task in C.F.S. is to understand genetic backgrounds, decrease or eliminate
pathogen loads, decrease environmental pollution, optimize immune function,
heal any intestinal disorder, optimize nutrition (consider nutrigenomics),
counter oxidative stress, and allow restoration of all cellular function
All of this is in
the setting of the consciousness of the person who is intimately involved
in this healing task.
It necessarily involves
ongoing conversations that allow each person in her or his own way to
co-evolve the healing outcome.
I like to call this a dance of understanding
This fits with my
idea that evolution whether it be in the changes in the cosmos, in biological
systems, or in our thinking, never ceases.
The healing processes could produce a change from an ill
or dysfunctional state of homeostasis to an optimally functioning
It should be stated from the outset that in practice this is sometimes
a far from satisfactory area.
Hypotheses need much more work on them.
We are accessing the work of many authors, some of whom are laboratory
researchers, others clinicians and yet others modelers of molecular
biology. Some are readers who like to word and reword the work of others.
How can we evaluate the merit of claims?(
Indeed is it possible
at any point in time to put therapies in some sort of order?
Which can be used together?
Taking all these things into consideration some specific therapies have
been suggested and some of these are designed to rectify chemical abnormalities
and others are to protect and help the cell membrane to improve. I cite
some of these therapies.
In what follows there will be a strong emphasis on nutrition.
The quality and nature of nutrients could provide the body with everything
it needs for optimal health.
It seems likely that not only are there nutrient deficiencies in the
third world, but in the midst of plenty, Western countries have not
achieved ideal nutrition. Vitamins C and D should be especially considered.
If impaired ATP production by mitochondria is important, the Sarah Myhill
plan is endorsed by cardiologists Stephen Sinatra and James Roberts.
I emphasize that
this work needs ongoing research, sifting of evidence and willingness
to change ideas.
I encourage readers to beware of claims that are exaggerated or unwilling
to rethink the evidence.
Viral factors (top)
Are foods or nutrients useful in viral illnesses and their aftermath?
I am a strong encourager of good nutrition.
Glyconutrients with the less common sugars, mannose, fucose, xylose,
N-acetyl glucosamine, N-acetyl galactosamine, and n-acetyl neuraminic
acid are crucial parts of functional glycoproteins such as immune cell
Dr Darryl See claims
that glyconutrients from some plants enhance T (NK) (TH1) cell function,
(e.g. by acetyl mannans enhancing the receptor response to antigen,)
but resulting in decreased viral loads, and decreasing fatigue symptoms.
occur in aloe vera, garlic, and onion, yams and sweet potato, turnip,
parsnip and carrot, cabbage, cauliflower, broccoli and brussel sprouts,
tomato, pineapple, paw paw and rice bran. Dr See would recommend plants
free from pesticide.
This work has not been adequately evaluated, but there is no risk from
these foods in moderate amounts.
It will increasingly emerge that we will see the development of effective
I would like to emphasize that if viral infection cannot be proven,
it may be sensible not to use antiviral agents, especially if they pose
risks to the patients.
Herpes viruses may be decreased by acyclovir, and famciclovir (HSV1
These agents are
used in acute episodes, and must be started promptly to be effective.
Because of the widespread infection rate, the majority of people have
HSV1 antibodies, (also EBV, varicella- zoster virus), but many never
manifest clinical disease. It is interesting to map circumstances where
these viruses reactivate.
Acyclovir inhibits viral replication but does not eradicate virus. It
is converted to active forms by phosphorylation in virus-affected cells,
and host cell kinases bring the monophosphate to acyclovir triphosphate,
which inhibits virus induced DNA polymerase.
It is effective in HHV1 and 2 in terms of shortening and lessening the
severity of attacks.
Clinical trials in EBV infectious mononucleosis have not shown any advantage
over placebo treatment.
Ganciclovir is a guanosine analogue that is more active against CMV.
It is converted in cells by a viral phosphotransferase encoded by CMV
gene region UL97, and the ganciclovir triphosphate is a selective inhibitor
of CMV DNA polymerase.
Most clinical trials have occurred in patients with HIV infections or
other immunocompromized states, because CMV infections in patients with
AIDS are very serious.
It is not yet clear whether there is a sub group of CFS sufferers who
could benefit by IV ganciclovir, but Dr A Martin Lerner claims that
there is a mild CMV related cardiomyopathy which presents as a CFS like
illness, and that it responds to ganciclovir therapy. Ganciclovir does
have some bone marrow toxicity, which should make us cautious in less
Ganciclovir has poor oral bioavailability.
An orally available drug called valganciclovir (Valcyte) is available,
but is restricted under Australias PBS.
It may be the best agent for persistent CMV of HHV6A infection.
At this time I look more closely at myocardial function in CFS sufferers,
especially if they report any dyspnoea.
Sarah Myhill certainly thinks the cardiac side of severe CFS has been
In my searches I am not finding this.
Although this is a reminder of what we have not yet found, claims have
not been verified so far.
The recent virus claim is around XMVR (see below)
A major advocate for anti viral therapies is Dr W John Martin from California,
with unfolding evidence about Stealth viruses, a variety
of mutated CMV.
Martin has seemingly disappeared from the CFS scene.
This subject always
needs substantiation, but Martin claimed his data includes cytopathic
effects produced by CFS patients cells in vitro, induced illness
when it is injected into cats, and also extensive PCRs confirming CMV
viral sequences on the viral material.
He has further identified a simian (green monkey) CMV in some of his
These materials are infective and cause illness in cats that are injected
with this material.
Unfortunately, his work has not been verified and he is no longer working
in this field.
This is more a reminder that the persistence of viruses may turn out
to be important in particular diseases.
Foscamet has an antiviral spectrum against all of the herpes virus group,
and can be active against CMV infections that are resistant to ganciclovir.
It also has some antiretroviral activity, and inhibits the viral DNA
polymerases from hepatitis B.
Foscamet does not require activation by thymidine kinase (TK) or other
kinases. (Theoretically it might be active against herpes virus mutants
which are deficient in TK, and in vitro this has been demonstrated.)
It is not an agent to be used lightly. It appears to be ineffective
in HHV6 infections and reactivations.
As mentioned above
nutritional substances such as some fatty acids such as lauric, capric
and caprylic acids, and derivatives such as monolaurin, milk ingredients
(lactoferrin), plant antioxidants (kaempferol) and vitamin A have activity
It is notable that prostaglandin E2 increases CMV activity.
Lysine at doses of 2 gms/day may enhance reduction of herpes viruses.
St Johns Wort (hypericum) also has activity against herpes viruses,
EBV and oral stomatitis virus. The Newcastle group suggest that some
viruses are favoured by certain lipid profiles and one might attempt
to change lipid patterns.
It should be noted
that St.Johns Wort is an inducer of the cytochrome P450 enzyme
CYP3A4 and decreases the efficacy of the oral contraceptive pill.
It can also decrease the levels and antiviral effects of HIV protease
inhibitors such as indinavir, and the anti-rejection drug cyclosporin.
This reminds us that we need to know more about interactions between
drugs and herbal medicines.
Piperine in pepper has quite potent effects upon the absorption and
metabolism of some drugs and heral substances.
These are peptides of some 40 amino acid lengths, which enhance antimicrobial
activity and also greatly increase T natural killer cell functions.
They appear to down regulate auto-immune activity.
Bovine and human transfer factors seem to be identical.
The natural situation leads to the offspring getting immunity to infections
encountered by the mother, but the pathogens of the cow differ significantly
from human pathogens.
They appear to be very safe.
Darryl See has tested transfer factor and shows that it has a marked
effect in increasing natural killer cell activity.
favours its use in CFS.
There is very little literature on transfer factors.
Finally, some claim that IV vitamin C 30 Gms infusion may help to deal
with any acute viral illness or flare-up. (Lack of controlled trials
here, but it should be considered in all serious infections and with
Vitamin C is in highest amounts in all immune cells, adrenal cortex
Every person is intensive care and heart units, and indeed in every
hospital should be replete in Vitamins C and D.
Higher than RDA doses of vitamin C are needed during illness.
I suggest at least 500 mg tds.
I have wondered about the pretreatment of some patients before embarking
on the other therapies, and this is where Sarah Myhills background
therapies are likely to be protective.
Mycoplasma infection can be treated acutely with tetracyclines, macrolides
With chronic persistence of mycoplasmas, we are not usually able to
prove whether they are pathogens or not.
If Trevor Marshall
PhD is correct then with all chronic bacterial infections we should
consider that killing the organisms can result in cytokine release and
in some persons this may make them feel ill. This could suggest starting
with much lower doses than those mentioned below!)
of 200 mgm/day at first (6 weeks) then 100 mgm/day (further 6 weeks).
It is uncertain as to what is the optimum duration of these therapies.
Minocycline has better intracellular penetration than doxycycline.
Doses are possibly 50 mg alternate days, increasing as tolerated to
50 mg daily, then and 100 mg daily.
The prescriber will need to be aware of side effects such as benign
intracranial hypertension with ongoing minocycline therapy.
If used supplements of minerals, (Fe, Ca, Mg, Mn, Mo, Se and Zn etc)
should be delayed to at least 4 hours after the tetracycline dose, since
these minerals may impair doxycycline bioavailability and effects.
A difficulty exists in discerning whether resident mycoplasmas are,
non pathogenic or pathogenic
Azithromycin, clarithromycin, josamycin and also ciprofloxacin have
also been used widely to eradicate mycoplasmas that are pathogens.
The ketolide, telithromycin will emerge as useful for some of these
organisms that are resistant to macrolides.
Macrolides (except azithromycin) must not be given with statins (azithromycin
is not metabolized by CYP 3A4), and the antihistamines, astemizole,
terfenadine and chlorpheniramine, since they are potent inhibitors of
CP450 3A4 isoforms.
higher tissue concentrations and intra cellular levels than other macrolides.
It has a much longer life in the body.
As stated earlier in regards to Rickettsiae, Cecile Jadin recommends
one week on and three weeks off with these antibiotic courses.
It is likely that chronic infection requires more courses because the
organism can persist inside cells in a dormant state. I would consider
continuing these courses for many months, and possibly changing from
doxycycline to either a macrolide or ciprofloxacin in resistant cases.
Jadin suggest that in chronic rickettsial disease, the mean time to
achieve recovery is about 8 months.
The quinolines are potentially more toxic that some other classes.
There is little published data to help us here!
Classical and established doses appear to be doxycycline 100mg bd in
adults, but children where teeth and bones are still growing should
My previous plan was to use doxycycline 100mg twice daily for cycles
of 7-10 days on 10 days off. (There may be a need to vary the cycle
If the situation is of some standing, minocycline with better intracellular
penetration may be preferred.
If I use minocycline, I am wary of long courses and as mentioned, we
need to consider the risk of benign intracranial hypertension as a side
In the past, if 2 cycles hadnt helped, I use clarithromycin 500mg
bd for 7 days (15mg/kg/day) or azithromycin 500mg one twice per day
for 2 or 3 days (10mg/kg/day) can given before the next doxycycline
I now tend to follow Marshalls protocol for most suitable persons,
but I am very careful how I choose this. I never let vitamin 25 D3
levels become too low!
This is also a situation where persons with CFS may be more prone to
the reaction that Marshall thinks is a Herxheimer reaction. This may
be more likely with treponemes and borrelia(Lyme disease).
He strongly recommends much lower doses such as 250 mg every third day.
He writes and lectures that each molecule entering the germ weakens
Azithromycin has high intracellular concentration and a long 1/2 life.
bd for weekly cycles can also be considered, as can clindamycin (A lincoside)
at 250 mg bd.
Jadin has case numbers in the thousands and reports 84-96% success rates
in the chronic rickettsial group.
She needs to publish the sero-positivity rate of South Africans who
are well, and co morbidity data.
Now we can note Prof Kenny De Meir Leirs findings and the interesting
work of Trevor Marshall.
In recent presentations
(2006), Marshall reports 40/77 CFS cases and 20/34 FMS cases responding
to his protocol, usually taking well over a year to achieve this!
I will later address the Marshall protocol more fully!
A task is damp down any reaction to killing bacteria, as well as to
shift things to decrease microbial survival.
For the TH1 state
he suggests that we may have the task to decrease the high 1,25 dihydroxy
D3 in the Th1 set immune set patient, but he says the marker may well
be the 25 D3 level, as this may be a blocker on the 1,25 D3 receptor
(VDR) interfering with efficiency of innate immunity.
We are still not privy to what is happening in the intranuclear sites
of the VDR or indeed on other intranuclear family receptors!
I have not been able to support Marshalls ideas of reducing vitamin
D by either less daylight or avoidance of D containing foods.
D3 intake along with avoiding sunlight could make sense only in some
cases of sarcoidosis or sensitivity to excessive daylight. So despite
Marshalls claims, we need to be wary of inducing vitamin D deficiency.
I always follow up 25 D3 and 1,25 D3 levels at 2-3 months intervals.
I am much stricter than Marshall in ensuring that persons do not become
D deficient!! I like to keep 25 D3 at 80 nmol/L or higher.
If low I check parathyroid hormone and calcium levels.
Olmesartan appears to rapidly reduce 1,25 dihydroxy D3 levels, but not
to subnormal levels.
The dose is 20- 40 mg 3-4 times per day.
Minocycline and azithromycin are better than doxycycline, in dealing
with cell wall deficient bacteria, because of better intra cellular
In this situation dosing could follow Marshalls recommendations,
at least as far as a cautious beginning!
A suggested dose is minocycline 12.5 - 25mg on alternate days for 30
days, then azithromycin 250mg every 3 days for 21 days.
The dose is remarkably low, but it may need to be repeated.
Each of these medications
has capacity to decrease inflammation directly as they decrease matrix
metalloproteinases such as MMP9.
I need to state my clinical experience that many CFS and fibromyalgia
patients appear to have adverse reactions when given antibiotics.
These responses may include worsening of fatigue, aches, nausea, headache
and just feeling really ill.
My search of the literature has failed to reveal the reasons for these
reactions though many explanations have been offered.
The commonest explanations including Marshalls ideas seem to be
a Herxheimer type reaction, and/or release of cytokines,
secondary to microbial death.
Since I am committed
to holistic approaches, I restate my use of the following supportive
therapies to the above antibiotic protocols.
is apparent that many doctors do not pay much attention to fine tuning
or ideal nutrition to each person. (This may be quite different from
person A to person B.)
(1) Fresh pineapple.(top)
This contains bromelain a protease which increases the absorption of
any quercetin in the diet, and is 40% absorbed itself. It is fibrinolytic
and the intention is to decrease fibrin deposition at vascular and other
This plant flavonoid and antioxidant is an inhibitor of phospholipaseA2,
and its antiinflammatory effects include vessel protection.
A bonus is its cancer preventing and antioxidant effect of LDL cholesterol.
Effective doses may be 600-1,000 mg per day in divided doses.
It may also quell some of the Herxheimer type reactions.
Details on Quercetin.
Glycosides are compounds that yield one or more sugars among the products
of hydrolysis. Glycosides may be considered sugar ethers.
The non-sugar component is known as the aglycone, and the sugar component
is called glycone. The flavonoid glycosides and their aglycones are
generally termed flavonoids.
and the citrus bioflavonoids, including hesperidin, hesperetin, diosmin,
and naringen, are among the best known flavonoid constituents.
Quercetin is the aglycone of quercitrin, rutin and other flavonoids.
Quercetin (3,5,7,3,4-pentahydroxyflavone) may delay oxidant
injury and cell death by: scavenging oxygen radicals; protecting against
lipid peroxidation, and thereby terminating the chain-radical reaction;
chelating metal ions, to form inert complexes that cannot take part
in the conversion of superoxide radicals and hydrogen peroxide into
Plants/Food Which Contain Quercetin:
Bearberry (Arctostaphylos uva-ursi)
Black Catechu (Acacia catechu)
Boneset (Eupatorium perfoliatum
Elder flowers (Sambucus canadensis)
Eucalyptus (Eucalyptus globulus)
Euphorbia (Euphorbis piluifera)
Fenugreek (Trigonella foenum-graecum)
Hydrangea (Hydrangea arborescens)
Pale catechu (Uncaria gambir)
Passionflower (Passiflora incarnata)
Podophyllum (Podophyllum peltatum)
Squill (Urginea maritima)
Tea ( bioavailability is about half that of quercetin from onion.)
Witch hazel (Hamamelis virginica)
Is a potent antioxidant.
Is a PPAR agonist, down regulating inflammatory cytokines.
Inhibits the following enzyme systems:
(an enzyme which promotes the synthesis and intracellular
Accumulation of sorbitol)
AR is a critical regulator of TNF-alpha-induced apoptotic signaling
in endothelial cells.
The inhibition of aldose reductase (AR) provides an interesting strategy
to prevent the complications of chronic diabetes.
Cyclic nucleotide phosphodiesterases
This may decrease histamine induced inflammatory injury.
Matrix metalloproteinase 9
Thus effects are
Anti-inflammatory - prevents mast cell and basophil degranulation
Helps reduce the formation of leukotrienes of the 4 series
Increases cyclic AMP
Inhibits phospholipase A 2
Inhibits platelet aggregation
Prevents breakdown of collagen matrix of connective tissue and ground
beta cells from damaging effects of free radicals
effect on epinephrine
*Inhibits apolipoprotein B secretion by liver and intestinal cells.
*Decreases diacylglycerol acyl transferase activity.
*Has inhibitory effects on glycation of proteins
Antiviral - herpes virus I, para-influenzae 3, polio virus I,
Respiratory syncytial virus
Benign prostatic hypertrophy (BPH)
Cataract prevention- if diabetic
Fibrocystic breast disease
Irritable bowel syndrome
Ovarian cancer - inhibition of tumour promotion (squamous cell carcinoma,
ovarian carcinoma and oestrogen receptor negative breast cancer)
Diabetic cataracts, neuropathy, retinopathy
400 mg. 20 minutes before meals, TID
Bromelain may enhance quercetin absorption
Quercetin is an inhibitor
of CYP450 3A4 isoforms and may increase the blood levels of 3A4 metabolized
drugs and hormones.
A major caution is interaction with common HMG CoA reductase inhibitors
(3) Be sure that the patient is taking adequate zinc and vitamin C,
and lots of coloured plant products.
(4) Lactobacilli of the acidophilus and bifidus groups, and perhaps
the yeast, Saccharomyces boulardii (these can also decrease antibiotic
It is very desirable
to actually assess gut flora in order to find and correct any dysbiosis.
In some cases the above lactobacilli should not be used!
If irritable bowel symptoms are present, the special use of E coli Nissle.
intake of fructo-oligosaccharide (inulin) as in artichoke, pear, asparagus
and similar plants, supports healthy colonic flora.
Probiotics are usually very well tolerated. (See more details below)
(5) Other microbicidal
substances in colostrum and milk may emerge as having a role in dealing
with some infections, while protecting normal gut flora.
This consists of a series of glycoproteins with activity against staphylococci,
gut bacterial pathogens, candida, and viruses such as hepatitis C. As
well it has been shown to heal experimentally induced colitis.
Actions include depriving some bacteria of needed iron, breaking up
biofilm which colonies of bacteria use to be less susceptible to body
chemicals, and also enhancing of neutrophil phagocytic activity.
There are species differences in these molecules, and most commercial
products are of bovine origin.
from coconut or coconut milk 300 ml per day.
This contains lauric acid, which can be converted into monolaurin in
the intestine, and has anti microbial actions, particularly against
staphylococci (see later) but including CMV and allied viruses.
Other fatty acids, capric acid especially as its monoglyceride, monocaprin
and caprylic acid have antimicrobial activity. Monocaprin can inhibit
Chronic sinus, skin, respiratory and urogenital tract infections should
be treated with appropriate antibiotics. At the same time attention
needs to be paid to keeping the gut flora as healthy as possible. Some
plants exhibit a capacity to inhibit bacterial proliferation. For example
cinnamon, garlic, ginger, olive leaf, turmeric and St Johns Wort.
The use of a nasal cream containing mupirocin, neomycin or bacitracin
could kill bacteria in the anterior nares. Cleansing lotions and soaps
containing chlorhexidine or similar might help cleanse the skin in general
and the perineum in particular.
Dental hygiene and particularly healing gingivitis is also likely to
Herbalists may like to use locally placed and diluted tea tree oil or
lavender oil as these have been shown to have anti-staphylococcal activity.
Systemic antibiotic to eradicate coagulase negative staphylococci is
probably not justified (or possible)
Further research is needed in this area.
Other antimicrobial therapies should be explored especially in the light
of resistance to antibiotics.
If studies in Hungary on olive leaf extracts are true, (Robert Lyons
in Budapest) doses of 750mg (standardized to contain12.5mg oleuropein)
2-4 times per day could be tried. None of the patients that I have seen
seem to respond to this.
Olive leaf seems to be more helpful when used in combination with hops
Newcastle research suggests that in some chronic fatigue sufferers the
total count of intestinal flora is lower than normal and that there
may be in particular sub normal levels of aerobes such as E coli or
anaerobes such as bacteroides. (Note the previous data on bacteriophages
that attack E Coli.)
E coli appear to provide synthesis of amino acids, tyrosine, phenyl
alanine, and trytptophan as well as coenzyme Q10, folic acid and B12.
There is commonly
an overgrowth of alpha haemolytic and non haemolytic streptococci and
enterococci, all of which cam make D and R Lactic acid.
The D lactatye appears to contribute to mitochondrial dysfunction, hence
low enery and brain fog!
can be reduced with low doses of erythromycin, ampicillin (made into
a slow release form), or cephalexin such as 250 mg bd for 1-2 days.
There may also be a lack of lacto bacilli. Lactobacilli of the acidophilus
group appear to be protective in the upper intestine and the bifidus
group protective to the lower bowel.
There is a strong case to treat other all chronic fatigue sufferers
with lactobacilli (acidophilus and bifidus) together with fructooligosaccharides
from onion, artichoke, asparagus and pear) but this is particularly
important when antibiotics are used.
We need to evaluate which forms of probiotics are best.
In the future we may find non-pathogenic strains of E coli can be reintroduced
into the intestine in much the same way that we use lacto bacilli today.
Recent data suggests that E coli Nissle may be helpful especially in
irritable bowel syndromes. (Check through Google search)
is needed on the subject of optimum probiotics in human intestinal disorders,
e.g. irritable bowel syndrome and chronic fatigue.
At present I strongly avoid the use of the drug tegaserod (Zelmac).
and avoidance of dietary ingestion of yeasts (saccharomyces), which
might have common antigens, may be one component of lessening inflammatory
changes in small intestinal epithelial structures.
Lactoferrin found in fresh milks has potent anticandidal activity; principally
through its iron-binding effects.
If the claims of yeast over-proliferation in the intestine are true
it is astonishing that gastroenterologists doing endoscopic examinations
have not identified candida more often. (These claims are common in
naturopathic circles, but my perusal of the literature has failed to
find support for the claims.)
Even if there is no clear link between chronic fatigue syndromes and
candida it is important to protect the body from any low grade inflammation
in the functional inner surfaces of the intestine.
I support the use of lactoferrin in these situations.
Perhaps there should be more dialogue between gastroenterologists and
microbiologists and those who claim that yeasts do cause other effects
than those documented in medical texts.
One area that needs a truly scientific study is that of live blood
This involves the use of very high magnification (8.000-18000x) of live
blood samples, combined with the ease of changing from direct viewing
to phase contrast and dark field illumination.
This was presented
at the Chicago conference about Marshalls work.
There is also facility to obtain photographic and video records of these
It would be possible to comprehensively compare this data with the biochemical,
microbiological, and immunological data that I have mentioned in this
A formal adequate study on this subject is long overdue and would include
special stains, special culture media, immunofluorescent studies and
PCR testing for microbial DNA.
Amoebae are very common throughout the world. It is estimated that they
are present in one third of the worlds people.
People are vulnerable to pathogenic amoebae, especially in places that
lack high quality water reticulation or sewerage.
Dr Peter Snow in New Zealand feels that amoebae (principally Giardia
Lamblia) may be important in some cases of C.F.S.
He favours an acute amoebicidal agent (e.g. tinidazole 2 Gm) followed
by some 3 weeks of daily metronidazole 400 mgm bd (or similar) to eradicate
encysted forms of the protozoa.
These agents have activity against gut anaerobes such as bacteroides.
Herbalists use Artemisia (wormwood) and one drop of pure oil of cloves
to kill intestinal parasites. (Both are given orally.)
Artemisinin has been used in Malaria.
We need more research on the prevalence of pathogenic amoebae in the
human intestine, particularly in countries like Australia.
It may be useful to take glyconutrients in the form of vegetables, fruits
and salads on a daily basis and in some particular cases to use powdered
concentrates of these substances. Helpful glyconutrients include those
found in aloe vera, garlic, and onion, yams and sweet potato, turnip,
parsnip and carrot, cabbage, cauliflower, broccoli and brussel sprouts,
tomato, berries, pineapple, paw paw and rice bran.
From a strictly scientific viewpoint, more evidence is needed on this
subject, but these plants are good choices anyway.
Although this summary will include recommendations by others who support
these empirical nutrient trials, there is an urgent need for data collection
to throw light on any of these claims.
It is well established that many people eat inadequate diets.
If a CFS sufferer comes to believe that food makes her or him ill, there
is a serious danger that she or he may end up with mal or subnutrition.
A recent report suggests that some of the people reporting chemical
sensitivity are possessed with acute sense of smell and taste.
They appear to have
particular smells and tastes, which they dislike and the aversive reaction
(via the limbic system.) can be strong.
This area of human
thinking connects strongly with control issues, which in turn are strongly
connected with fear and experiences of guilt and anger.
The medical professions
find it extremely difficult to find ways to help the problem of the
person who believes she or he has major food and chemical sensitivities.
My thinking has paralleled writings from Dr Martin Pall, Paul Cheney,
Dr Stephen Sinatra and especially an innovative general practitioner
in Wales, Dr Sarah Myhill,www.drmyhill.co.uk
She is using
Acetyl-l carnitine 500mg 3 times per day,
Vitamin B3 100mg 3-4 x per day,
Co-enzyme Q10 200-300mg per day,(with piperine in black pepper to increase
R-alpha lipoic acid 100mg 3-4 times per day,
D-ribose 3-5Gm /day to increase energy availability
The D-ribose is helpful to an alternative energy pathway(hexose monophosphate
shunt), as well as being a component of ATP and RNA. It helps muscles
including the heart muscle, generate ATP. It is very safe. After oral
dosing, there is good availability, and both fibromyalgia improvement
and better endurance have been noted.
It is helpful in almost all heart diseases.
FATTY ACID CHOICES
Fatty acids are carboxylic acids.
Human fatty acids are long chain fatty acids.
The overall intention is to minimize the production of inflammatory
prostaglandins, which are metabolites of arachidonic acid.
Inflammatory prostaglandins are of the 2 series and inflammatory leukotrienes
belong to the 4 series.
An optimum ratio of omega 3 fatty acids, omega 6 fatty acids and omega
9 fatty acids is still being debated.
A diet that is very high in sunflower or safflower oil is very high
in the omega 6 fatty acid, linoleic acid.
While linoleic acid is essential, excessive amounts can increase the
generation of arachidonic acid metabolites. For this reason some reduction
of these oils is important in inflammatory states.
There is evidence that increased secretion of insulin induced by foods
with a high glycaemic index, enhances linoleic acid conversion into
arachidonic acid. This suggests an advantage in avoiding more than small
amounts of such foods.
Cooking in olive oil
which contains 80% omega- 9 mono unsaturated fatty acid (oleic acid) will
not produce proinflammatory metabolites. It too should not be overheated!
Pure canola oil also has quite a good ratio of omega9, 6 and 3 fatty acids
(Also Australian canola oil has less than 1% trans fatty acids). Flaxseed
oil has 50-60% alpha linolenic acid (an omega 3 fatty acid) and can be
used to supplement olive though it should not be heated at all.
Fish oils (omega 3 fatty acids) are likely to be helpful.
Fish obtain fatty acids from algae and distribution happens up the food
Eicosapentaenoic acid (C20) and docosahexanoic acid (C22) have anti-inflammatory
and cell membrane protective properties.
Recent research continues to show brain protection, and even mild antidepressant
Recently Dr Bob Gibson in Adelaide has shown that supplements of flaxseed
oil had little effect on EPA and DHA levels.
This does not mean it has risks.
He suggests that the elongases and desaturases are competed for by polyunsaturated
fatty acids, leaving the conversion rate low.
If this is the case, I favour giving both flaxseed and fish oils.
If one gave only the EPA and DHA, one should consider giving the fatty
acid transporter acetyl-l- carnitine as well. (See below) (top) It is pertinent to note that labeling of edible
oil products in Australia is inadequate. In Australia, only 2 manufacturers
make all margarines.
The consumer needs to know that trans fatty acids are at very low levels
(<1%), and that omega 3,6, and 9 unsaturated fatty acids are balanced.
It should state on the product container that the trans level is 0.03
G (or less)/5g serve of the product.
A good rule is to avoid all cheap or inadequately labeled margarines.
It is unacceptable for manufacturers to continue to leave the high trans
fatty acid products on the market!
Peanut pastes are now usually labeled in Australia.
I believe we should continue to protest to the Government until other
food labeling is adequate!
In Australia, Flora
Canola spread, Golden canola, Flora Monosun spread and Meadow Lea Canola
spread appear to be safe. (There are others)
Oxidized fatty acids, and trans fats appear to increase the risk of
macular degeneration in the eyes.
All polyunsaturate increases in diet need the use of anti-oxidants.
Butter usually contains about 2% trans fatty acids, but the trans palmito-oleic
acid in milk fat does not confer any risks.
I regard butter as safe as long as the cows are pasture fed.
We need governments to enforce adequate food labeling about trans fatty
is mediated through leukotrienes of the 4 series (principally LTB4)
there is a case for using fatty acids from sea creatures such as the
sea cucumber and the New Zealand green lipped mussel.
The preparation called Lyprinol (Lyprinex) is a purified mixture of
eicosatetraenoic acids analogous to arachidonic acid and inhibits both
5 and 12 lipoxygenases radically reducing proinflammatory leukotrienes.
The dose is 5 mgm per kg of body weight per day.
While in vitro activity has been demonstrated by Dr Henry Betts at The
Queen Elizabeth Hospital in Woodville, South Australia, there is a need
for proof of activity in human inflammatory states.
Lyprinol might be indicated when neutrophils are implicated in the ongoing
pathology, as LTB4 is a potent chemotactic agent for neutrophils.
In these inflammatory states it may also emerge that there is a role
for the use of cetyl myristoleate, which is an esterified form of a
monounsaturated fatty acid known as myristoleic acid.
This substance exists naturally in small quantities in some animals,
(for example mice with natural levels of CMO were resistant to polyarthritis
induced with Freunds adjuvant.)
Subsequently this has been found to apparently turn off inflammation
in a range of human inflammatory conditions such as rheumatoid arthritis.
The dose is 2.5 grams twice a day for a month.
This is also work that needs validation from other researchers.
It is disappointing
that there is so little literature on this.
Its effect seems
to be enhanced by adding digestive enzymes containing lipases and by
concomitant use of glucosamine and perhaps Lyprinol.
In summary it appears that there is an optimum ratio of omega 3, omega
6 and omega 9 fatty acids, and we will integrate these with antioxidants
such as mixed tocopherols, tocotrienols and coenzyme Q10 which decrease
lipid peroxide levels.
Other plant antioxidants such as quercetin also protect against lipid
The full improvement of each persons diet is the subject of my
ongoing commitment to people finding health promoting and protective
(and OTHER CELLS) (top)
Kenny De Meir Leir emphasizes the abnormalities in the gut in many forms
Restoration of normal gut flora and optimal health of epithelial and
other gut cells might be enhanced by the following methods:
(1) Adequate protein intake and this might well include supplements
of specific amino acids such as those reported as low by the Newcastle
group (eg serine). Their belief is that protein digestion is incomplete,
thus many sufferers are requiring amino acids in the diet.
Specific amino acid
supplements ((glutamine, taurine, serine, glycine, glutathione, alpha
keto glutarate and carnitine are suggested) and the antioxidant,R alpha
lipoic acid could well be important.
This is particularly for intestinal cells but as well to be certain
that all other body cells get adequate essential amino acids as well
as to overcome putative metabolic blocks.
It seems that there is no evidence that oral glutathione is effective
in boosting cellular levels of glutathione.
There is some evidence (as mentioned earlier) that whey proteins from
milk may be good way to increase amino acids and increase glutathione
production inside cells.
I have not seen success with amino acid supplements, and am presently
following Cheney in recommending whey protein devoid of casein and lactose.
(2) Vegan diets are deficient in Vitamin B12, carnitine and taurine.
There is some evidence of carnitine deficiency in CFS.
On days when meat is not consumed, take 2 grams of acetyl-L-carnitine.
Vegetarians should supplement their diet with acetyl L-carnitine (best
absorbed form) by taking 2 grams daily. (See Website of Dr Sarah Myhill
(3) Eating evenly.
(4) Avoid excessive
intake of foods with high glycaemic index (avoiding functional hyperinsulinaemia).
(5) Consider using D-ribose. In order to make new ATP, one needs a sugar,
namely D-ribose. Normally the body can manufacture this for itself from
glucose, but if energy levels are very low, then it may be unable to
synthesize enough of this essential sugar. So when the CFS sufferers
push themselves too much, ADP is converted into AMP, which they cannot
recycle. It normally takes a few days to make new ATP from D-ribose,
but the CFS sufferers may really struggle to make D-ribose.
(6) Avoiding foods which might cause gut sensitization,
or other injury, (e.g. dairy products, gluten). (Also excluding gluten
This aspect needs
elaboration in light of the possible role of lectins in grain husks
promoting some disease states.
At least 3 weeks of exclusion and perhaps more should be considered
in refractory CFS.
(7) Adequate folate, B12, B5 and B6 and vitamin A,C and D.
(8) The recent evidence
of people avoiding sunlight has led to studies on levels of vitamin
D in various populations. This has uncovered many people with low levels.
A recent Australian
study (Geelong, Victoria) revealed that about half of psychiatric patients
had low levels of vitamin D3
Low vitamin D in childhood gives rise to rickets, and in adulthood to
osteomalacia. I check to see that PTH has not risen.
Immune cells need 1,25 D3I am keeping an open mind about this subject.
Now there is further evidence of vitamin D helping immune function.
In multiple sclerosis, rheumatoid arthritis and Sjogrens syndrome,
low vitamin D levels increase the risk of these diseases.
(9) The Newcastle researchers favour pancreatic enzyme supplements to
increase the adequacy of digestive processes.
(10) Fish and flaxseed oil also appear to be protective to the gut.
(11) Vitamin C in small repeated doses during each day. I make the comment
that whenever we cook foods and destroy vitamin C, it makes sense to
take vitamin C to replace that loss.
I always favour taking it with the plants we eat.
(12) In true vitamin D deficiency, cholecholecalciferol (vitamin D3)
can be added as 4,000 IU/day until levels are 80-100 nmol/L (Daylight
skin exposure is also needed.)
Magnesium in a highly bioavailable form up to 300 -500 mgm elemental
Mg/day can correct any chronic magnesium deficiency, and perhaps act
as a functional calcium channel blocker. Magnesium may enhance sleep,
decrease irritability, and diminish central nervous system NMDA activation.
Serum magnesium levels are not a good guide to cellular magnesium levels
and red cell magnesium is a better measure.
Potassium supplementation (or use of spironolactone or amiloride) could
increase total body potassium and this is being studied further by Dr
R Burnet, as it appears to only apply to the low potassium group.
I prefer the potassium supplements if I can establish potassium deficiency.
(The potassium and above drugs should not be used with ACE inhibitors
or angiotensin 2 receptor blockers.)
It is important for people to be replete in chromium, manganese, molybdenum,
selenium and zinc, so that metallo-enzymes using these elements can
Molybdenum is only added if hair analysis shows low levels. It is usually
adequate in leafy vegetables and legumes.
Suggested daily allowances would be
Further research is needed to appraise cations in people who have a
high urinary citric acid level.
The subject of mineral ratios is another area that is being explored
in human and veterinary medicine.
We probably need to rethink the subject of the correct balance of minerals
if further research supports Mark Purdeys evidence that high manganese
and low copper in environments, and in animal and human brains increases
the emergence of abnormal prions as in Creutzfeld-Jacob disease and
bovine spongiform encephalopathy.
Aside from the ignorance and arrogance, which led to people feeding
herbivores with products from animals, and transferring prions in this
way, we can have more vigilance about the interplay of causative factors
Possibly exposure to organo-phosphorus pesticides is another risk factor.
I mention this in order to remind ourselves of the need to evaluate
care of the environments in which we live.
Persons from rural locations and users of these chemicals are the main
ones at risk!
Mineral contamination of human food may include excessive mercury, aluminium,
copper, lead, nickel and cadmium.
(Dr Igor Tabrizian from Western Australia writes about this)
High mercury can come from fish high up in the food chain.
Some of the metals can be used by gut flora, but with permeable gut
disorders may harm human health.
Kenny de Meirleir
has a special interest in this area.
Some protective chelation can be given through coriander, chlorella
and free-range organic eggs.
It is also important to get all minerals in balance, as described by
Dr Igor Tabrizian.
Drs Ian Brighthope, Robert Buist, Paul Cheney, Henry Osiecki, Sarah
Myhill, Jeffrey Bland and Martin Pall are all in favour of multiple
anti oxidants to cover a wider range of sites and oxidant situations.
Oxidation involves electron donation, and antioxidants are electron
It follows logically that when antioxidants mop up free radicals,
they are themselves oxidized.
The net outcome of this depends on how much the products can still
cause cell membrane or other cellular injury.
Some evidence is emerging that single antioxidants such as vitamin
C or E are not particularly protective and may even become pro-oxidant.
For example, pure D alpha tocopherol can mop up a free radical and
become a free radical itself.
e.g. EH + R -> RH + E E is a free radical
Co enzyme Q10 has been shown to quench the vitamin E free radical
and is also better at reducing oxidized LDL cholesterol, than is vitamin
A number of trials with pure D-alpha(RRR-alpha) tocopherol have failed
to produce evidence of protection against cardiovascular disease.
It is known that gamma tocopherol can mop up the E free radical.
The Heart Protection Study (HPS) is a recent example of 8 years of
D-alpha tocopherol 500IU, vitamin C 500 mg and beta-carotene in combination
failing to alter outcomes in people with heart disease.
We need trials of mixed tocopherols (alpha,beta,gamma and delta,)
and tocotrienols (alpha,beta,gamma and delta), particularly because
nature tends to have these antioxidants together.
The richest sources of these substances are edible vegetable oils.
D alpha tocopherol is high in wheat germ oil,
gamma tocopherol is high in soybean and corn oil.
Palm oil is high in alpha and gamma tocopherols and alpha and gamma
Thus antioxidant therapy would include:
1. D alpha tocopherol succinate 500IU orally daily (needs another
substance to deal with the generated vitamin E free radicals. (e.g
mixed tocopherols, gamma tocopherol, tocotrienols, vitamin C, R-alpha
lipoic acid, and coenzyme Q10 could each carry out this function.)
2. Co enzyme Q10 100-300 mgm daily (paper in coenzymeQ10 conference,
Boston1998) (enhances mitochondrial energetics and mitochondrial DNA
repair, and mops up oxidized vitamin E)
3. Plant flavonoids from many coloured vegetables, salads and fruits
mixed carotenes (carrots, yellow and orange vegetables),
lutein and zeaxanthin(egg yolks, spinach),
proanthocyanidins (grape seed and pine bark)
quercetin ( apples, brussel sprouts, ginkgo biloba, onions, pears)
resveratrol (grapes and peanuts)
A minimum of seven different vegetables per day is recommended (pesticide
free) specifically ensuring many different anti oxidants.(more is
Specific herbal agents are now being tested for anti-inflammatory
actions and I note that
(1) Humulones from hops, and curcumin from turmeric
are PPAR agonists
(2) Nettle stops activation of NF kappa beta by TNF alpha and
acids from frankincense (boswellia) are potent elastase inhibitors.
(4) Curcumin (from turmeric) is a good elastase inhibitor, but
it also needs piperine from black pepper to improve absorption and to
prolong its half life)
(The drug Kenny De Meir Leir uses is cefoperazone)
This is the herb that Kenny De Meir Leir uses in cases with abnormal
Now evidence is emerging that curcuminoids are neuroprotective.
They may also have useful anti-inflammatory actions.
In time, ginger, turmeric, cinnamon and other spices will be
further explored for anti-inflammatory actions. Feverfew has anti-migraine and anti-inflammatory actions and
may also be protective to bone.
4. Vitamin C in doses of up to 500 mgm 5-6 times per day. I rate this as extremely important.
Human beings lack an enzyme needed to synthesize vitamin C.
In other animals that cannot make vitamin C (primates, fruit eating
bats, and guinea pigs), there is a turnover equivalent to many grams/day
(as much as 10-20 gm/day in a creature weighing 60-70 kg).
It is largely because we cook our food that human beings eat so much
Since nature provides antioxidants in combination rather than in isolation,
there is a pattern for maximum mopping up of free radicals with less
residual damaging products.
Thus I eat a plant with colour with each dose of vitamin C
It is worth considering infusions of vitamin C in people who do not
eat well or have gut abnormalities.
The Australian College of Nutritional and Environmental Medicine teach
practitioners of the value of IV vitamin C, particularly in any one
getting an acute infection and as an adjunct to cases not responding
to appropriate antibiotic regimes.
5. R-Alpha lipoic acid 200 mgm twice a day can be used to quench peroxynitrite
anions (ONOO-) and gamma tocopherol 300 mgm a day does the same thing.
R Alpha lipoic acid (ALA) converts into dihydrolipoic acid (DHLA) but
both are capable of quenching free radicals covering antioxidant effects
in both water and fat soluble domains.
DHLA thus neutralises reactive oxygen species such as super oxide radicals,
peroxyl and singlet oxygen and is a co factor in acyl transfer reactions
regenerating reduced glutathione and ascorbic acid and maybe indirectly
helping the recycling of vitamin E.
As lipoamide, ALA/DHLA function as a co factor in oxidative decarboxylation
reactions of pyruvate, alpha keto glutarate and branched change keto
acids. Both also have metal chelating activity.
It is emerging as
one of the best neuro-protectors currently available.
It appears to protect in all neuropathies and neurodegenerative diseases.
6. Gamma tocopherol has more immediate activity than d alpha tocopherol
in dealing with already present free radicals and in any event probably
needs to be present at above 20% of total tocopherols to lessen damage
to the D alpha tocopherol.
7. Hydrogen atoms with an extra electron loosely attached (negative
hydrogen ions) are present in glacial water in mountains in the north
of Pakistan (Hunzaland) and it is claimed by Dr Patrick Flanagan that
this results in water with low surface tension, and effective electron
donation with potent antioxidant effects.
Flanagan microclusters are tiny mineral clusters which act as transport
vehicles delivering nutrients into cells.
They have a very high negative electrical charge and Flanagan claims
that they enhance removal of metabolic products from cells.
They are marketed as MICROHYDRIN.
Electron loss is part of all oxidations and electron donation is part
of all antioxidant effect.
Flanagan says that plants produce negative hydrogen in fresh ripened
fruit , but the negative hydrogen is lost in cooking or canning.
I cannot find independent validation of Flanagans claims.
Claims about colloidal minerals are also worth scientific exploration.
I cannot find a sound basis for these substances, but suspect that they
have not been adequately tested.
ADDRESSING THE ORGANIC ACID CHANGES(top)
It may be worth giving supplements of glutathione (e.g. in undenatured
whey protein), or glycine, serine, glutamine and cysteine. Dr Paul Cheney
favours using oxygen in some of these situations.
Dr Robert Buist claims his Isowhey preparation is ideal
for this purpose!
Perhaps extra vitamin B12 increases succinyl CoA levels enhancing succinic
acid levels.It is certainly worth bringing B12 levels up to the high
end of the therapeutic range.
As stated in chapter 13,
injections of hydroxycobalamin 1mg, or oral methyl cobalamin are important.
Methyl cobalamin may allow increased delivery across the bloodbrain
Some clinicians have recommended extra alpha keto glutaric acid.
LOW BLOOD PRESSURE, POSTURAL HYPOTENSION
Increased intake of salt and fluids are recommended.
Drs Richard Burnet and Peter Rowe (Johns Hopkins) did add fludrocortisone
perhaps with potassium supplements if the above failed, and postural
hypotension is confirmed. Electrolytes should be monitored if fludrocortisone
or liquorice is used.
In a recent article in the Journal of the American Medical Association,
the John Hopkins group found that a trial of fludrocortisone was not
superior to placebo in this type of CFS.
In the laboratory situation most of these postural changes do not seem
to be of significance, and my emphasis is simply that of maintaining
adequate blood volume.
I do not support the use of fludrocortisone. I do not use fludrocortisone!
It is possible that a sub group of CFS sufferers are low in blood levels
of dehydroepiandrosterone (DHEAS). This may relate to low cholesterol
In chronic disease, DHEAS levels may be low, and levels decrease with
By contrast adding DHEA can reduce inflammatory cytokines such as TNF?.
(This latter occurs at supraphysiological levels.
Studies continue on its role in immune regulation.
There is some use of this by some doctors, but in general endocrinologists
do not support its use in CFS. There are anecdotal examples of improvements
in some cases.
There is a Swedish interest group concerned with the increasing use
of equipment and lines that generate electromagnetic fields.
It is now clear that by measurement there are many potential areas of
human exposure to these significant fields.
It is estimated that 10% of workers are presently exposed to such fields
with significant adverse effects in health.
Computers, copying machines, printers, mobile telephones, electric motors,
electric blankets, fluorescent lighting and coils of cable all generate
electric and magnetic fields.
It seems likely that some people are much more sensitive to these effects
and in particular sufferers of chronic fatigue give many accounts of
One sub group may be getting adverse effects from chemicals sprayed
on new electronic circuits for flame resistant protection.
The medical profession at large has not accepted hypersensitivity to
these fields as proven, but Don Maisch in Tasmania has visited homes
of people with severe chronic fatigue and established that fields from
two to ten milligauss are able to produce symptoms. When a person was
removed, for example, from sleeping on an electric blanket or their
bed was moved so that the pillow was no longer next to the refrigerator
motor on the other side of the wall, the patient became normal in four
to six weeks.
We are in a strong position to say that people with chronic fatigue
syndrome should do their utmost to avoid significant EMF fields and
if in doubt they may need to contact experts in the field to test particular
Sarah Myhills supplements can also help this foggy thinking, and
there is now a great deal of evidence that these are neuroprotective.
If specific eradication of pathogens is achieved there is often a return
of normal clear thinking.
Treating Rickettsiae adequately seems to clear this mind fog.
Dr Ian Brighthope points out that in chronic fatigue in at least one
major subcategory particularly where there are CNS type disabilities
ordinary B12, in the form of cyanocobalamin or hydroxy cobalamin do
not cross the blood brain barrier. For this reason he believes it is
necessary to use methyl cobalamin 1 mgm by injection daily for about
a week and thereafter weekly.
Normally there should be no difficulty in converting hydroxy cobalamin
into methyl cobalamin or S-adenosyl cobalamin, and this too needs some
Methyl cobalamin is unstable in solution, and needs to be shipped from
the manufacturer in a frozen form and thawed overnight in the refrigerator
for injection the next morning. Dr Brighthope suggests that this can
greatly improve mind or brain fog. It is stable in powder form.
I have tried a product called Methylguard, which contains methyl cobalamin400mcg,
folinic acid 400mcg, pyridoxal -5-phosphate 6.8mg and trimethylglycine,
600mg. This would enhance methylation and hopefully enhance brain function
in this group of people. It would also increase formation of S adenosyl
Methyl cobalamin is also available as oral 1mg lozenges.
S-adenosyl methionine is claimed to be a natural antidepressant and
may have a place in treating depression or brain fog in CFS.
It is crucial that people get adequate folic acid which should be redefined
to at least 400 mcg per day (E coli in the gut may contribute a substantial
amount of folic acid in the normal person).
More (up to 1mg) is needed in people who have elevated levels of homocysteine.
This subgroup has now been characterized. (Modern Nutrition Textbook)
About 15-20% of Caucasians have a point mutation(double T configuration)
in the gene which is responsible for the enzyme 5,10 methylene tetrahydrofolate
reductase that converts homocysteine into methionine by adding a methyl
group. These individuals have about 50% of the enzyme activity of the
If we add the heterozygotes
at C677T and A1298C, up to 35% of person have raised fasting homocysteine
It is suggested that folate is given in increasing doses until the homocysteine
drops well into the normal range. I suggest a target of 7-8 micromols/L.
Trimethylglycine can be added if this is not successful.
If the levels do not drop, there may be a deficiency in dihydrofolate
reductase so that they cannot turn folate into dihydrofolate and tetrahydrofolate.This
can be overcome with either folinic acid or methylene tetra hydrofolate.
High homocysteine is also associated with more rapid shortening of telomeres
as we age. It is also associated with increased risks of vascular disease
,and if persons are developing Alzheimers disease, correcting
the raised homocysteine by the above steps is protective.(Dr David Smith,
Dr Brighthope is a strong supporter of high amounts of vitamin C spread
out over the day (equivalent 2-10 Gms) and niacin (mixture of nicotinic
acid and nicotinamide) to a total of at least 500 mgm a day (a supraphysiological
dose), in this brain fog group.
All of this makes sense since NIACIN is also a precursor to the NAD/NADH
reactions. NADH can be purchased in the USA, and there are claims that
it helps in CFS.
Tim Roberts also mentions amino acids as being helpful in this group,
but I have not been impressed with this therapy.
We need to find all persons with insulin resistance and hyperinsulinaemia,
and this will include persons with fatty liver and metabolic syndrome
For the scientist I elaborate on this research.
Peroxisome proliferator activated receptors (PPAR)
Nuclear peroxisome proliferator-activated receptors (PPARs) are ligand-activated
transcription factors belonging to the nuclear receptor superfamily.
As transcription factors, PPARs regulate the expression of numerous
genes and affect glycaemic control, lipid metabolism, vascular tone
This subfamily consists
of three isotypes, alpha (NR1C1), gamma (NR1C3), and beta/delta (NRC1C2)
with a differential tissue distribution.
PPAR alpha is expressed primarily in tissues with a high level of fatty
acid catabolism such as liver, brown fat, kidney, heart and skeletal
PPAR beta is ubiquitously expressed.
PPAR gamma has a restricted pattern of expression, mainly in white and
brown adipose tissues, whereas other tissues such as skeletal muscle
and heart contain limited amounts.
Activation of the subtype PPAR-gamma improves insulin sensitivity.
Furthermore, PPAR alpha and gamma isotypes are expressed in vascular
cells including endothelial and smooth muscle cells and macrophages/foam
PPARs are activated by ligands, such as naturally occurring fatty acids,
which are activators of all three PPAR isotypes.
In addition to fatty acids, humulones from hops (agonists for alpha
and gamma), several synthetic compounds, such as fibrates (alpha), one
angiotensin receptor blocker (telmisartan (gamma), and thiazolidinediones
(rosiglitazone and pioglitazone), bind and activate PPAR alpha and PPAR
Rosiglitazone, which acts on the alpha receptors, has some adverse effects
on lipids, but pioglitazone, which acts on the gamma receptors, does
not adversely affect lipids.
These are not indicated long term and must be avoided in persons with
any heart failure. They appear to increase the risk of osteoporosis
Telmisartan has about 1/3 the PPAR agonist effect of pioglitazone, and
Trevor Marshall says it is an antagonist to the 1,25 D3 receptor.
At present I do not use thiazolidinediones or telmisartan in CFS.
As well, apigenin, chrysin, and kaempferol significantly stimulated
PPAR gamma transcriptional activity in a transient reporter assay. In
addition, these three flavonoids strongly enhanced the inhibition of
inducible cyclo-oxygenase and inducible nitric oxide synthase promoter
activities in lipopolysaccharide-activated macrophages which contain
the PPAR gamma expression plasmids.
There are also PPAR
agonist actions with curcumin.
In order to be transcriptionally active, PPARs need to heterodimerize
with the retinoid-X-receptor (RXR).
PPAR-RXR heterodimers bind to DNA specific sequences called peroxisome
proliferator-response elements (PPRE) and stimulate transcription of
target genes. PPARs play a critical role in lipid and glucose homeostasis,
but lately they have been implicated as regulators of inflammatory responses.
A role for PPAR
gamma in inflammation has also been reported in monocyte/macrophages,
where ligands of this receptor inhibited the activation of macrophages
and the production of inflammatory cytokines (TNF alpha, interleukin
6 and 1beta), although part of the anti-inflammatory effects of these
ligands seems to be mediated by a mechanism not involving PPARgamma.
All these findings suggest a role of PPARs in the control of the inflammatory
response with potential therapeutic applications in inflammation-related
Actions of some PPAR agonists will probably play important roles in
many inflammatory diseases.
Protection from hepatic fibrosis is another recent hope, as Xu, Fu and
Chen demonstrated, for the first time, that curcumin dramatically induced
the gene expression of PPAR-gamma and activated PPAR-gamma in activated
Blocking its trans-activating activity by a PPAR-gamma antagonist markedly
abrogated the effects of curcumin on inhibition of cell proliferation.
Orphan nuclear receptors belong to this gene super-family but their
target genes and physiological function are still being studied.
The orphans belonging to the PPAR, LXR and FXR family function as lipid
and bile-acid sensors while PXR and CAR function as xenobiotic sensors.
Small-molecule modulators of LXR and FXR control key genes involved
in cholesterol and lipid metabolism. PXR is a highly promiscuous xenosensor
that responds to xenobiotic ligands (antibiotics, statins, glucocorticoids)
and induces the Cyp3A gene, thereby playing a role in hepatoprotection
and bile acid metabolism.
A related receptor from the gene subfamily, CAR, displays high ligand
selectivity and modulation of its activity in humans may significantly
alter metabolism of drugs and other xenobiotics.
The role of the ER relatives, the ERRs will become more apparent as
ligands are identified and linked to target genes and physiological
function. These targets offer multiple opportunities for therapeutic
intervention with small-molecule drugs, in diseases related to neuronal
function, inflammation, lipid homeostasis, metabolic function and cancer.
Homocysteine (Hcy) induces nuclear factor-B (NF-B) . On the other hand,
a negative correlation between high levels of Hcy and peroxisome proliferator-activated
receptor (PPAR) expression has been demonstrated
Also, PPAR agonists inhibit the metalloproteinase activation in macrophages.
Thiazolidinediones (pioglitazone and rosiglitazone should not be used
in patients with heart failure, and seem to increase the risk of fractures.
Both have measurable effects in decreasing bone strength.
At this time I am avoiding their use!
I note that Dr Ritchie
Shoemaker had a phase of recommending them, but in my view, this can
no longer be supported.
There is evidence
that intestinal flora influence PPAR expression in intestinal locations.
I have restated this to illustrate that there are complex aspects of
the use of specific substances in therapy.
With the discovery of significant under perfused medial temporal regions
of the brain by Casse and colleagues, vasodilators are being considered
to improve this blood flow.
Several vasodilators are being tried, and my emphasis is in finding
safety and efficacy in these medications.
Angiotensin inhibitors could vasodilate the brain areas shown on the
SPECT scans (R Casse, R Kwiatek et al), but telmisartan is also a PPAR
agonist and down regulates inflammatory cytokines!
Olmesartan has been
used by clinicians working with Dr Trevor Marshall in both sarcoidosis
and CFS, with claims of success.
I have decided to comment upon this much-publicized material, noting
that this material needs to be repeatedly re-evaluated.
The material here comes from Trevor Marshall PhD from California .http://www.marshallprotocol.com
with my own added
comments, as I was in a meeting for the visit of Trevor Marshall to
Adelaide in Dec -06.
I am indebted to Marshall for opening up my thinking around ligands
Marshall makes quite strong claims about persistent diseases that seem
to be related to microbial infections either directly, indirectly or
as post-infective and immune response (probably mostly mediated through
macrophage and lymphocyte responses including genetically related cytokinevariations.
The Marshall Protocol springs out of someone thinking about biology,
with certain observations and certain ability to explore patterns, here
informed by advanced X-ray crystallography and computer images of receptors
and their ligands.
The basic property of atoms allows certain arrangements, and the coming
together of hydrogen in stars allows the emergence of more and more
complex elements. (This is the subject of some of my other reflections)
When life appears in this corner of the cosmos, it has critical properties
and this includes abilities to coexist with,connect to, and in various
ways to interplay.
We call these processes evolution. In fact there are many
the flexibility to survive and replicate in various places and various
phenomena such as plasmid transfer, viral trans-fection and curious
microtubular structures connecting some cells, mean that DNA and RNA
are being continuously traded between life forms. Intracellular bacteria,
lacking one kind of cell wall, have learned to live inside animal and
plant cells, deriving their energy from those cells.They also incite
immune cell activations and chemical release, both inside and outside
We are often using inadequate methods to discover the presence of bacteria!
In any event antibodies alone are not able to deal with intracellular
cell events as they do not cross into cell interiors nor reach cell
wall deficient bacteria, living inside cells.
Serology alone is also inadequate in determining and dealing with pathogens
that incite specific TH1 activations.
The MP is part of the unraveling of these processes and patterns.
Yet vitamin D is actually a secosteroid transcriptional
activator, at the heart of innate immunity. Vitamin D is immunomodulatory,
and molecular biologists are working as fast as they can to more fully
elucidate all of its actions, and those of its nuclear receptor, the
VDR, upon the human body, and upon human disease.
The knowledge that vitamin D activates the VDR to transcribe (or repress)
913 genes, and the possibility that it might affect expression of as
many as 27,091, portends a paradigm shift in the way that clinical medicine
has visualized this Sunshine Vitamin. Historically,
it has been associated solely with bone formation and calcaemia, yet
physicians are now being told that vitamin D closely regulates genes
associated with diseases ranging from cancers to multiple sclerosis."
Low values of vitamin D in disease are a result of the disease
process, and not the cause. Molecular biology has now taught us that
the body is capable of making its vitamin D directly from 7-dehydro-cholesterol,
and that the generation of the vitamin D metabolites is modulated by
inflammatory disease processes.
Not only does the whole concept of vitamin D deficiency need reconsideration,
one should question whether it is misleading to even use the word vitamin
when discussing this secosteroid.
VDRthe vitamin D nuclear receptor and the transcriptional pathways
that it controls
The VDR is a type 1 nuclear receptor, a transcription factor that forms
homodimers and heterodimers active in the transcription and transrepression
In their 2003 BioEssay, Lin and White examined the structure of the
VDR, endogenous vitamin D synthesis, and its subsequent hydroxylation
to active metabolites in the liver and kidney.
Their research group
at McGill University has since identified 27,091 genes that might be
transcribed or repressed by the VDR.
Several of these genes, and the resulting proteins, are known to be
active in cancer. Included are the beta-defensin(2) and cathelicidin,
antimicrobial peptides, key to innate immunity and to the bodys
response to intracellular pathogens.
D is needed for at least one of the toll like receptors.
It is thus becoming clear that the clinically accepted role of the vitamin
D metabolites, that of regulating calcium homeostasis, is just a small
subset of the functions actually performed by these
essence of the Marshall Protocol seems to me to be as follows. (top)
(1) Some Chronic diseases are TH1 set.
TH1 cytokines are IL6, TNF alpha and IF gamma.There are genes that code
for these cytokines and their receptors.
(2) These cytokines are likely to be driven by intracellular bacteria
that avoid phagolysosomal dissolution, and Marshall is exploring mechanisms.
(3) The presence of these bacteria can result in direct activation of
IKB kinases and production of NF kappa beta, which translocates to the
cells nuclei and switches on the genes for the above cytokines.
(4) The cytokines contribute in a major way to the inflammatory changes
in target sites
(5) Sarcoidosis is the initial disease which Marshall and colleagues
Classical RA, Crohns disease, some CFS and many FMS states are
probably such disorders
(6) Overactivity of immune cells possessing the 1 alpha hydroxylase
enzyme, results in increasing local 1,25 D3 production and in some cases
raises the serum levels of 1,25 D3.
Marshall pays attention to the 1,25/25D3 ratio, and believes >1.7
There is no living cell work or independent research to validate this
(7) Decreasing the level of 1,25 D3 decreases the recruitment of and
activation of monocytic stem cells into macrophages. Marshall continues
to claim that 25 D3 is partially blocking the VDR .
I quote his writings,
Molecular biology has now taught us that the body is capable of
making its vitamin
D directly from 7-dehydro-cholesterol and that the generation of the
vitamin D metabolites is modulated by inflammatory disease processes.
Not only does the whole concept of vitamin D deficiency need reconsideration,
one should question whether it is misleading to even use the word vitamin
when discussing this secosteroid.
VDRthe vitamin D nuclear receptor and the transcriptional pathways
that it controls
The VDR is a type 1 nuclear receptor, a transcription factor that forms
homodimers and heterodimers active in the transcription and transrepression
of genes. In their 2003 BioEssay, Lin and White examined the structure
of the VDR, endogenous vitamin D synthesis, and its subsequent hydroxylation
to active metabolites in the liver and kidney.
Their research group at McGill University has since identified 27,091
genes that might be transcribed or repressed by the VDR.
Several of these genes, and the resulting proteins, are known to be
active in cancer. Included are the beta-defensin and cathelicidin antimicrobial
peptides, key to innate immunity and to the bodys response to
It is thus becoming clear that the clinically accepted role of the vitamin
D metabolites, that of regulating calcium homeostasis, is just a small
subset of the functions actually perfor med by these hormones.
Most biologists understand that the murine model frequently fails to
accurately model human immune disease and human cancers. Much of this
is due to evolutionary divergence between the murine and human VDR.
Wang et al. found many differences between the genes targeted by the
murine and human VDR.
For example, the gene encoding cathelicidin antimicrobial peptide is
not expressed by the murine VDR at all.
Further, we have described how the relatively low structural homology
between the murine and human VDR can help to explain murine modeling
Unraveling the intricacies of the human D metabolism is often made extremely
difficult by the inter mingling of murine and human biologies in the
This is why he recommends stringent methods to avoid daylight with its
UV B frequencies that convert 7 dehydrocholesterol into Vitamin D3,
and why he recommends reduction of dietary vitamin D3.
I do not like vitamin
D3 levels to be low but try to get 1,25 D3 to normal levels.
(8) The angiotensin receptor blocker olmesartan has a high affinity
for vascular A2 receptors, but also has affinity for the chemokine receptors
CCR2b on monocytes.
The best-known ligand
for CCR2b is monocyte chemotactic protein 1 (MCP1).Olmesartan locates
on this receptor and evidence suggests that it blocks the monocyte activation,
and the IKB kinase activation.(9) Marshall and colleagues have demonstrated
a rapid fall in 1,25 D3 levels within 2 weeks of starting patients on
Interestingly olmesartan also locates on intranuclear 1,25 D3 receptors,
with agonist effects.
These researchers report clinical improvement in brain fog and energy,
with olmesartan use. They stress that the required dose of olmesartan
is 40mg 3-4 times per day, spaced evenly. This dose may be important
to adequately inhibit the CCR2b activations.
The dose can be started at a lower level to ensure patient tolerance
of this dose.
Baseline and follow up renal function, initial and serial sitting and
standing BP and maintenance of adequate blood volume are part of a safe
Doctors who are accustomed to thinking of olmesartan and other sartans
(A2R blockers) as anti-hypertensive agents can find it difficult to
understand these new aspects of olmesartan use.(10) Specific antibiotics
are used because they penetrate into infected cells and enter the bacterial
ribosomes blocking peptide assembly of proteins.
Minocycline enters the 30 ribosomal location, and is started at a low
dose to avoid Herxheimer reactions (see Marshall protocol website).
50 mg on alternate days or even lower.
If tolerated, the dose can be increased to the usual antimicrobial doses.
Azithromyin, an azolide enters the 50 S site, and has a very long persistence
It can be started
at 250mg every 3 days and increased if tolerated.
Marshall holds the view that the long duration of the illness and the
persistence of bacteria, means the therapy will usually be very long
has training in computer technology and has access to sophisticated
computer programs, which are able to represent biological molecules
in 2D and 3D images. It is too early to confirm the exact relevance
to inflammatory states and human TH1 diseases.
As there is elegant data on precise structures of receptors, specific
proteins in bacteria and the ligands which bind to them, he is able
to look at molecular affinities right down to positions of atoms on
the ligand which locate close enough to specific atoms on the receptor
to enable interactions to occur. (Van der Waals forces)
At this computer image level, he can work out Ki values suggesting affinities
of both natural ligands such as 1,25 D3 or drugs such as olmesartan
to cell membrane receptors that are G coupled protein receptors and
intranuclear receptors such as Vitamin D receptors. PPAR receptors,
steroid receptors and thyroid receptors.
There is serendipity about discovery of some drug actions.
Any number of 1 or less indicates high affinity for the agent for the
It has often emerged
that agents have other actions than those first proposed.
Telmisartan is marketed as an A2R blocker, and has a high affinity for
and strong binding to the A2R receptor.
It also has high affinity for the VDR and the PPAR gamma receptor.It
would be predicted to be a blocker on the VDR and an agonist on the
PPAR gamma receptor.
(This might mean it is not the A2R blocker to use in CFS.)The latter
action has been well verified in animal and human studies.
Candesartan has adequate A2R blocker effects but is predicted to have
significant blocking effects on both the alpha and beta thyroid receptors.
Irbesartan has high affinity for A2R receptors where it is a blocker,
a mild moderate agonist effect on PPAR gamma and a greater affinity
for the PPAR alpha receptor. It also has predicted affinity for the
glucocorticoid receptor, and should be a significant blocker of the
T beta 1 receptor.
Olmesartan has high affinity for and strong binding to A2R receptors
as a blocker, and also the chemokine receptor CCR2b on monocytes and
monocytic stem cells. It is likely to exhibit strong binding to the
progesterone receptor and interestingly docks on protein SAR 0276, which
is a membrane protein on MRSA 252 staphylococci.
This should alert us to the possibility that doctors are likely to be
getting effects that are not planned.
Marshall thinks olmesartan is very safe, but uses a higher than usual
He thinks its Vitamin
D agonist action is significant, but its Ki value is not suggestive
of this and I so far cannot find evidence for this.
He says it provides palliation, protects from organ damage by cytokines
and is anti-inflammatory.
Simvastatin is an inhibitor of HMG CoA reductase, but also has predicted
high affinity for A2R, PPAR gamma, progesterone receptor and the thyroid
There is a need for laboratory work to check out these computer predictions!
The vitamin D receptors
(VDR) are located in gut cells, bone, skin, renal tubule cells, breast,
gonadal cells, muscle, heart muscle, parathyroid, brain and immune cells
such as monocytes and macrophages.
Aside from the well known action in enabling intestinal cells to absorb
When 1,25 D3 docks
on its receptor, the vitamin D receptor (VDR)
(1) Decreases PTH transcription,
(2) Enables intestinal epithelium to absorb calcium
(3) Regulates Toll-like receptors (TLR2 and 4) in macrophages as part
of the innate immune response (especially to bacteria),
(5) Regulates TAGO gene (involved in mycobacterium TB intraphagocytic
(6) As VDR/RXR, binds IL2 promoter,
(7) Promotes transcription of insulin receptors
(8) Is involved with steroid receptors SRC-1 and SRC-3, and GM-CSF.
(9) Is involved in regulating cell differentiation and apoptosis.
Items (2)-(5) suggest that vitamin D is very important in immune
One can say that we see parsimony in biology (one signaling substance
acting in many places) and that regulation is more complex than we first
understand. Concentrations at receptor sites and affinity are crucial
to actions. (e.g. 1,25 with greater potency by a factor of 10 compared
with 25 D3, works at picomolar concentrations) Ki for 1,25 D3=0.03,
and Ki for 25 D3=0.3
The hydroxyl group at the 1 position is crucial to this potent agonist
action of 1,25 dihydroxy D3!
It is one reason why we should not lose familiarity with mathematics,
physics, chemistry and basic sciences
Perhaps it is not
an exaggeration to say that from mathematics to physics and chemistry
through the amazing existence of complex biology and the existence of
consciousness we are contemplating who we may be in panoply of dancing
patterns, representing specificities of the energies of our Kosmos at
every level from origins to evolutions and current measurable elements,
patterns,links, connectiveness and even outcomes.
Everything is indeed connected, but some connections are very different
To say the least there is the potential for better refining of what
we do in therapeutics
There is now independent evidence that angiotensin can be pro-inflammatory
in some situations, and that A2R blockade is anti-inflammatory in its
own right. (Especially in vessels walls)
Marshall is emphatic in maintaining that olmesartan is best in the TH1
set forms of CFS.
He adds, Pretty well all the VDR ligands also are PPAR gamma and
alpha ligands too. It is important to view the Type 1 nuclear receptors
which are active in the immune system as a unity, as the function with
a delicate balance of their primary ligands, and the primary ligands
of their partner receptors.
They are VDR PPAR-g PPAR-a GCR MCR Thyroid-alpha1 Thyroid-beta1.
Olmesartan has an affinity of between 1 and 28 nanomolar across this
whole spectrum. Pioglitazone is a ligand for the Thyroid alpha and beta
and the PPAR gamma and Alpha, with highest affinity for the Thyroid
Olmesartan is at least as safe as any other available A2R blocker!!This
is cheaper than through international pharmacies.
At this early stage of research, I have used irbesartan instead of olmesartan,
and Quercitone or Lymphodran plus as my preferred forms of quercetin,
but I encourage doctors to watch closely for more research in this field.
Because telmisartan has been used extensively in hypertension, we have
good data on its safety aside from potential effects on bone! We now
need to note its high affinity for the VDR.
It binds firmly to the receptor and has a long duration of action.
I repeat that the worlds vitamin D experts have so far not verified
In practice, most CFS sufferers are not worse when we give them vitamin
I never let vitamin25 D3 fall below 60 nmol/L.
Clearly if people have low blood pressure as part of CFS, caution with
olmesartan is needed, but so far this is rarely a problem.
How do we choose what to use in particular people as we draw from this
enormous range of options?
I try to discover the particular differences that the history and tests
reveal and design treatment plans to fit
with these patterns.
Correction of sleep disorders has improved with the advent of sleep
I try to avoid the use of medications in most sleep disorders.
Clearly there is much yet to be worked out about the mechanisms of chronic
fatigue but I think the evidence now is in that we should regard it
as an organic disease where the degree of the symptoms can provoke secondary
It is important to be very aware of all the varieties of depression,
since very effective therapies are available in major depressions and
Competent health professionals need to explore this area in depth in
order to be clear about each form of depression.
Some people will have both CFS and depression.
Since depression is also common in the community, we cant exclude
that some cases of depression can feel fatigued, but I think the degree
of fatigue is seldom this great and it is still a bit unclear as to
which case with chronic fatigue can be helped by the various anti depressants.
Moclobemide is said to be helpful in some cases.
Many people with CFS seem to get side effects from specific serotonin
reuptake inhibitor (SSRI) type medications. All of us sometime find
someone who improves markedly on SSRIs, even in some one who did not
regard himself or herself depressed.
I personally think these agents are overused.
The careful exploration of what the person means by fatigue is central
to this area of clinical work.
In old paradigms people often thought EITHER/OR, that is
problems were either in the mind or in the body.
It is not possible for us not to be physical beings and we must necessarily
feel our symptoms in our bodies.
As a whole person physician I am extremely interested in all levels
and dimensions of what it is to be human. If you dont pay attention
to each of these levels you cannot really respond to them all.
In particular all symptoms such as anxiety, depression, anger, frustration
and grief have a context.
It is always relevant to be vigilant about depression in these conditions.
When people are distressed this reflects difficulties in the processes
In a real sense what is within a person can be described as conserved
in our manner of living and experience. This is always to be respected.
When we feel ill, for whatever reason, it is impossible for there to
be no psychological component.
Chronic fatigue sufferers are often despairing, frustrated and depressed
and in the whole management of a life there are many things that people
can do to better cope with their symptoms. Many health professionals
may have a part to play in the support of fatigue sufferers and many
forms of self help are really worthwhile.
The model is that of co-evolving solutions.
Updating our information in all fields of biology has never been so
We will see the emergence of much more studies on genes and their products
and already have practical examples of how this suggests ways of optimizing
food and medication use.
Biology. The occurrence of different forms, stages, or types in individual
organisms or in organisms of the same species, independent of sexual
Although more than 99% of human DNA sequences are the same, variations
in DNA sequence can have a major impact on how humans respond to disease;
environmental factors such as bacteria, viruses, toxins, and chemicals;
and drugs and other therapies. This makes SNPs valuable for biomedical
research and for developing pharmaceutical products or medical diagnostics.
SNPs are also evolutionarily stablenot changing much from generation
to generationmaking them easier to follow in population studies.
SNPs occur normally throughout a persons DNA. They occur once
in every 300 nucleotides on average, which means there are roughly 10
million SNPs in the human genome. Most commonly, these variations are
found in the DNA between genes. They can act as biological markers,
helping scientists locate genes that are associated with disease. When
SNPs occur within a gene or in a regulatory region near a gene, they
may play a more direct role in disease by affecting the genes
SNP maps will help them identify the multiple genes associated with
complex ailments such as cancer, diabetes, vascular disease, and some
forms of mental illness. These associations are difficult to establish
with conventional gene-hunting methods because a single altered gene
may make only a small contribution to the disease.
The information on the MTHFR gene and homocysteine is a very practical
example of this kind of polymorphism.
You can ask your health professional to go beyond conventional practices
as well as checking for yourself just what research is displayed on
internet sites such as Medline. (pubmed)
Health professionals now can raise their own awareness about staying
up to date, and appreciate how exciting it feels to commit to this lifetime
of expanding our personal knowledge.
Can you imagine how much more is possible through integral thinking
It is my hope that people who have chronic fatigue syndromes will reappraise
the journey of life that they and others experience, holding on to a
belief in their inner strengths, and being open to the many old and
new insights that will be available the more we search.