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Lipid Replacement Therapy with a Glycophospholipid Formulation with NADH and CoQ10 Significantly Reduces Fatigue in Intractable Chronic Fatiguing Illnesses and Chronic Lyme Disease Patients

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  • Institute for Molecular Medicine
  • Sierra Productions Research, LLC

Abstract and Figures

Objectives: A preliminary open label study was initiated to determine if a combination oral supplement containing a mixture of phosphoglycolipids, coenzyme Q10 and microencapsulated NADH could affect fatigue levels in long-term patients with intractable fatigue. Fatigue was determined by the validated Piper Fatigue Scale before, during and after the trial. Participants included 58 patients (30 females and 28 males) with chronic fatigue syndrome/myalgic encephalomyelitis, chronic Lyme disease or other fatiguing illnesses, such as fibromyalgia syndrome or Gulf War illness. These patients had been symptomatic for an average of 17.1 ± 0.6 years, had been seen by many physicians (15.2 ± 0.7) and had used many other supplements and drugs (35.4 ± 2.7) without apparent reductions in their fatigue. Results: Participants in the study responded to the combination test supplement, showing a 30.8% reduction in overall fatigue within 60 days (P < 0.001). Analysis of subcategories of fatigue indicated that there were significant improvements in the ability to complete tasks and activities as well as significant improvements in mood and cognitive abilities. Regression analysis of the data indicated that reductions in fatigue were gradual, consistent, and occurred with a high degree of confidence (R2 = 0.960). The data also suggested that further reductions were likely if the participants had continued the supplement beyond the 8-week trial. Males responded slightly better to the combination supplement than females, and the patients with the most severe forms of fatigue responded slightly better than those with milder fatigue, independent of their diagnosis. Conclusions: The combination supplement was a safe and effective method to significantly reduce fatigue in long-term patients with intractable chronic fatigue.
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International Journal of Clinical Medicine, 2012, 3, 163-170
doi:10.4236/ijcm.2012.33034 Published Online May 2012 (http://www.SciRP.org/journal/ijcm) 163
Lipid Replacement Therapy with a Glycophospholipid
Formulation with NADH and CoQ10 Significantly Reduces
Fatigue in Intractable Chronic Fatiguing Illnesses and
Chronic Lyme Disease Patients
Garth L. Nicolson1*, Robert Settineri2, Rita Ellithorpe3
1Department of Molecular Pathology, The Institute for Molecular Medicine, Huntington Beach, USA; 2Sierra Research, Irvine, USA;
3Tustin Longevity Center, Tustin, USA.
Email: *gnicolson@immed.org
Received January 17th, 2012; revised February 25th, 2012; accepted March 19th, 2012
ABSTRACT
Objectives: A preliminary open label study was initiated to determine if a combination oral supplement containing a
mixture of phosphoglycolipids, coenzyme Q10 and microencapsulated NADH could affect fatigue levels in long-term
patients with intractable fatigue. Fatigue was determined by the validated Piper Fatigue Scale before, during and after
the trial. Participants included 58 patients (30 females and 28 males) with chronic fatigue syndrome/myalgic encepha-
lomyelitis, chronic Lyme disease or other fatiguing illnesses, such as fibromyalgia syndrome or Gulf War illness. These
patients had been symptomatic for an average of 17.1 ± 0.6 years, had been seen by many physicians (15.2 ± 0.7) and
had used many other supplements and drugs (35.4 ± 2.7) without apparent reductions in their fatigue. Results: Partici-
pants in the study responded to the combination test supplement, showing a 30.7% reduction in overall fatigue within
60 days (P < 0.001). Analysis of subcategories of fatigue indicated that there were significant improvements in the abil-
ity to complete tasks and activities as well as significant improvements in mood and cognitive abilities. Regression
analysis of the data indicated that reductions in fatigue were gradual, consistent, and occurred with a high degree of
confidence (R2 = 0.960). The data also suggested that further reductions were likely if the participants had continued the
supplement beyond the 8-week trial. Males responded slightly better to the combination supplement than females, and
the patients with the most severe forms of fatigue responded slightly better than those with milder fatigue, independent
of their diagnosis. Conclusions: The combination supplement was a safe and effective method to significantly reduce
fatigue in long-term patients with intractable chronic fatigue.
Keywords: Fatigue; Chronic Fatigue Syndrome; Lyme Disease; CoQ10; NADH; Phospholipids
1. Introduction
In the last few years natural supplements have been used
to reduce fatigue in patients with chronic fatigue and other
chronic illnesses [1,2]; however, few if any of these natural
supplements were considered effective [2]. Chronic or
intractable fatigue that is not reversed by sleep is the
most common complaint of patients seeking general
medical care [3,4]. Fatigue occurs naturally during aging,
and it is also an important secondary condition in many
chronic diseases [4].
Fatigue and especially chronic fatigue have been de-
scribed as a multidimensional sensation, and clinical
studies have determined the extent of fatigue in aging and
in various medical conditions (neurological, respiratory,
coronary, musculoskeletal, metabolic, autoimmune and
gastrointestinal diseases, cancer, infections) [3,5-7]. Most
patients consider fatigue to be a loss of overall energy
and inability to perform even simple tasks without exer-
tion [3,4]. At the cellular level fatigue is related to cellu-
lar energy systems found primarily in the cellular mito-
chondria and specifically in the inner mitochondrial
membrane electron transport chain [8,9]. Damage to mi-
tochondrial components, especially mitochondrial mem-
branes, occurs in various diseases, mainly by oxidation,
and this can result in increased ion leakage across mito-
chondrial membranes and impairment in the ability of
mitochondria to produce high-energy molecules needed
for survival and growth [10,11].
During aging and most chronic diseases the production
of oxidative molecules, such as Reactive Oxygen and
*Corresponding author.
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Lipid Replacement Therapy with a Glycophospholipid Formulation with NADH and CoQ10 Significantly
Reduces Fatigue in Intractable Chronic Fatiguing Illnesses and Chronic Lyme Disease Patients
164
Nitrogen species (ROS/RNS) that are free radical oxy-
gen- and nitrogen-containing molecules, such as nitric
oxide, oxygen and hydroxide radicals and other molecules,
can cause oxidative stress and cellular damage [10-12].
This results in oxidation of lipids, proteins and DNA
[10-13]. When oxidized, these molecules are structurally
and sometimes functionally changed [13,14]. Important
targets of ROS/RNS damage are cellular membranes, and
in particular, mitochondrial and membranes, especially
their phospholipid components [11-14].
In fatiguing illnesses, such as chronic fatigue syndrome/
myalgic encephalomyelitis (CFS/ME), patients have in-
tractable fatigue for at least six months and show in-
creased susceptibility to oxidative stress and peroxidation
of membrane lipids [15,16]. To some degree this excess
oxidative stress can be reduced with antioxidant supple-
ments [18,19], but these antioxidants cannot repair the
oxidative damage to cells.
Recent clinical trials have shown the effectiveness of
lipid replacement therapy (LRT) plus antioxidants in the
treatment of certain clinical disorders and conditions,
such as chronic fatigue [6,12]. LRT results in the actual
replacement of damaged cellular lipids with undamaged
(unoxidized) lipids to ensure proper function of cellular
structures, mainly cellular and organelle membranes. LRT
can result in the cellular delivery of unoxidized, undam-
aged membrane glycophospholipids in order to replace
damaged lipids and restore function to oxidized cellular
membranes. Combined with antioxidant supplements, LTR
has proven to be an effective method to prevent ROS/
RNS-associated changes in cellular activities and func-
tions and for use in the treatment of various clinical con-
ditions [6,12,20].
Here we tested the results of using a formulation of
glycophospholipids, CoQ10 plus microencapsulated NADH
and other nutrients on suppression of fatigue during an
open label two-month trial. The subjects in this study
were long-term chronic illness patients with intractable
fatigue that had tried unsuccessfully many drugs and sup-
plements to reduce their fatigue.
2. Materials and Methods
2.1 Materials and Methods
An open label, institutionally approved, clinical trial was
initiated to study the effects of an all-natural supplement
on fatigue. The supplement product, ATP Fuel®, con-
taining NT Factor®, microencapsulated NADH, CoQ10,
pro- and pre-biotics and other nutrients (Researched Nu-
tritionals, Inc., Los Olivos, CA), is a patent-pending pro-
prietary nutrient complex containing an exogenous source
of polyunsaturated phosphatidylcholine, phosphatidy-
glyerol, phosphatidylserine, phosphatidylinositol, and
other membrane phospholipids, as well as coenzyme Q10
(CoQ10), microencapsulated reduced nicotinamide ade-
nine dinucleotide (NADH) and other micronutrients (Ta-
ble 1). The participants took the suggested daily dose (5
capsules in the morning and 5 at night) for 8 weeks.
Table 1. Test supplement (ATP Fuel® with NTFactor®, NADH and CoQ10).
Component Amount per Serving % Daily Value*
Vitamin E (as D-α-tocopheryl succinate, mixed tocopherols) 20 IU 67
NADH and Coenzyme Q10 35 mg **
Calcium (as dicalcium phosphate, carbonate, pyruvate
borogluconate, ascorbate and dicalcium pantothenate)
phosphorus (as dicalcium phosphate), magnesium
(as magnesium oxide)
260 mg 13
Alpha keto glutaric acid, L-tyrosine 180 mg **
L-Carnipure® (L-carnitine L-tartrate), pantethine 160 mg **
NT Factor®# 2000 mg
**
ATP Fuel® is a registered trademark of Researched Nutritionals, Inc., Los Olivos, CA; *Daily values are based on a
2000 calorie per day diet; **Daily values not established; #NT Factor® is a nutrient complex extracted from soy lipids
and purified using proprietary processes. It is composed only of food and food components: phosphoglycolipids (poly-
unsaturated phosphatidylcholine, glycolipids and other polyunsaturated phosphatidyl nutrients), Bifido and Lactobac-
cillus bacteria (freeze-dried and microencapsulated in viable form), growth media (bacterial growth factors and food,
including rice bran extract, arginine, beet root fiber, black strap molasses, glycine, magnesium sulfate, para-amino ben-
zoate, leek, pantethine, taurine, garlic, calcium borogluconate, potassium citrate, spriulina, bromelain, natural vitamin E,
calcium ascorbate, -lipoic acid, oligosaccharides, vitamin B-6, niacinamide, riboflavin, vitamin B-12, folic acid, inositol,
calcium pantotenate, chromium ficolinate). NT Factor® is a registered trademark of Nutritional Therapeutics Inc.,
Commack, NY.
Copyright © 2012 SciRes. IJCM
Lipid Replacement Therapy with a Glycophospholipid Formulation with NADH and CoQ10 Significantly
Reduces Fatigue in Intractable Chronic Fatiguing Illnesses and Chronic Lyme Disease Patients 165
Fatigue was scored using the Piper Fatigue Scale (PFS).
The PFS is a validated instrument composed of 22 nu-
merically scaled questions rated from 0 (no fatigue) to 10
(severe fatigue) [21,22]. These items measure four di-
mensions of subjective fatigue: behavioral/severity (6
items); affective/meaning (5 items); sensory (5 items);
and cognitive/mood (6 items). These are used to calculate
the four sub-scale/dimensional scores and the total fa-
tigue scores. The standardized alpha (Cronbach’s alpha)
coefficient of reliability did not drop below 0.960 for any
of the subscale data, and the standard alpha for the entire
scale of 22 questions was 0.979, indicating excellent re-
liability and internal consistency for this established in-
strument [23]. The study participants took the PFS survey
at days 0, 7, 30 and 60.
2.2. Subjects
Participants were prescreened after an initial contact to
determine whether their symptoms were consistent with
persistent, intractable fatigue, or merely an intermittent
condition linked to their work, lifestyle or sleep patterns.
Those who described a condition consistent with the
definition of moderate to severe fatigue as defined in the
PFS [20-22] were directed to take an online survey after
they completed an Informed Consent document. A fol-
low-up was conducted to determine any physician’s di-
agnosis as well as complete description of their condition
and laboratory tests that were used to confirm their diag-
nosis (Table 2). Potential subjects were also asked how
long their condition existed, whether it had been affected
by any drug or supplement, and how many physicians
they had been to before entering the trial. They were also
asked if they were currently using any prescription
medications to see if this might exclude them from the
study, as determined previously [26]. The completed on-
line surveys were scored as described previously [27].
After the initial PFS survey and confirmation of their
condition, 68 participants with an overall PFS fatigue
score greater than 5 were admitted to this open-label pilot
study, if their fatigue could not be explained by a pre-
existing clinical condition. There were 58 respondents
(30 females and 28 males) who were fully compliant and
completed the study. The mean age ± standard deviation
(SD) of participants completing the study was 55.0 ± 1.4
years (females, 51.8 ± 1.7 years and males, 58.5 ± 2.1
years, respectively).
2.3. Study Design
Subjects signed an informed consent document and were
admitted into the study with measurable moderate to se-
vere fatigue (5 - 10 in the overall average PFS). Each
participant was given instructions to take the glycophos-
pholipid supplement with NADH and CoQ10 daily after
an initial PFS assessment (time 0). All subjects repeated
the PFS assessment at the end of the first week on line
without access to their previous scores. After the partici-
pants completed their PFS questionnaires at 30 and 60
days, all of the electronic forms were checked for verifi-
cation, completion and scoring accuracy [27].
2.4. Statistics
Data were analyzed by ANOVA, with significance de-
fined as P < 0.05. Further data analysis was performed
with Tukey test and linear regression analysis, with sig-
nificance defined as P < 0.05. The standardized alpha
(Cronbach’s alpha) was used to confirm reliability and
internal consistency of the data [23].
Table 2. Study participants’ diagnosis.
No. Patients* Diagnoses** Notes on Diagnoses
30 Chronic Fatigue Syndrome Myalgic encephalomyelitis (CFS/ME) Canadian
consensus definition [24]
17 Lyme Disease Symptoms, positive Western blot analysis [25]
16 Other Fatiguing Illnesses Fibromyalgia syndrome, Gulf War illness
4 Autoimmune Disease Rheumatoid arthritis
2 Cancer Active, secondary disease
2 Diabetes Active, under control
*Some patients had more than one diagnosis; **Diagnosis made by physician of record.
Copyright © 2012 SciRes. IJCM
Lipid Replacement Therapy with a Glycophospholipid Formulation with NADH and CoQ10 Significantly
Reduces Fatigue in Intractable Chronic Fatiguing Illnesses and Chronic Lyme Disease Patients
166
3. Results
3.1. Subjects in the Study
The subjects in this study were long-term chronic illness
patients who had moderate to severe chronic fatigue for
years without improvement (mean ± SD years without
improvement of fatigue = 17.1 ± 0.6 years). Most had
been to multiple physicians (mean ± SD = 15.2 ± 0.7) and
had taken a variety of drugs and supplements (mean ± SD
= 35.4 ± 2.7) without expected relief of their fatigue
symptoms. As expected, the majority of the subjects (n =
30) had a diagnosis of chronic fatigue syndrome/myalgic
encephalomyelitis (Canadian consensus definition), but
there was a significant group (n = 17) that had chronic
Lyme disease (over two years, confirmed by Western blot
analysis) or other fatiguing illnesses (n = 16, fibromyal-
gia syndrome or Gulf War illness) (Table 2). Of the 68
subjects that started the study, 58 completed the study.
Almost all of the subjects that withdrew from the study
did so without ever completing the day 0 PFS survey and
taking the test supplement, or they were omitted from the
data analysis for non-compliance during the trial. One
participant left the trial because of severe headaches,
which had occurred intermittently before the trial, and
one participant left because of gastrointestinal complaints.
In both cases these symptoms resolved after stopping the
test supplement, and no further complaints were recorded.
3.2. Effects of Test Supplement on Fatigue
We examined the effects of the combination glycophos-
pholipid-NADH-CoQ10 preparation used in this study
(Table 1) on fatigue scores in a 2-month open label trial
and found significant improvements in the overall fatigue
scores of the 58 study subjects as measured by the PFS
(Table 3). The initial PFS group mean total fatigue score
± SD was 7.51 ± 0.29, and after 8 weeks of supplement
this improved to 5.21 ± 0.28, or a 30.7% reduction in
fatigue. The mean decrease in fatigue scores was signifi-
cant by t-test (P < 0.0001) and Wilcoxon signed-rank (P
< 0.0001) analyses.
The PFS can be further dissected into subcategories
that include: behavior/severity, affective meaning, sen-
sory and cognitive/mood (Table 3). All of these sub-
categories showed significant reductions at the end of the
8-week trial (P < 0.0001), indicating that there were sig-
nificant improvements in all subcategories of fatigue. For
example, there was a 30.7% reduction (P < 0.0001) in
severity/behavior of fatigue, indicating that there was a
significant reduction in the intensity of fatigue, and a
significant increase in the ability to complete tasks, so-
cialize and engaging in sexual and other activities. Also,
there was a 28.0% improvement (P < 0.0001) in mood
and cognitive ability, such as the ability to concentrate,
remember and think clearly (Table 3).
3.3. Regression Analysis of Fatigue Data
To see if the trends in fatigue reduction over time during
the trial were consistent, occurred with a high degree of
confidence and could predict further reductions we con-
ducted regression analyses of the data. As shown in Fig-
ure 1, the regression analysis of overall fatigue in each of
the subcategories of fatigue (behavior/severity, affective
meaning, sensory and cognitive/mood) indicated signifi-
cant and consistent downward trends in the fatigue data,
suggesting that further reductions in fatigue would have
been likely if the trial had been continued (Figure 1). The
regression R2 values for the various subgroups were: be-
havior/severity, 0.956; affective meaning, 0.960; sensory,
0.950; and cognitive/mood, 0.980. Regression analysis of
the overall fatigue yielded a R2 = 0.960. This indicates a
high level of confidence in the downward trends in all
fatigue data.
Table 3. Results from overall fatigue and subcategories of the piper fatigue scale survey.
Category Mean Fatigue
Day 0 Level ± S.E.M.
Day 60 Percent
Reduction t-test
P
Overall Fatigue 7.51 ± 0.29 5.21 ± 0.28 30.7 <0.0001
Behavior/Severity 7.43 ± 0.26 5.15 ± 0.12 30.7 <0.0001
Affective/Meaning 8.36 ± 0.14 5.90 ± 0.16 29.4 <0.0001
Sensory 7.75 ± 0.22 5.49 ± 0.17 29.2 <0.0001
Cognitive/Mood 6.40 ± 0.24 4.61 ± 0.21 28.0 <0.0001
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Lipid Replacement Therapy with a Glycophospholipid Formulation with NADH and CoQ10 Significantly
Reduces Fatigue in Intractable Chronic Fatiguing Illnesses and Chronic Lyme Disease Patients 167
3.4. Regression Analysis of Data Based on Sex
We examined participants’ data to see if there was any
difference between males and females. Differences be-
tween the response to the test supplement in males and
females were obvious in the regression analyses (Figure
2). Females showed more fatigue at the beginning of the
trial as well as at the end compared to males (Figure 2).
Males showed an average of 35.9% improvement in
overall fatigue by the end of the trial (P < 0.0001),
whereas females ended the trial with an average im-
provement in fatigue of 23% (P < 0.0001). The regres-
sion analysis R2 values for males = 0.951, and for fe-
males R2 = 0.970. This indicates a high level of confi-
dence in the fatigue data in both males and females.
Figure 1. Data regression analyses of various patient sub-
groups taking the test supplement in a 60-day trial. X axis,
days; Y axis, Piper Fatigue Score. The regression R2 values
for the various subgroups were: G1: behavior/severity, 0.956;
G2: affective meaning, 0.960; G3: sensory, 0.950; and G4:
cognitive/mood, 0.980. Total: regression analysis of the over-
all fatigue, R2 = 0.960.
Figure 2. Data regression analyses of male and female sub-
groups taking the test supplement in a 60-day trial. X axis,
days; Y axis, Piper Fatigue Score. The regression R2 values
for males was 0.961, and females, 0.970.
3.5. Analysis of Data Based on Severity or
Diagnosis
We also examined the data to see if there was a differ-
ence in response to the test supplement that was depend-
ent on fatigue severity. As expected from previously tri-
als that used NT Factor® alone [28], the most severely
fatigued subjects showed the greatest reductions in fa-
tigue scores. For example, subjects with initial overall
fatigue scores above 8 in the PFS scale showed greater
reductions in fatigue scores on day 60 (35.3% improve-
ment in overall fatigue) than subjects with lower scores
(intial PFS score 4 - 8, 25% improvement by day 60).
Examination of chronic fatigue syndrome/myalgic en-
cephalomyelitis, Lyme disease or other diagnosis catego-
ries did not reveal major differences in overall fatigue or
its reduction by the test supplement that were related to
diagnosis. For example, the CFS/ME, Lyme disease and
other fatiguing illness groups total fatigue was reduced
on day 60 by 29.6%, 27% and 34.6%, respectively. The
differences between the diagnosis groups on day 60 were
not significant. However, in these diagnosis subgroups
differences between initial overall fatigue at day 0 and
overall fatigue on day 60 were highly significant (P <
0.0001).
4. Discussion
LRT using the glycophospholipid supplement NT Fac-
tor® has been used successfully in animal and clinical
lipid replacement studies [6,12,20,26-28]. In this formu-
lation encapsulated lipids are protected from oxidation in
the gut and can be absorbed and transported into tissues
without oxidative damage. NT Factor® contains a variety
of components, including phospholipids, glycophosphol-
ipids and other lipids, nutrients, probiotics, vitamins,
minerals and plant extracts [6,12].
In animal studies NT Factor® has been used to prevent
hearing loss associated with aging [30]. Seidman et al.
[30] found that NT Factor® prevented hearing loss asso-
ciated with aging and shifted the threshold hearing from
35 - 40 dB in control aged animals to 13 - 17 dB in the
treatment group (p < 0.005). They also found that NT
Factor® preserved cochlear mitochondrial function. NT
Factor® also prevented aging-related mitochondrial DNA
deletions found in the cochlear [30].
LRT has also been successfully used in clinical studies
to reduce fatigue and protect cellular and mitochondrial
membranes from oxidative damage [6,12]. For example,
NT Factor® has been used in a vitamin and mineral mix-
ture (PropaxTM) in cancer patients to reduce the effects of
cancer therapy, such as chemotherapy-induced fatigue,
nausea, vomiting and other side effects associated with
chemotherapy [30,31]. In a double-blinded, cross-over,
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Lipid Replacement Therapy with a Glycophospholipid Formulation with NADH and CoQ10 Significantly
Reduces Fatigue in Intractable Chronic Fatiguing Illnesses and Chronic Lyme Disease Patients
168
placebo-controlled, randomized trial on cancer patients
receiving chemotherapy Colodny et al. [30] showed that
LRT improved fatigue, nausea, diarrhea, impaired taste,
constipation, insomnia and other quality of life indicators.
NT Factor® has been used in a study with severe
chronic fatigued patients to reduce their fatigue [26]. We
found that fatigue was significantly reduced from severe
to moderate fatigue, after eight weeks of LRT supple-
mentation with NT Factor® [26]. We also examined the
effects of NT Factor® on fatigue in moderately and mildly
fatigued subjects and determined if their mitochondrial
function improved with administration of NT Factor®
[28]. Use of NT Factor® for 12 weeks resulted in 35.5%
reduction in fatigue (P < 0.001). In this clinical trial there
was good correspondence between reductions in fatigue
and gains in mitochondrial function. After 8 weeks of
LRT with NT Factor®, mitochondrial function was sig-
nificantly improved (P < 0.001), and after 12 weeks of
NT Factor® supplementation, mitochondrial function was
found to be similar to that of young healthy adults [28].
After 12 weeks of supplement use, subjects were placed
on placebo without their knowledge for an additional 12
weeks, and their fatigue and mitochondrial function were
again measured. After the 12-week placebo period fa-
tigue and mitochondrial function were intermediate be-
tween the initial starting values and those found after
eight or 12 weeks on supplement, indicating that contin-
ued supplementation is likely required to show improve-
ments in mitochondrial function and to maintain lower
fatigue scores [28]. Similar results were found with chro-
nic fatigue syndrome and/or fibromyalgia syndrome pa-
tients [20]. Thus the results were similar to those found
here for CFS/ME, Lyme disease, fibromyalgia syndrome
and Gulf War illness patients.
Here we used a supplement preparation containing NT
Factor®, CoQ10 and microencapsulated NADH. Prior
studies reported that microencapsulated NADH alone had
a positive effect on fatigue in some patients. Analysis of
those studies indicated that a subset of patients responded
or the response was for a limited time. In the randomized,
cross-over study of Forsyth et al. [32] on CFS/ME pa-
tients 8 of 26 (30.7%) responded to microencapsulated
NADH compared to 2 of 26 (8%) on placebo (P < 0.05).
However, these results were not considered significant by
others [33,34]. When Santaella et al. [35] compared the
effectiveness of oral NADH versus a combination of
psychological/nutritional therapy for 31 CFS/ME patients
during a 24-month clinical trial, they found that NADH
demonstrated a reduction in fatigue in the first trimester
of the trial. In subsequent trimesters, symptom scores were
similar in NADH and psychological/nutritional therapy
arms of the trial. In another study oral NADH was given
for two months to CFS/ME patients. While the NADH
group showed a decrease in anxiety and maximum heart
rate after a stress test, differences were not found in the
functional impact of fatigue, quality of life, sleep quality,
exercise capacity or functional reserve between the test
and placebo group [36].
NADH is an important cofactor that is required in
many cellular enzyme pathways, including those involv-
ing certain transferases, polymerases, synthases, deacety-
lases and other enzymes [37]. It is also important in sig-
nal transduction, DNA repair, salvage pathways and post-
translational protein modifications [38]. NADH in its re-
duced form is a product of the mitochondrial electron
transport chain, and it plays an important role in pro-
grammed cell death [39]. Thus the NAD+/NADH system
has a major physiological impact on cellular health and
metabolism [40]. When mitochondria are functioning pro-
perly, enough NADH is produced to meet cellular re-
quirements [39].
CoQ10 is an essential electron carrier in the mitochon-
drial respiratory chain and an important antioxidant as
well as a molecule involved in gene regulation [41,42]. It
has been used as an important supplement in a variety of
chronic illnesses and age-related conditions [42-44]. Here
CoQ10 was used to improve energy transduction and com-
bat oxidative stress [42,45]. This cofactor has been used
extensively for combined nutraceutical therapy in mito-
chondrial cytopathies [45,46].
The present study used a combination nutraceutical
formulation containing NT Factor®, CoQ10 and NADH
and included a variety of chronic illness patients who had
been sick with chronic fatigue for an average of over 17
years. Chronic fatigue is known to cause loss of mito-
chondrial function [28,46]. These patients had tried a
large number of supplements and drugs (over 35) with
little or no effect on their fatigue. Thus this sample of pa-
tients could be considered as having intractable fatigue,
yet they responded quite well to the combination sup-
plement containing NT Factor®, CoQ10 and NADH. In
addition, regression analysis indicated that the data were
consistent with a high degree of confidence. The regres-
sion analysis also suggested that the trial may have ended
too soon, and the peak benefits on fatigue were yet to be
realized. The supplement was safe, and only two partici-
pants experienced minor symptoms that resolved after the
supplement was discontinued and could not be directly
attributed to the effects of the test supplement since their
problems preceded entry into the trial. Thus the clinical
trial demonstrated that the test supplement was effective
and safe for long-term chronic illness patients.
5. Conclusion
After 60 days use of a supplement containing a mixture
of phosphoglycolipids, CoQ10 and NADH, fatigue meas-
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Lipid Replacement Therapy with a Glycophospholipid Formulation with NADH and CoQ10 Significantly
Reduces Fatigue in Intractable Chronic Fatiguing Illnesses and Chronic Lyme Disease Patients 169
ured with the validated Piper Fatigue Scale was signifi-
cantly reduced in 58 patients with chronic fatigue syn-
drome/myalgic encephalomyelitis, chronic Lyme disease
or other fatiguing illnesses, such as fibromyalgia syn-
drome or Gulf War illness. The supplement was safe and
effective and reduced overall fatigue 30.8% in these long-
term patients with intractable chronic fatigue.
6. Acknowledgements
The authors would like to thank Researched Nutritionals,
Inc. and the Institute for Molecular Medicine for clinical
trial financial support.
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... However, another study in elderly subjects with age-associated memory impairment that received 300-600 mg PS daily for 12 weeks did not show memory improvements [122]. Although supplementing with a single class of glycerolphospholipid alone, such as PS, has been shown to have health benefits, the use of more complex mixtures of membrane GPL may be more beneficial, possibly as some of the PS does not have to be enzymatically converted to other GPL [1][2][3]123,124]. ...
... In some patients, homocysteine levels decreased from high-risk levels to normal ranges [128]. In a different study, 58 middle-aged patients with fatiguing illnesses received doses of 4 g per day oral NTFactor ® for 2 months without any adverse incidents [123]. Some of these patients continued using the MLR supplement for years without reporting any adverse events. ...
... For example, MLR has been used in several studies in patients with fatiguing illnesses to reduce moderate to severe chronic fatigue. Patients complaining of fatigue lasting more than 6 months are considered patients with chronic fatigue [123,124,145,175,189]. The effects of NTFactor ® on chronic fatigue in moderately fatigued subjects were documented to determine if mitochondrial function improved simultaneous with reductions in fatigue in patients taking oral NTFactor ® [145]. ...
Article
Full-text available
Membrane Lipid Replacement (MLR) uses natural membrane lipid supplements to safely replace damaged, oxidized lipids in membranes in order to restore membrane function, decrease symptoms and improve health. Oral MLR supplements contain mixtures of cell membrane glycerolphospholipids, fatty acids, and other lipids, and can be used to replace and remove damaged cellular and intracellular membrane lipids. Membrane injury, caused mainly by oxidative damage, occurs in essentially all chronic and acute medical conditions, including cancer and degenerative diseases, and in normal processes, such as aging and development. After ingestion, the protected MLR glycerolphospholipids and other lipids are dispersed, absorbed, and internalized in the small intestines, where they can be partitioned into circulating lipoproteins, globules, liposomes, micelles, membranes, and other carriers and transported in the lymphatics and blood circulation to tissues and cellular sites where they are taken in by cells and partitioned into various cellular membranes. Once inside cells, the glycerolphospholipids and other lipids are transferred to various intracellular membranes by lipid carriers, globules, liposomes, chylomicrons, or by direct membrane–membrane interactions. The entire process appears to be driven by ‘bulk flow’ or mass action principles, where surplus concentrations of replacement lipids can stimulate the natural exchange and removal of damaged membrane lipids while the replacement lipids undergo further enzymatic alterations. Clinical studies have demonstrated the advantages of MLR in restoring membrane and organelle function and reducing fatigue, pain, and other symptoms in chronic illness and aging patients.
... The improvements in mitochondrial function assessed by inner mitochondrial membrane transmembrane potential matched the clinical data and showed enhancement up to 45% while on the MLR supplement, but these gains were slowly reversed after the patients were switched to the placebo arm of the study [113]. Similar positive results on the effects of MLR phospholipid supplements on reducing fatigue from 26-43% were found in various chronic conditions, including CFS/ME, fibromyalgia, Gulf War illness, chronic Lyme disease and other infections, and various cancers [33,102,103,[112][113][114][115]. ...
... One of the symptom categories in the studies discussed in the previous section was pain, and MLR supplements, such as NTFactor Lipids ® , have been used to help reduce widespread musculoskeletal pain, peripheral neuropathy and gastrointestinal symptoms, like stomach pain, in chronically ill patients [115][116][117][118][119]. Pain is a complex phenomenon that can be initiated by injury, illness or environmental exposures. ...
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Full-text available
The Fluid-Mosaic Model has been the accepted general or basic model for biomembrane structure and organization for the last 50 years. In order to establish a basic model for biomembranes, some general principles had to be established, such as thermodynamic assumptions, various molecular interactions, component dynamics, macromolecular organization and other features. Previous researchers placed most membrane proteins on the exterior and interior surfaces of lipid bilayers to form trimolecular structures or as lipoprotein units arranged as modular sheets. Such membrane models were structurally and thermodynamically unsound and did not allow independent lipid and protein lateral movements. The Fluid-Mosaic Membrane Model was the only model that accounted for these and other characteristics, such as membrane asymmetry, variable lateral movements of membrane components, cis-and transmembrane linkages and dynamic associations of membrane components into multimolecular complexes. The original version of the Fluid-Mosaic Membrane Model was never proposed as the ultimate molecular description of all biomembranes, but it did provide a basic framework for nanometer-scale biomembrane organization and dynamics. Because this model was based on available 1960s-era data, it could not explain all of the properties of various biomembranes discovered in subsequent years. However, the fundamental organizational and dynamic aspects of this model remain relevant to this day. After the first generation of this model was published, additional data on various structures associated with membranes were included, resulting in the addition of membrane-associated cytoskeletal, extracellular matrix and other structures, specialized lipid-lipid and lipid-protein domains, and other configurations that can affect membrane dynamics. The presence of such specialized membrane domains has significantly reduced the extent of the fluid lipid membrane matrix as first proposed, and biomembranes are now considered to be less fluid and more mosaic with some fluid areas, rather than a fluid matrix with predominantly mobile components. However, the fluid-lipid matrix regions remain very important in biomembranes, especially those involved in the binding and release of membrane lipid vesicles and the uptake of various nutrients. Membrane phospholipids can associate spontaneously to form lipid structures and vesicles that can fuse with various cellular membranes to transport lipids and other nutrients into cells and organelles and expel damaged lipids and toxic hydrophobic molecules from cells and tissues. This process and the clinical use of membrane phospholipid supplements has important implications for chronic illnesses and the support of healthy mitochondria, plasma membranes and other cellular membrane structures.
... The trial only examined one dose level of the MLR glycerolphospholipid supplement, which we determined in case studies to be sufficient to reduce pain and other symptoms in Gulf War veterans. Additionally, the study could have benefited from the addition of other mitochondrial natural supplements, as we have done in other studies, including those with NTFactor Lipids ® , CoQ10 and other mitochondrial supplements [35]. Here, we found that MLR with oral glycerolphospholipids appeared to be a simple, safe and potentially effective method of slowly reducing the severities of multiple symptoms in chemically exposed veterans. ...
... Most if not all of these symptoms are also related to mitochondrial function, and MLR supplements like the test supplement are known to enhance mitochondrial function [32][33][34]. There are a number of other possible mitochondrial and cellular membrane supplements that could be useful in various combinations for reducing symptoms in GWI patients, and these should also be investigated [35,36]. ...
Article
Full-text available
Background: Chemically exposed veterans of the 1991 Gulf War have few options for treatment of conditions and symptoms related to their chemical exposures. Membrane Lipid Replacement (MLR) with oral membrane glycerolphospholipids is a safe and effective method for slowly removing hydrophobic organic molecules from tissues, while enhancing mitochondrial function and decreasing the severity of certain signs and symptoms associated with multi-symptom illnesses. Methods: A preliminary open-label study utilizing 20 male veterans who were deployed to combat areas, exposed to environmental toxic chemicals and subsequently diagnosed with Gulf War Illnesses (GWI) were utilized. These subjects took 6 g per day oral glycerolphospholipids for 6 months, and the severities of over 100 signs and symptoms were self-reported at various times using illness survey forms. Results: In the sixteen patients that fully complied and completed the study, there were gradual and significant reductions of symptom severities in categories related to fatigue, pain, musculoskeletal, nasopharyngeal, breathing, vision, sleep, balance, and urinary, gastrointestinal and chemical sensitivities. There were no adverse incidents during the study, and the all-natural oral study supplement was extremely well tolerated. Conclusions: MLR with oral glycerolphospholipids appears to be a simple, safe and potentially effective method of slowly reducing the severities of multiple symptoms in chemically exposed veterans.
... For general muscle weakness and fibromyalgia, a supplement of 250 mg/day of carnitine and 100 mg/day coenzyme Q10 (CoQ10) can improve symptoms [92,93]. Carnitine is a natural compound that is an essential cofactorin fatty acid metabolism. ...
... It may present in the first decade of life and progress to poorsleep and post-exertional dyspnea [88].Fatigue can progress to severe post-exertional malaise and disabling morningfatigue. Supplements such as CoQ10, magnesium, nicotinamide adeninedinucleotide (NADH), and alpha-lipoic acid may ameliorate fatigue [96].A meta-analysis demonstrated improvement in fatigue with CoQ10 supplementationamong heart failure, multiple sclerosis, fibromyalgia, and healthy individuals [97].In subjects with chronic fatigue syndrome, NADH taken in combination with CoQ10has also been proven to improve fatigue [92].Magnesium levels have been shown to be lower in individuals with chronicfatigue syndrome compared to controls [98]. Furthermore, Cox et al. demonstrated in a randomized, double-blind study thatintramuscular magnesium sulphate weekly for 6 weeks resultedin less pain, improved emotional state, and overall higher energy levelscompared to placebo. ...
Article
Full-text available
Purpose of Review Dysautonomia and hypermobility syndrome are two distinct but often overlapping clinical conditions that are recognized for their complex multiorgan system afflictions. The purpose of this review is to investigate dietary strategies to reduce symptoms and augment quality of life in this growing patient population. Recent Findings There is increasing evidence supporting dietary modifications to include food rich in probiotics and prebiotics, along with fiber supplements to reduce gastrointestinal symptoms. Adequate salt and fluid intake may reduce orthostatic hypotension symptoms. Dietary supplements may help with osteoarticular, musculoskeletal, and fatigue symptoms. Summary Individualized diet strategies and supplements can reduce the multiorgan system symptoms observed in dysautonomia and hypermobility syndrome.
... When on the MLR supplement, their mitochondrial function tests were similar to results found in much younger subjects (average age of 31 years old), but only if they continued to take the MLR oral supplement [101]. Similar positive results on the effects of the MLR GPL supplement NTFactor ® or NTFactor Lipids ® on reducing fatigue were found in various patients with chronic fatigue syndrome (CFS/ME), fibromyalgia, Gulf War illness, chronic Lyme disease and various cancers, with reductions in fatigue ranging from 26% to 43% [90,92,93,96,[102][103][104][105]. ...
Article
Full-text available
Early cell membrane models placed most proteins external to lipid bilayers in trimolecular structures or as modular lipoprotein units. These thermodynamically untenable structures did not allow lipid lateral movements independent of membrane proteins. The Fluid–Mosaic Membrane Model accounted for these and other properties, such as membrane asymmetry, variable lateral mobilities of membrane components and their associations with dynamic complexes. Integral membrane proteins can transform into globular structures that are intercalated to various degrees into a heterogeneous lipid bilayer matrix. This simplified version of cell membrane structure was never proposed as the ultimate biomembrane description, but it provided a basic nanometer scale framework for membrane organization. Subsequently, the structures associated with membranes were considered, including peripheral membrane proteins, and cytoskeletal and extracellular matrix components that restricted lateral mobility. In addition, lipid–lipid and lipid–protein membrane domains, essential for cellular signaling, were proposed and eventually discovered. The presence of specialized membrane domains significantly reduced the extent of the fluid lipid matrix, so membranes have become more mosaic with some fluid areas over time. However, the fluid regions of membranes are very important in lipid transport and exchange. Various lipid globules, droplets, vesicles and other membranes can fuse to incorporate new lipids or expel damaged lipids from membranes, or they can be internalized in endosomes that eventually fuse with other internal vesicles and membranes. They can also be externalized in a reverse process and released as extracellular vesicles and exosomes. In this Special Issue, the use of membrane phospholipids to modify cellular membranes in order to modulate clinically relevant host properties is considered.
... [72,73]; and viral infections such as human herpes virus 6 (HHV-6) [14,74], as well as other medical problems causing overlapping sources of inflammation with downstream effects [13]. These include up to 16 factors identified on the MSIDS model [75,76], including immune dysfunction/immune deficiency [13,15,77], environmental toxins with detoxification problems [78], GI problems, food allergies [79,80], nutritional deficiencies [81,82], hormone and autonomic nervous system dysregulation [83][84][85], mitochondrial dysfunction [86,87], neuropsychiatric problems, and/or sleep disorders [13,[88][89][90]. All patients reported here had evidence of multiple overlapping etiologies accounting in part for resistant symptoms, including evidence of associated co-infections (Babesia, Bartonella, Mycoplasma fermentans), hormonal dysfunction, food allergies and leaky gut, environmental toxin exposure with mineral deficiencies, POTS/dysautonomia, neuropsychiatric problems, and sleep disorders. ...
Article
Full-text available
Three patients with multi-year histories of relapsing and remitting Lyme disease and associated co-infections despite extended antibiotic therapy were each given double-dose dapsone combination therapy (DDD CT) for a total of 7–8 weeks. At the completion of therapy, all three patients’ major Lyme symptoms remained in remission for a period of 25–30 months. A retrospective chart review of 37 additional patients undergoing DDD CT therapy (40 patients in total) was also performed, which demonstrated tick-borne symptom improvements in 98% of patients, with 45% remaining in remission for 1 year or longer. In conclusion, double-dose dapsone therapy could represent a novel and effective anti-infective strategy in chronic Lyme disease/post-treatment Lyme disease syndrome (PTLDS), especially in those individuals who have failed regular dose dapsone combination therapy (DDS CT) or standard antibiotic protocols. A randomized, blinded, placebo-controlled trial is warranted to evaluate the efficacy of DDD CT in those individuals with chronic Lyme disease/PTLDS.
... MLR has been successfully used for reducing fatigue in patients with chronic fatigue (fatigue lasting more than 6 months), chronic illnesses, such as CFS/ME, fibromyalgia, and other fatiguing illnesses [11,13,[26][27][28] in symptoms, such as fatigue scores, but does this more quickly, in several days to a week or more instead of several months [32,33]. ...
Article
Full-text available
Membrane Lipid Replacement (MLR) is the use of functional dietary supplements containing cell membrane glycerolphospholipids and antioxidants to safely replace and remove damaged essential membrane phospholipids that accumulate during aging and in various chronic and acute illnesses. Most, if not all, clinical conditions and aging are characterized by cellular membrane phospholipid free radical oxidative damage, resulting in loss of membrane and cellular functions. In particular, loss of mitochondrial function, the key organelle responsible for over 90% of cellular energy production, can result in excess fatigue and other symptoms, and this is a common problem in almost all, if not all, age-related chronic diseases. Clinical trials have shown the benefits of MLR supplements in replenishing damaged membrane phospholipids and restoring mitochondrial function, resulting in reductions in fatigue and other symptoms in aged subjects and patients with a variety of clinical diagnoses. Here we have specifically reviewed the beneficial results of MLR on subjects older than 60 years. MLR provides general membrane and nutritional support during aging and illnesses to improve membrane function and overall health without risk of adverse effects. The case reports here and elsewhere and published clinical trials demonstrate that this is a safe and effective alternative or addition to pharmaceutical approaches for alleviating fatigue, pain, gastrointestinal and other symptoms associated with normal aging and age-related chronic illnesses.
... [72,73]; and viral infections such as human herpes virus 6 (HHV-6) [14,74], as well as other medical problems causing overlapping sources of inflammation with downstream effects [13]. These include up to 16 factors identified on the MSIDS model [75,76], including immune dysfunction/immune deficiency [13,15,77], environmental toxins with detoxification problems [78], GI problems, food allergies [79,80], nutritional deficiencies [81,82], hormone and autonomic nervous system dysregulation [83][84][85], mitochondrial dysfunction [86,87], neuropsychiatric problems, and/or sleep disorders [13,[88][89][90]. All patients reported here had evidence of multiple overlapping etiologies accounting in part for resistant symptoms, including evidence of associated co-infections (Babesia, Bartonella, Mycoplasma fermentans), hormonal dysfunction, food allergies and leaky gut, environmental toxin exposure with mineral deficiencies, POTS/dysautonomia, neuropsychiatric problems, and sleep disorders. ...
Preprint
Full-text available
Three patients with multi-year histories of relapsing and remitting Lyme disease and associated co-infections despite extended antibiotic therapy were each given double dose dapsone combination therapy (DDD CT) for a total of 7-8 weeks. At the completion of therapy, all three patients major Lyme symptoms remained in remission for a period of 25-30 months. In conclusion, Double dose dapsone therapy could represent a novel and effective anti-infective strategy in chronic Lyme disease/PTLDS, especially in those individuals who have failed regular dose dapsone combination therapy (DDS CT) or standard antibiotic protocols. A randomized, blinded, placebo-controlled trial is warranted to evaluate the efficacy of DDD CT in those individuals with chronic Lyme disease/PTLDS.
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