary heart disease, defined as requiring daily administration of anti-anginal drugs or as New York Heart Association Class III or IV heart failure * malignancy of any type in any anatomical location
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Interaction of DCA and/or Tyrosine Breakdown Products and Maleylacetoacetate Isomerase (MAAI) in Vivo. | One week | Subjects are administered an infusion of the amino acids leucine and tyrosine. The next day they start a five day course of dichloroacetate(DCA). At the end of five days they receive another infusion of tyrosine and leucine. The pharmacokinetics of DCA is calculated following the second infusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Inhibition of Tyrosine and Individual's Haplotype | one week | Given the infusion of the above amino acids and DCA administration the inhibition of tyrosine will be measured in the KRT haplotype and non KRT haplotype. |
Countries
United States
Participant flow
Recruitment details
The participants were recruited by a posted advertisement.
Pre-assignment details
Two subjects were enrolled but did not participate in the study. One subject was delayed because the solution for the infusion had particles in it and then didn't continue(didn't receive any intervention) due to funding issues, and the second one was enrolled but didn't receive any intervention due to funding issues that have been explained.
Participants by arm
| Arm | Count |
|---|---|
| Haplotypes and DCA Metabolism Healthy men and women with different haplotypes will receive an infusion of leucine and tyrosine. The following day they begin a 5 day course of dichloroacetate (DCA)at a dose of 2.5mcg/kg/day. On day 6 they return and receive another infusion of leucine and tyrosine. After a 30 day washout period the subject returns and again receives an infusion of leucine and tyrosine. Then on day 2 they begin a dose of DCA at 25mg/kg for 5 days and then return for the final infusion of leucine and tyrosine. | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Infusion cost exceeded funding | 2 |
Baseline characteristics
| Characteristic | Haplotypes and DCA Metabolism |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 |
Outcome results
Primary
The Interaction of DCA and/or Tyrosine Breakdown Products and Maleylacetoacetate Isomerase (MAAI) in Vivo.
Subjects are administered an infusion of the amino acids leucine and tyrosine. The next day they start a five day course of dichloroacetate(DCA). At the end of five days they receive another infusion of tyrosine and leucine. The pharmacokinetics of DCA is calculated following the second infusion.
Time frame: One week
Population: No statistical analysis. The data was incomplete and was not analyzed.
Secondary
Inhibition of Tyrosine and Individual's Haplotype
Given the infusion of the above amino acids and DCA administration the inhibition of tyrosine will be measured in the KRT haplotype and non KRT haplotype.
Time frame: one week
Population: No statistical analysis. The data was incomplete and was not analyzed.