U.S. patent application number 13/722020 was filed with the patent office on 2013-05-16 for five and fifteen carbon fatty acids for treating metabolic disorders and as nutritional supplements.
This patent application is currently assigned to Baylor Research Institute. The applicant listed for this patent is Baylor Research Institute. Invention is credited to Charles R. ROE.
Application Number | 20130123359 13/722020 |
Document ID | / |
Family ID | 33476904 |
Filed Date | 2013-05-16 |
United States Patent
Application |
20130123359 |
Kind Code |
A1 |
ROE; Charles R. |
May 16, 2013 |
FIVE AND FIFTEEN CARBON FATTY ACIDS FOR TREATING METABOLIC
DISORDERS AND AS NUTRITIONAL SUPPLEMENTS
Abstract
According to the present invention, acquired metabolic
derangements or fatty acid disorders in humans that are manifested
by a deficiency in at least one enzyme involved in fatty acid
metabolism are treated with a five carbon or a fifteen carbon fatty
acid source. Rapid nutritional supplementation can also be provided
to a mammalian cell by providing either a five carbon or fifteen
carbon fatty acid source. Dietary formulations suitable for human
consumption comprising either a five carbon fatty acid, a fifteen
carbon fatty acid or triglycerides thereof is also disclosed.
Inventors: |
ROE; Charles R.; (Rockwall,
TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Baylor Research Institute; |
Dallas |
TX |
US |
|
|
Assignee: |
Baylor Research Institute
Dallas
TX
|
Family ID: |
33476904 |
Appl. No.: |
13/722020 |
Filed: |
December 20, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10557310 |
Oct 30, 2006 |
8399515 |
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PCT/US04/15633 |
May 19, 2004 |
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13722020 |
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60471949 |
May 20, 2003 |
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Current U.S.
Class: |
514/558 ;
435/375; 514/557 |
Current CPC
Class: |
A61K 31/202 20130101;
A23L 33/12 20160801; A61P 3/00 20180101; A61K 31/22 20130101; A23L
33/40 20160801; A61K 31/23 20130101; A23K 20/158 20160501; A61K
31/225 20130101; A61K 31/19 20130101; A61K 31/20 20130101 |
Class at
Publication: |
514/558 ;
514/557; 435/375 |
International
Class: |
A61K 31/20 20060101
A61K031/20; A61K 31/19 20060101 A61K031/19 |
Claims
1. A method for treating acquired metabolic derangements or fatty
acid disorders in humans that are manifested by a deficiency in at
least one enzyme involved in fatty acid metabolism, comprising
treating said human with a five carbon fatty acid source.
2. A method for treating fatty acid disorders in humans that are
manifested by a deficiency in at least one enzyme involved in fatty
acid metabolism, comprising treating said human with a fifteen
carbon fatty acid source.
3. The method of claim 1, wherein said fatty acid disorder is
MCAD.
4. The method of claim 1, wherein said fatty acid disorder is
SCAD.
5. The method of claim 1, wherein said fatty acid disorders are
selected from VLCAD, MTP, and LCHAD.
6. The method of claim 2, wherein said fatty acid disorder is
SCAD.
7. The method of claim 2, wherein said fifteen carbon fatty acid is
administered orally.
8. A method for providing rapid nutritional supplementation to a
mammalian cell, comprising providing a five carbon fatty acid
source to said cell.
9. A method for providing rapid nutritional supplementation to a
mammalian cell, comprising providing a fifteen carbon fatty acid
source to said cell.
10. A method for providing nutritional supplementation to a human
or animal, comprising providing a fatty acid source comprising five
carbons, administered enterally or parenterally.
11. A method for providing nutritional supplementation to a human
or animal, comprising providing a fatty acid source comprising
fifteen carbons, administered enterally or parenterally.
12. The method of claim 11, wherein said administration is
oral.
13. The method of claim 1 or 2, wherein said acquired metabolic
derangement concerns increased metabolic needs by cardiac
tissue.
14. A dietary formulation suitable for human consumption comprising
an odd numbered carbon chain fatty acid selected from the group
consisting of five carbon fatty acids and fifteen carbon fatty
acids and triglycerides thereof.
15. The dietary formulation of claim 14, wherein said fatty acid is
pentanoic acid.
16. The dietary formulation of claim 14 or 15, wherein said
formulation is adapted for consumption by a human during a 24 hour
time period and comprises from about 15 to about 40% of the dietary
caloric requirement of said human for said 24 hour time period.
17. The dietary formulation of claim 14 or 15 wherein said
formulation is adapted for consumption by a human during a 24 hour
time period and comprises from about 20 to about 35% of the dietary
caloric requirement of said human for said 24 hour time period.
18. The dietary formulation of claim 14 or 15, wherein said
formulation is adapted for consumption by a human during a 24 hour
time period and comprises about 25-35% of the dietary caloric
requirement of said human for said 24 hour time period.
19. The dietary formulation of any of claims 14-18, wherein said
formulation is suitable for enteral administration.
20. The dietary formulation of any of claims 14-18, wherein said
formulation is suitable for parenteral administration.
21. The dietary formulation of claim 14, 16, 17 or 18 wherein said
formulation is suitable for oral consumption.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 60/471,949 filed May 20, 2003.
TECHNICAL FIELD OF THE INVENTION
[0002] The invention relates to methods of treating inherited
metabolic disorders and acquired metabolic derangements and
nutritional supplements for normal humans and animals.
BACKGROUND OF THE INVENTION
[0003] Fatty acid oxidation disorders (FODs) can cause serious
clinical manifestations or even death. There have been a variety of
inherited metabolic FODs identified which are enzyme deficiencies,
and there are also various acquired metabolic derangements
manifested by inadequate energy reaching particular muscles, such
as the heart under stress conditions. In addition, normal
individuals experience nutritional inefficiencies due to metabolism
of the food choices that they make.
[0004] Previously, the use of a seven carbon fatty acid was found
to be effective in a method for treating an inherited disorder in
at least one enzyme involved in fatty acid metabolism. This use was
described and claimed in U.S. Ser. No. 09/890,559, filed Aug. 1,
2001 which is hereby incorporated by reference. U.S. Ser. No.
09/890,559 claims priority to U.S. Provisional Application
60/119,038 filed 5 Feb. 1999 and PCT/US00/03022 filed 3 Feb. 2000.
In that work, seven carbon fatty acids were also found to be
effective as an energy source for humans not suffering from an
enzyme deficiency, but in need of nutrients that provide fuel for a
metabolic pathway that is underutilized due to the lack of odd
chain fatty acids in normal foodstuffs.
[0005] For individuals suffering from Medium Chain Acyl-CoA
Dehydrogenase (MCAD) Deficiency, an inherited metabolic disorder
characterized by a deficiency of the enzyme medium chain acyl-CoA
dehydrogenase, there remained a need for a treatment other than the
administration of seven carbon fatty acids. MCAD participates in
the initial oxidation of seven carbon fatty acids; therefore
deficiency of MCAD cannot be treated with seven carbon fatty acids.
Conventional dietary therapy for MCAD patients is to eat a high
carbohydrate, fat restricted diet, avoiding fasting and eating
often throughout the day. However, there is no reliable parenteral
approach for rescue of MCAD patients during crisis. Further,
dietary control is more difficult with infants since some of the
enzymes needed by humans to metabolize certain carbohydrates, such
as starches, do not become active until nearly six months of age.
Cornstarches may be useful for treatment of babies and children
above six months of age, but may cause undesirable effects such as
constipation.
[0006] It has now been found that five carbon fatty acids are
useful as a treatment for MCAD. Further, five carbon fatty acids
can be used to treat long-chain FODs that are also treatable with
seven carbon fatty acids. Five carbon fatty acids present a
metabolic profile differing from that presented upon administration
of seven carbon fatty acids, and this may be advantageous in some
circumstances.
[0007] Further, it has been found that a fifteen carbon fatty acid
(C15) can be administered as a precursor to five carbon fatty acids
in normal humans and animals and for certain metabolic disease
states such as Short-chain acyl-CoA dehydrogenase (SCAD)
deficiency, and are preferred to C5 fatty acids for oral
administration. C5 fatty acids have been found to have an
undesirable taste due to breakdown by enzymes present in the
saliva, and such enzymes are not active on C15 compounds and
therefore C15 has a more pleasant taste.
SUMMARY OF THE INVENTION
[0008] In one aspect, the invention is a method for treating
acquired metabolic derangements or fatty acid disorders in humans
that are manifested by a deficiency in at least one enzyme involved
in fatty acid metabolism, comprising treating the human with a five
carbon fatty acid source. The treatment can be used for treating
fatty acid disorders including but not limited to MCAD, SCAD,
VLCAD, MTP, and LCHAD fatty acid disorders. The treatment is useful
for acquired metabolic derangement concerning increased metabolic
needs by cardiac tissue.
[0009] In another aspect, the invention is a method for treating
fatty acid disorders in humans that are manifested by a deficiency
in at least one enzyme involved in fatty acid metabolism,
comprising treating the human with a fifteen carbon fatty acid
source. The treatment can be used to treat fatty acid disorders
including but not limited to SCAD. In one exemplary method, the
fifteen carbon fatty acid is administered orally.
[0010] In another aspect, the invention is a method for providing
rapid nutritional supplementation to a mammalian cell, comprising
providing a five carbon fatty acid source to the cell.
[0011] In another aspect, the invention is a method for providing
rapid nutritional supplementation to a mammalian cell, comprising
providing a fifteen carbon fatty acid source to the cell. In one
exemplary method, administration is oral.
[0012] In another aspect, the invention is a method for providing
nutritional supplementation to a human or animal, comprising
providing a fatty acid source comprising five carbons, administered
enterally or parenterally.
[0013] In another aspect, the invention is a method for providing
nutritional supplementation to a human or animal, comprising
providing a fatty acid source comprising fifteen carbons,
administered enterally or parenterally.
[0014] In another aspect, the invention is a dietary formulation
suitable for human consumption comprising an odd numbered carbon
chain fatty acid selected from the group consisting of five carbon
fatty acids and fifteen carbon fatty acids and triglycerides
thereof. In a preferred dietary formulation, the fatty acid is
pentanoic acid. In one embodiment, the formulation is adapted for
consumption by a human during a 24 hour time period and comprises
from about 15 to about 40% of the dietary caloric requirement of
the human for the 24 hour time period. In another embodiment, the
formulation is adapted for consumption by a human during a 24 hour
time period and comprises from about 20 to about 35% of the dietary
caloric requirement of the human for the 24 hour time period. In
yet another embodiment, the formulation is adapted for consumption
by a human during a 24 hour time period and comprises about 25-35%
of the dietary caloric requirement of the human for the 24 hour
time period. According to the present invention, these formulations
are generally suitable for enteral administration and parenteral
administration, and with the exception of pentanoic acid, oral
consumption.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 depicts the use of propionyl-CoA and acetyl-CoA in
the Citric Acid Cycle.
[0016] FIG. 2 depicts the oxidation of tripentanoin in the
mitochondrion and pentadecanoate in the peroxisome and
mitochondrion.
[0017] FIG. 3 depicts levels of propionlycarnitine and
myristenoylcarnitine in a VCLAD patient on a diet of triheptanoin
(C7) or tripentanoin (C5) monitored over a 3 hour interval.
[0018] FIG. 4 depicts relative blood levels of fatty acid chain
lengths in a SCAD patient following C5 or C7 treatment.
DETAILED DESCRIPTION OF THE INVENTION
[0019] It has now been found that odd-carbon fatty acids comprising
five carbon fatty acids (C5) or fifteen carbon fatty acids (C15)
can be used to treat inherited metabolic disorders in humans and
acquired metabolic derangements (e.g., congestive heart failure,
cardiomyopathy) in humans and other mammals. These fatty acid
sources may also be used for enhanced nutrition of normal,
non-diseased humans and animals.
[0020] Metabolism of these source fatty acid sources is effective
to provide, simultaneously, propionyl-CoA and acetyl-CoA inside the
mitochondrion. Provision of these two CoA thioesters is useful for
four main reasons: (1) they participate in anaplerosis, or the
filling up with intermediates, of the Citric Acid Cycle (CAC),
thereby enhancing the rotation of the CAC, which results in
enhanced production of ATP via proton transfer from reduced
co-enzymes (FADH and NADH) to the respiratory chain; (2) acetyl-CoA
participates in the citrate synthase reaction which produces
citrate in the CAC; (3) both acetyl-CoA and propionyl-CoA stimulate
the production of oxaloacetate, which is gluconeogenic; and (4) the
metabolism of odd-chain fatty acid C15 via mitochondrial beta
oxidation is also ketogenic, since the metabolism of the ketones
formed results in additional acetyl-CoA and propionyl-CoA in the
mitochondria. A representation of the entry of acetyl-CoA,
propionyl-CoA into the CAC is provided in FIG. 1 and a
representation of oxidation of tripentanoin (C5) and pentadecanoate
(C15) is provided in FIG. 2.
[0021] In one embodiment of the invention, a C5 or a C15 fatty acid
source is provided for enteral administration or consumption by a
person in need of treatment or nutritional supplementation.
Tripentanoin can be obtained by the esterification of n-pentanoic
acid, which is commercially available (Sigma Chemical Company, St.
Louis Mo.), and glycerol by methodology known in the art for the
making of triglycerides. As used herein, a C5 fatty acid source may
be the fatty acid or its triglyceride. A C15 fatty acid source,
n-pentadecanoic acid (C15) is also commercially available. (Sigma).
A C-15 triglyceride may be made by esterification with glycerol
through methods known in the art. Preferred types of enteral
administration are oral, parenteral and nasogastric administration.
Although it is subject to all types of enteral administration, it
is most preferred that when a C5 fatty acid is used, that it be
administered non-orally, since it has a disagreeable taste. It has
been found that C15 does not have a disagreeable taste, and that
oral administration of C15 is more preferred over oral
administration of C5. C15 is most preferred over C5 in foods and
beverages used for nutritional supplementation, since it has an
agreeable taste and since it serves as a metabolic precursor for C5
and therefore for propionyl-CoA and acetyl-CoA.
[0022] The amount of C5 or C15 fatty acid to provide to a human in
need of treatment for an inherited metabolic disorder or acquired
metabolic derangement is from 15 to 40% of the daily dietary
caloric requirement. Preferably, the amount supplied will be from
about 25-35% and most preferred about 35%. If C5 or C15 is used as
a nutritional supplement, it is advantageous in any amount as an
additive to food, beverages, or parenteral nutrient formulas.
However, it is most advantageous to provide the fatty acids in the
same amounts useful for treatment.
[0023] The efficacy of pentadecanoate [C15] and pentanoate [C5] for
treating fat oxidation disorders is demonstrated in Table 1. Data
is compared with that obtained for treatment with heptanoate [C7],
an odd carbon fatty acid earlier found useful for treatment of
certain disorders. (See PCT WO 00/45649, published 10.08.00).
[0024] Fibroblasts obtained from patients with inherited defects of
mitochondrial fat oxidation were cultured in the presence of omega
deuterated odd-carbon numbered fatty acids, as described in Roe, C.
R., Sweetman, L., Roe, D. S., David, F., Brunengraber, H.,
"Effective Dietary Treatment of Cardiomyopathy & Rhabdomyolysis
in Long-Chain Fat Oxidation Disorders using an Anaplerotic
Odd-Chain Triglyceride," J. Clin. Invest. 110 (2): 259-269
(2002).
[0025] The relative amounts of the precursors as acylcarnitines and
the relative amounts of propionyl-CoA (as propionylcarnitine [C3]
produced after 72 hours incubation provides information as to
whether the tested fatty acid is useful for producing propionyl-CoA
in the various defective fibroblast cell lines. These results
reflect the presence of the required enzyme systems for dietary
therapy.
[0026] The data in Table 1 represents testing of cultured
fibroblasts derived from ten patients afflicted with
Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (six
patients with the severe cardiac form and four with the non-cardiac
milder phenotype), two patients with Mitochondrial Trifunctional
Protein (MTP) deficiency, five patients having L-3-hydroxy-acyl-CoA
dehydrogenase (LCHAD) deficiency and three patients with
Short-chain acyl-CoA dehydrogenase (SCAD) deficiency.
[0027] Results of incubations with C5 fatty acid for all of these
cell lines produced consistently greater quantities of
propionylcarnitine than was observed with the same cells incubated
with heptanoate (C7). This is reflected in the ratios of the amount
of propionylcarnitine produced by C5 compared to the amount from
C7.
TABLE-US-00001 TABLE 1 Propionylcarnitine from Oxidation of
Odd-Carbon Fatty Acids in Fibroblasts (Results in nmol/mg
Protein/72 hours) No. Carbons in Fatty Acid Ratio: Ratio: Disease
C5 C7 C15 C5/C7 C5/C15 VLCAD 28.2 17.8 8.0 1.6 3.5 Cardiac 34.7
20.4 6.6 1.7 5.3 50.6 25.0 9.9 2.0 5.1 47.0 28.7 11.7 1.6 4.0 27.2
13.0 5.3 2.1 5.2 67.8 44.5 21.6 1.5 3.1 AVG. 1.8 AVG. 4.4 VLCAD
44.4 22.6 16.4 2.0 2.7 Non- 28.3 20.3 19.2 1.4 1.5 Cardiac 51.8
24.3 36.0 2.1 1.4 19.7 14.4 11.5 1.4 1.7 AVG. 1.7 AVG. 1.8 MTP 38.3
24.1 31.4 1.6 1.2 63.6 48.1 46.5 1.3 1.4 AVG. 1.5 AVG. 1.3 LCHAD
65.4 53.2 34.6 1.2 1.9 34.5 23.5 15.1 1.5 2.3 35.0 24.0 15.9 1.5
2.2 24.4 10.6 6.9 2.3 3.5 36.8 22.7 13.9 1.6 2.6 AVG. 1.6 AVG. 2.5
SCAD 80.2 57.7 56.7 1.4 1.4 43.6 32.4 30.3 1.4 1.4 48.2 39.2 37.6
1.2 1.3 AVG. 1.3 AVG. 1.4 VLCAD--Very-Long-Chain Acyl-CoA
Dehydrogenase Deficiency (Cardiac and Non-Cardiac)
MTP--Mitochondrial Trifunctional Protein Deficiency
LCHAD--L-3-Hydroxy-Acyl-CoA Dehydrogenase Deficiency
SCAD--Short-Chain Acyl-CoA Dehydrogenase Deficiency
[0028] It has been found, however, that although there is no bad
taste associated with oral administration of triheptanoin (C7),
there is a very bad taste when tripentanoin (C5) is used as a fatty
acid source, due to cleavage of the triglyceride by salivary
enzymes that yields free valeric acid and mono- and diglycerides.
However, for nasogastric, gastrostomy, or parenteral feeding,
tripentanoin (C5) is advantageous for treatment of all fat
oxidation disorders, including MCAD deficiency, as well as other
diseases of amino acid metabolism that do not involve enzymes of
the HMG pathway (ketogenesis) or ketone utilization.
[0029] Although application of equivalent amounts of C15 fatty
acids yielded less propionylcarnitine than did application of C5 or
C7 fatty acids, C15 fatty acids were also found effective in
providing propionyl-CoA to the Kreb's cycle. Particularly in the
case of normals and humans with SCAD deficiency, the amount of
propionyl-CoA produced upon provision of C15 approaches that
produced upon provision of a C7 source. In contrast, C7 was found
to be more efficient than C15 for VLCAD, MTP, and LCHAD cells.
[0030] It has also been found that C5-fatty acid sources are useful
in a method for treating MCAD (Medium chain acyl-CoA dehydrogenase)
deficiency. It has been found that odd-carbon fatty acids
containing seven or more carbons require medium chain acyl-CoA
dehydrogenase for oxidation. (Table 2). It is demonstrated in Table
3 that C5 fatty acids are effective in providing energy to cells
even when medium chain acyl-CoA dehydrogenase is missing.
[0031] Fibroblasts from four patients with MCAD deficiency and one
heterozygote (carrier) indicate that odd-carbon fatty acids
containing more than seven carbons can not be effectively used in
that disease. Incubation of MCAD deficient fibroblasts with C15
illustrates a block in oxidation at C9 & C7 (substrate
chain-length requiring the MCAD enzyme). Incubation with C9 is
associated with accumulation of C9 as expected for the same reason.
Similarly, C7 is blocked, indicating that the MCAD enzyme is
required for its oxidation. The C3 produced from these odd-carbon
compounds is significantly reduced as expected. That any C3 was
produced is presumably due to overlapping
TABLE-US-00002 TABLE 2 Fate of Odd-Carbon Fatty Acids in
MCAD-Deficient Fibroblasts TRIPENTADECANOIN (C15 triglyceride) MCAD
*C3 *C5 *C7 *C9 *C11 *C13 *C15 Mean 9.8 1.2 6.5 10.9 0.7 0.4 2.6 SD
7.0 0.5 3.1 5.7 0.3 0.4 1.6 SEM 3.5 0.2 1.5 2.8 0.2 0.2 0.8 Minimum
3.1 0.5 3.5 4.3 0.3 0.0 1.0 Maximum 19.6 1.6 9.9 17.5 1.0 0.9 4.7 N
4 4 4 4 4 4 4 MCAD 33.5 1.7 0.6 1.7 0.5 0.2 1.9 Carrier CONTROL
MEAN 46.8 2.8 0.8 2.2 0.9 0.7 3.8 S.D. (N = 4) 8.8 0.7 0.5 2.0 0.6
0.6 1.77 TRINONANOIN (C9 triglyceride) MCAD *C3 *C5 *C7 *C9 Mean
3.0 0.5 2.8 7.3 SD 1.8 0.1 1.1 2.6 SEM 0.9 0.1 0.5 1.3 Minimum 1.6
0.3 1.6 4.0 Maximum 5.5 0.7 4.2 10.3 N 4 4 4 4 MCAD 6.0 0.4 0.4 3.2
Carrier CONTROL 3.9 0.4 0.3 2.0 MEAN S.D. (N = 4) 1.5 0.2 0.1 0.6
TRIHEPTANOIN (C7 triglyceride) MCAD *C3 *C5 *C7 Mean 8.3 1.1 8.3 SD
4.8 0.5 4.2 SEM 2.4 0.2 2.1 Minimum 5.7 0.7 2.4 Maximum 15.4 1.8
12.0 N 4 4 4 MCAD 16.3 0.9 0.5 Carrier CONTROL 24.3 1.3 0.4 MEAN
S.D. (N = 4) 5.6 0.3 0.2
TABLE-US-00003 TABLE 3 Propionylcarnitine from Odd Carbon
Precursors- MCAD Fibroblasts (nmol/mg Protein/72 hours) PRECURSOR
NORMAL MCAD-1 MCAD-2 C15 46.8 6.9 19.6 C9 3.9 1.8 2.9 C7 24.3 10.6
17.4 C5 25.8 25.8 58.5
chain-length specificity of other short chain acyl-CoA
dehydrogenases in the mitochondrial matrix.
[0032] Experiments with 2 MCAD deficient fibroblast cell lines
(MCAD 1 and MCAD 2) revealed that C5 was very effective for
producing propionyl-CoA, in vitro, compared to pentadecanoate
(C15), nonanoate (C9), or heptanoate (C7). Using a C5 fatty acid
source produced normal or greater than normal propionyl-CoA in
culture. It was also found that C15 is more effective in normal
cells in boosting the production of propionyl-CoA than C7 or C5
(which are comparable). Therefore, C15 is a candidate for use in
nutritional supplementation of normal patients.
Example 1
Use of Tripentanoin to Treat Patients with Fat Oxidation disorders
(VLCAD and SCAD)
[0033] A VLCAD patient and an SCAD patient, both of whom had
gastrostomy sites for enteral administration, each were provided
with separate meals containing equimolar amounts of triheptanoin
(C7) and tripentanoin (C5) at different times on the same day. Each
patient was given the amount in 1 of 4 daily meals equivalent to a
diet of 3 gms/Kg/day or about 30% of total Kcal as the
triglyceride. Serial blood samples were obtained hourly and
individual urines were collected at baseline and during the
meal.
[0034] The patient with VLCAD (FIG. 3) was monitored over a 3 hour
interval and the SCAD patient was monitored for 4 hours after
beginning the meal. There was no clinical or biochemical toxicity
associated with these tests. One way the VLCAD patient was
monitored was for myristenoylcarnitine (cis-5-C14:1), which
reflects oxidation of oleate and is therefore an indication of
ongoing lipolysis during the meal tests (it is not derived from
either C7 or C5). A reduction of C14:1 associated with increasing
levels of C3 (propionylcarnitine) demonstrates complete oxidation
for both triglycerides and direct evidence for the inhibition of
lipolysis by the anaplerotic effects of these odd-carbon
triglycerides. These changes are not observed with even-carbon
triglycerides. Results are provided in Table 4 and FIG. 3.
[0035] The second patient with SCAD deficiency (FIG. 4) had been
receiving the triheptanoin diet for more than 2 years. This
disorder is due to an inherited deficiency of butyryl-CoA
dehydrogenase (SCAD) and is known to oxidize even carbon fatty
acids of 4-6 carbon chain length. The fact that C5 never
accumulated during therapy with triheptanoin indicated that C5 was
being oxidized by another enzyme in the mitochondrial matrix
(presumably isovaleryl-CoA dehydrogenase in the Leucine metabolic
pathway). In this patient, there was no limitation in oxidation for
either C7 or C5 in the meals. Data is given in Table 5 and shown in
FIG. 4.
TABLE-US-00004 TABLE 4 VLCAD PATIENT RESULTS Propionylcarnitine
Myristenoylcarnitine Level Level Time (hours) C7 C5 C7 C5 0 1.39
1.38 2.61 3.07 1 2.89 3.15 2.83 2.89 2 3.78 3.51 1.38 2.04 3 4.57
5.63 2.64 3.39
TABLE-US-00005 TABLE 5 SCAD PATIENT RESULTS Relative Blood Levels
Relative Blood Levels of Fatty Acid of Fatty Acid Chain Lengths
Chain Lengths After C7 Treatment After C5 Treatment Time (hours) C3
C5 C4 C3 C5 C4 0 3.00 0.13 0.34 2.61 0.14 0.30 1 2.08 0.23 0.16
2.78 0.24 0.26 2 2.42 0.32 0.23 3.19 0.51 0.27 3 3.29 0.27 0.26
3.73 0.67 0.30 4 2.61 0.14 0.30 4.99 0.34 0.27
[0036] In FIG. 4, C7-C3 represents the blood levels of C3 derived
from C7; and C5-C3 represents the blood levels of C3 derived from
C5, C7-C5 represents blood levels of pentanoylcarnitine (C5)
derived from C7 meals and C5-C5 represents blood levels of
pentanoylcarnitine (C5) derived from C5 meals. Neither of these
showed any significant accumulation during the course of the meals.
C7-C4 and C5-C4 represent the levels of the disease-specific
acylcarnitine (butyrylcarnitine [C4]) observed in SCAD deficiency.
There was no significant decrease in C4 which was already at very
low levels. However, the amount of C3 produced following the meal
containing C5 was significantly greater than that observed
following ingestion of C7. This increased quantity of C3
corresponds to those observed for SCAD deficiency in the fibroblast
studies above shown in Table 1.
Example 2
Use of C5 Fatty Acid to Treat Patients with MCAD Deficiency
[0037] An infant afflicted with MCAD deficiency would be diagnosed
via known screening methods. An infant formula having C5 as the
fatty acid source could be fed to the infant, preferably in a
manner other than orally due to the disagreeable taste, such as
through a feeding tube, to provide a nutrient which will be
metabolized into propionyl CoA and acetyl CoA. Oral administration
could be employed if a suitable taste-masking agent is available
and is employed. Alternatively, the infant could be fed
parenterally, such as during periods of illness, with an
appropriate parenteral nutrition formula supplemented with C5 fatty
acid.
Example 3
Use of C15 Fatty Acid in a Nutritional Supplement
[0038] A milkshake or smoothie could be formulated with C15 as a
fatty acid source or supplement. A person could drink the smoothie
and obtain the benefit of a substance that will be metabolized into
acetyl CoA as well as propionyl CoA, thus providing fuel for the
Krebs cycle from more than one entry point. This could enhance
performance of an athlete.
Example 4
Use of C5 Fatty Acid in Cardiac Care
[0039] A patient that has undergone heart surgery could be supplied
C5 fatty acid source via parenteral nutrition. The heart tissue
would directly benefit from this energy source, thereby leading to
more rapid recovery.
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