Acute and Long-Term Outcome Investigations of Fenofibrate on Severely Burned Patients
| Status: | Terminated |
|---|---|
| Healthy: | No |
| Age Range: | 4 - 20 |
| Updated: | 4/21/2016 |
| Start Date: | May 2012 |
| End Date: | February 2016 |
The purpose of this study is to learn the following: whether long-term treatment (6 months)
with fenofibrate will decrease burn related sugar and fat increased in the blood and help
prevent muscle loss and improve wound healing.
with fenofibrate will decrease burn related sugar and fat increased in the blood and help
prevent muscle loss and improve wound healing.
Following severe burn injury in human patients the mitochondrial fat oxygenation capacity is
decreased in muscle. This is associated with a corresponding progression in the severity of
the resistance to the action of insulin on glucose disposal and protein synthesis and
breakdown in muscle, regenerating wound and liver.
Fatty acids or their active intracellular products ( e.g. DAG, acyl- Coenzyme A(CoA) or
acylcarnitine) are the direct inhibitors of insulin action, rather than tissue
triglycerides(TG) itself. In other words, impaired mitochondrial fatty acid oxygenation is
the mechanism that causes altered lipid metabolism that ultimately contributes to insulin
resistance.
Accumulation of active fatty acid products, such as DAG, acyl-CoA or acylcarnitine esters in
muscle cells is due to the rate of uptake of plasma free fatty acids(FFA) exceeding the rate
of oxygenation within muscle due principally to a reduced capacity of mitochondria to
oxidize fatty acids.
Decreasing insulin sensitivity in muscle is related to impaired insulin signaling. This will
be reflected by increased activity of protein kinase C (PKC). Because PKC is thought to
exert its regulatory effect primarily on either tyrosine kinase activity on the insulin
receptor or downstream kinase insulin receptor substrate (IRS) phosphorylation, these
elements of the insulin signaling cascade will be decreased. In turn, elements of insulin
signaling related to the response of muscle glucose (PI3 Kinase) and protein
(P70S6k)metabolism will be reduced. The investigators propose that increased tissue PKC
activity will be associated with increased tissue concentration of DAG, acyl-CoA or
acylcarnitine. The investigators hypothesize that the treatment of patients with the
peroxisome proliferator-activated receptor (PPAR) alpha antagonist fenofibrate will improve
mitochondrial capacity to oxidize fatty acids. Insulin sensitivity in muscle, skin and liver
in terms of both glucose and protein metabolism will be improved by fenofibrate treatment.
decreased in muscle. This is associated with a corresponding progression in the severity of
the resistance to the action of insulin on glucose disposal and protein synthesis and
breakdown in muscle, regenerating wound and liver.
Fatty acids or their active intracellular products ( e.g. DAG, acyl- Coenzyme A(CoA) or
acylcarnitine) are the direct inhibitors of insulin action, rather than tissue
triglycerides(TG) itself. In other words, impaired mitochondrial fatty acid oxygenation is
the mechanism that causes altered lipid metabolism that ultimately contributes to insulin
resistance.
Accumulation of active fatty acid products, such as DAG, acyl-CoA or acylcarnitine esters in
muscle cells is due to the rate of uptake of plasma free fatty acids(FFA) exceeding the rate
of oxygenation within muscle due principally to a reduced capacity of mitochondria to
oxidize fatty acids.
Decreasing insulin sensitivity in muscle is related to impaired insulin signaling. This will
be reflected by increased activity of protein kinase C (PKC). Because PKC is thought to
exert its regulatory effect primarily on either tyrosine kinase activity on the insulin
receptor or downstream kinase insulin receptor substrate (IRS) phosphorylation, these
elements of the insulin signaling cascade will be decreased. In turn, elements of insulin
signaling related to the response of muscle glucose (PI3 Kinase) and protein
(P70S6k)metabolism will be reduced. The investigators propose that increased tissue PKC
activity will be associated with increased tissue concentration of DAG, acyl-CoA or
acylcarnitine. The investigators hypothesize that the treatment of patients with the
peroxisome proliferator-activated receptor (PPAR) alpha antagonist fenofibrate will improve
mitochondrial capacity to oxidize fatty acids. Insulin sensitivity in muscle, skin and liver
in terms of both glucose and protein metabolism will be improved by fenofibrate treatment.
Inclusion Criteria:
- ≥40% Burn
- ages 4-20years
- body weight ≥10kg
Exclusion Criteria:
- <40% burn
- ages <4->20 years
- body weight <10kg
- Respiratory insufficiency
- Multiple fractures
- History of cancer in last 5 years
- Bilirubin>3mg/dL
- Serum Creatinine>3mg/dL after fluid resuscitation
- Glutamyl-Oxaloacetic Transaminase(GOT) >40 Units/L
- Glutamyl-Pyruvate Transminase(GPT) >51 Units/L
- Associated head injuries requiring therapy
- Associated injuries to the chest or abdomen requiring surgery
- Receipt of any experimental drug other than the ones supplied within two months of
study
- Any metal in body including rods, neurofibrilators, pacemaker, etc
- Orthopedic casting which would prevent placement in MRI
- Hepatitis
- Abnormal EKG
- Electrical burns
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University of Texas Medical Branch Established in 1891 as the University of Texas Medical Department,...
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