Re: flagyl/tini users - Bleu

[Guest guest]

Bleu,

The only information I have found to research is the Stratton patent,

which I wasn't able to wade thru with a good understanding. I need to

weigh the evidence before starting anything new. Do you have a link to

the Stratton/Wheldon protocol? does this apply to Lyme/RA?

Thanks, robyn

> Robin are you doing high doses of B12 as per Stratton and Weldon

> suggests?

[Guest guest]

I have only a highly edited version of the patent, and spoken to Weldon

and he was the one who put me back onto the B12.

here is some research I have dug up on why b12 might be so useful

" "

Hydroxycobalamin tends to keep me awake when I have 1000mcg

intramuscularly. To overcome this I take 125 to 250 mg of

Nicotinamide

B3 (not niacin) and this puts me to sleep nicely.

http://www.nutrasanus.com/niacin.html

http://www.krysalis.net/b12.htm

http://www.autisme-montreal.com/congres/2003/Neubrander.html

"

Cobalamin/ " B12 " deficiency leads to three problems. First, when

adenosylcobalamin coenzyme is deficient, the substrate methylmalonic

acid cannot be converted into succinic acid. Therefore levels of

methylmalonic acid with continue to increase and spill over into the

urine, a phenomenon known as methylmalonic aciduria. Second, when the

methylcobalamin coenzyme is deficient, the substrate homocysteine

cannot be converted to methionine. Therefore levels of homocysteine

will continue to increase and may be seen in the blood or urine

resulting in homocystinemia and homocystinuria respectively. Third, a

phenomenon known as " folate trapping " occurs when hydroxycobalamin is

deficient in the presence of adequate methyl-tetrahydrofolate. When

this situation occurs, the methyl group on methyl-tetrahydrofolate is

trapped because " it wants to leave (to become tetrahydrofolate) but

can’t get away "

B12 - rationale for using vitamin B12

5th November 2003

Over the last 22 years of treating over 3,000 patients with chronic

fatigue syndrome, I have developed a programme of treatment which I

believe all patients must do as the foundation before proceeding to

other treatments. Vitamin B12 by injection I see as an integral part

of this programme and it is effective for many, regardless of the

cause of their chronic fatigue syndrome.

Those patients who respond to B12 are not obviously deficient in B12,

indeed blood tests usually show normal levels. The " normal " levels of

B12 have been set at those levels necessary to prevent pernicious

anaemia - this may not be the same as those levels for optimal

biochemical function. B12 has a great many other functions as well as

the prevention of pernicious anaemia. However, what is interesting is

how B12 is beneficial in so many patients with fatigue, regardless of

the cause of their CFS, and suggests that there is a common mechanism

of chronic fatigue which B12 is effective at alleviating.

General mechanism by which B12 relieves the symptoms of CFS

Professor Pall has looked at the biochemical abnormalities in

CFS and shown that sufferers have high levels of nitric oxide and its

oxidant product peroxynitrite. These substances may be directly

responsible for many of the symptoms of CFS and are released in

response to stress, whether that is infectious stress, chemical

stress or whatever. B12 is important because it is the most powerful

scavenger of nitric oxide and will therefore reduce the symptoms of

CFS regardless of the cause.(1, 2, 3, 4, 5, 6)

Nitric oxide is known to have a detrimental effect on brain function

and pain sensitivity. Levels are greatly increased by exposure to

chemicals such as organophosphates and organic solvents(7). When

sensitive tests of B12 were applied (serum methylmalonic acid and

homocysteine) before and after B12 therapy, the following symptoms

were noted to be caused by subclinical B12 deficiency: parasthesia,

ataxia, muscle weakness, hallucinations, personality and mood

changes, fatigue, sore tongue and diarrhoea.(8)

B12 in fatigue syndromes

The " foggy brain " with difficulty thinking clearly, poor short term

memory and multitasking are often much improved by B12.(9, 10, 11).

Mood and personality changes, so often a feature of patients with

chemical poisoning, can be improved by B12(12). The physical fatigue

and well being are often both improved.

A study

Twenty eight subjects suffering from non-specific fatigue were

evaluated in a double-blind crossover trial of 5 mg of

hydroxocobalamin twice weekly for 2 weeks, followed by a 2-week rest

period, and then a similar treatment with a matching placebo. The

placebo group in the first 2 weeks had a favourable response to the

hydroxocobalamin during the second 2 week period with respect to

enhanced general well being. Subjects who received hydroxocobalamin

in the first 2-week period showed no difference between responses to

the active and placebo treatments, which suggests that the effect of

vitamin B12 lasted for over 4 weeks. It is noted there was no direct

correlation between serum vitamin B12 concentrations and improvement.

Whatever the mechanism, the improvement after hydroxocobalamin may be

sustained for 4 weeks after stopping the medication. " A Pilot Study

of Vitamin B12 in the Treatment of Tiredness, " Ellis, F.R., and

Nasser, S., British Journal of Nutrition, 1973;30:277-283.

Practical Details

Vitamin B12 has no known toxicity and B12 surplus to requirement is

simply passed out in the urine (which may discolour pink). It is

theoretically possible to be allergic to B12, but in the thousands of

injections that I have sanctioned this has only ever occurred after

several injections and causes local itching, redness and swelling

(although the commonest cause of redness and swelling is poor

injection technique). It does not seem to matter whether

hydroxocobalamin or cyanocobalamin is used. I usually start with 2mgs

weekly by i.m. injection, then adjust the frequency according to

response - some patients will respond straight away, some need

several doses before they see improvement. I would do at least 10

injections before giving up. Many of my patients learn to inject

themselves - this means they can be independent of their doctors. The

cost is & #65443;1.60 per injection (2ml B12 plus syringe and needle).

(1) Pall ML. Elevated, sustained peroxynitrite level as the cause of

chronic fatigue syndrome. Medical Hypotheses 2000;54:115-125. Pall

ML. Elevated peroxynitrite as the cause of chronic fatigue syndrome:

Other inducers and mechanisms of symptom generation. Journal of

Chronic Fatigue Syndrome 2000;7(4):45-58.

(2) Pall ML. Cobalamin used in chronic fatigue syndrome therapy is a

nitric oxide scavenger. Journal of Chronic Fatigue Syndrome, 2001;8

(2):39-44.

(3) Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite

mechanism for the common etiology of multiple chemical sensitivity,

chronic fatigue syndrome and posttraumatic stress disorder. ls of

the New York Academy of Science 2001;933:323-329.

(4) Pall ML. Common etiology of posttraumatic stress disorder,

fibromyalgia, chronic fatigue syndrome and multiple chemical

sensitivity via elevated nitric oxide/peroxynitrite, Medical

Hypotheses, 2001; 57:139-145.

(5) Pall ML. Levels of the nitric oxide synthase product citrulline

are elevated in sera of chronic fatigue syndrome patients. J Chronic

Fatigue Syndrome 2002; 10 (3/4):37-41

(6) Pall ML. Chronic fatigue syndrome/myalgic encephalitis. Br J Gen

Pract 2002;52:762. Smirnova IV, Pall ML. Elevated levels of protein

carbonyls in sera of chronic fatigue syndrome patients. Mol Cell

Biochem, in press.

(7) Pall ML. NMDA sensitisation and stimulation by peroxynitrite,

nitric oxide and organic solvents mechanism of chemical sensitivity

in multiple chemical sensitivity. FASEB J 2002;16:1407-1417.

(8) Neuropsychiatric disorders caused by cobalamin deficiency in the

absence of anaemia or macrocytosis J Lindenbaum et al New Engl J Med

1988; 318: 1720-1728.

(9) Mac Holmes J. Cerebral manifestations of vitamin B12

deficiency. Br Med J 1956; 2: 1394-1398.

(10) Ellis FR, Nasser S. A pilot study of vitamin B12 in the

treatment of tiredness. Br J Nutr 1973; 30: 277-283

(11) Langdon FW. Nervous and mental manifestations of pre-pernicious

anaemia. J Amer Med Assoc 1905; 45: 1635-1638

(12) Strachan RW, JG. Psychiatric syndromes due to

avitamiosis B12 with normal blood and marrow. Ouart J Med New Series

XXXIV 1965: 303-317

Novel chronic fatigue syndrome (CFS) theory finally produces detailed

explanations for many CFS observations:

Help Support this Reseach

A novel theory of the cause of CFS has been published which is

supported by diverse biochemical and physiological observations of

CFS, while providing explanations for five of most difficult puzzles

about this medical condition. The theory has been published by Dr.

L. Pall (Professor of Biochemistry and Basic Medical Sciences,

Washington State University) in several publications (1-4,9). The

theory starts with the observation that infections that precede and

may therefore induce CFS and related conditions act to induce

excessive production of inflammatory cytokines that induce, in turn,

the inducible nitric oxide synthase (iNOS). This enzyme, in turn,

synthesizes excessive amounts of nitric oxide which reacts with

another compound (superoxide) to produce the potent oxidant

peroxynitrite (see Fig. 1). Peroxynitrite acts via six known

biochemical mechanisms to increase the levels of both nitric oxide

and superoxide which react to produce more peroxynitrite (Fig. 1). In

this way, once peroxynitrite levels are elevated, they may act to

continue the elevation, thus producing a self-sustaining vicious

cycle (ref.1). It is this cycle, according to the theory, that

maintains the chronic symptoms of CFS and it is this cycle,

therefore, that must be interrupted to effectively treat this

condition.

Twelve different observations on chronic fatigue syndrome and its

symptoms provide support for this theory:

1. The levels of neopterin, a marker for the induction of the

inducible nitric oxide synthase are reported to be elevated in CFS

(1).

2. Mitochondria are reported to be dysfunctional in CFS and

mitochondria are known to be attacked by peroxynitrite and also by

nitric oxide (1).

3. Both cis-aconitate and succinate levels are reported to be

elevated in CFS and the enzymes that metabolize these two compounds

are known to be inactivated by peroxynitrite (1).

4. The four inflammatory cytokines implicated have been reported to

been reported to be elevated in 10 different studies of CFS (1,2).

5. These same inflammatory cytokines have been reported to induce

fatigue when injected into humans (1).

6. An animal (mouse) model of CFS has " fatigue " induced by a

bacterial extract that can induce both the inflammatory cytokines and

also the inducible nitric oxide synthase.

7. Polyunsaturated fatty acid pools are reported to be depleted in

CFS and such polyunsaturated fatty acids are known to be oxidized by

oxidants such as peroxynitrite.

8. Anecdotal evidence has suggested that antioxidants such as

coenzyme Q-10, flavonoids and glutathione precursors may be useful in

CFS treatment, consistent with a role for an oxidant such as

peroxynitrite.

9. Women are reported to produce more nitric oxide than men, possibly

explaining the gender bias seen in CFS. A similar gender bias is seen

in autoimmune diseases characterized by excessive peroxynitrite (i.e.

lupus, rheumatoid arthritis).

10. Cases of CFS are associated with high levels of deleted

mitochondria DNA, suggesting but not proving that mitochondrial

dysfunction can produce the symptoms of CFS (1).

11. Biochemical similarities †" depletion of glutamine and cystine

pools †" have been reported in CFS and several diseases

characterized by elevated peroxynitrite levels, suggesting a similar

biochemical basis for all of these conditions (1).

12. Because peroxynitrite is a potent oxidant, this theory predicts

that oxidative stress will be elevated in CFS. There was no direct

evidence for this when the theory was published but three subsequent

papers have reported substantial evidence for such oxidative stress

in CFS (5-7A). These results, may therefore, be considered to confirm

important predictions of the theory, although the authors were

unaware of this theory when they initiated these studies.

CFS puzzles explained by the elevated nitric oxide/peroxynitrite

theory:

There are five different puzzles of CFS that are explained by this

theory. The first of these, the chronic nature of CFS, is explained

by the self-sustaining vicious cycle that is central to this theory.

The second is how infection and other stress which often precede CFS

may produce CFS. This theory predicts that each of these can lead

into this mechanism by inducing excessive nitric oxide. Infection is

not the only stress that may be involved in this way †" both

physical trauma and severe psychological trauma can produce excessive

nitric oxide synthesis (2). In addition, tissue hypoxia may induce

this cycle by increasing levels of superoxide (the other precursor of

peroxynitrite) (2).

A third puzzle about CFS is how it leads to the many

biochemical/physiological correlates reported to occur in CFS. This

is discussed with the list of 12 such correlates described above.

A fourth puzzle about CFS is how the diverse symptoms of this

condition may be generated. It turns out that a variety of factors,

including nitric oxide, superoxide, oxidative stress and

mitochondrial/energy metabolism dysfunction may have important roles

(2). For example, nitric oxide is known to stimulate the nociceptors

that initiate the perception of pain, and therefore excessive nitric

oxide may cause the multi-organ pain associated with CFS (2). Nitric

oxide has a central role in learning and memory and so its elevation

may also provide a partial explanation for the cognitive dysfunction

characteristic of CFS (2). Other symptoms explained by this theory

include orthostatic intolerance, immune dysfunction, fatigue and post-

exertional malaise (2). The immune dysfunction reported in CFS, may

allow for opportunistic infections to develop, such as mycoplasma or

HHV6 infections, which may exacerbate the basic CFS mechanism by

increasing inflammatory cytokine synthesis.

What about multiple chemical sensitivity, posttraumatic stress

disorder and fibromylagia?

A fifth puzzle regarding CFS is its variable symptoms and, most

importantly, its association with three other conditions of equally

puzzling etiology, multiple chemical sensitivity (MCS), posttraumatic

stress disorder (PTSD) and fibromylagia (FM). The theory explains the

variable symptoms, from one case to another, in part, by a somewhat

variable tissue distribution of the elevated nitric

oxide/peroxynitrite.

A common etiology (cause) for CFS with MCS, PTSD and FM has been

suggested by others (discussed in refs 4,9). A common causal

mechanism for these four conditions is suggested not only by the

association among these different conditions (many people are

afflicted by more than one) but also by the overlapping symptoms

typically found in these four conditions (see refs. 4 and 9 for

discussion). These overlaps raise the question about whether MCS, FM

and PTSD may be caused by excessive nitric oxide and peroxynitrite.

Each of these four conditions is reported to be often preceded by and

possibly induced by exposure to a relatively short-term stress that

can induce excessive nitric oxide synthesis.

Pall and Satterlee (4) present a substantial case for an excessive

nitric oxide/peroxynitrite cause for multiple chemical sensitivity

(MCS), including the following:

Organic solvents and pesticides whose exposure is reported to precede

and presumably induce multiple chemical sensitivity, are also

reported to induce excessive nitric oxide synthesis. Such chemicals

are also reported to induce increased synthesis of inflammatory

cytokines which induce, in turn, the inducible nitric oxide synthase

(leading to increased synthesis of nitric oxide).

Neopterin, a marker of induction of the inducible nitric oxide

synthase, is reported to be elevated in MCS.

Markers of oxidative stress are reported to be elevated in MCS, as

predicted if excessive peroxynitrite is involved.

In animal models of MCS, there is convincing evidence for an

essential role for both excessive NMDA activity (where such activity

is known to induce excessive nitric oxide) and for excessive nitric

oxide synthesis itself. If one blocks the excessive nitric oxide

synthesis in these animal models, the characteristic biological

response is also blocked. This and other evidence shows the nitric

oxide has an essential role (4).

Somewhat similar evidence is available suggesting an elevated nitric

oxide/peroxynitrite mechanism for both PTSD and FM (9). PTSD is

thought to be induced by excessive NMDA stimulation, which, as

discussed above, is known to produce excessive nitric oxide and

peroxynitrite (9). Two inflammatory cytokines known to induce

increased synthesis of nitric oxide have been reported to be elevated

in PTSD. PTSD animal model studies have reported an essential role

for both excessive NMDA stimulation and nitric oxide synthesis in

producing the characteristic biological response.

Interestingly, a recent study of FM implicates elevated nitric oxide

and also elevated NMDA stimulation (8), and such NMDA stimulation is

known to increase nitric oxide synthesis. As in the other conditions

discussed here, there is a pattern of evidence from studies of FM

patients, consistent with the proposed nitric oxide/peroxynitrite

mechanism (9). The theory that elevated nitric oxide/peroxynitrite is

responsible for the etiology of CFS, MCS, PTSD and FM appears to be

the only mechanism to be proposed that explains the multiple overlaps

among these four conditions. While the pattern of evidence supporting

it cannot be considered definitive, the many types of evidence

providing support for this view must be considered highly suggestive.

What does this proposed mechanism suggest about CFS treatment? As

discussed in ref 1, there are a number of agents that may be useful

in the treatment of CFS, based primarily on anecdotal evidence, that

are expected to lower the consequences of the proposed nitric

oxide/peroxynitrite mechanism. Possibly the most intriguing such

mechanism relates to the widespread use of vitamin B12 injections in

treatment of CFS (3). Two forms of vitamin B12 are being used here,

hydroxocobalamin, which is a nitric oxide scavenger and

cyanocobalamin, which is converted to hydroxocobalamin by Pall human

cells (3). These observations suggest that the nitric

oxide/peroxynitrite proposed mechanism for CFS makes useful

predictions for effective treatment. It is hoped that this proposed

mechanism may allow us to optimize the use of these and other agents

for treatment of CFS and related conditions.

Other sites with thoughtful presentations that you may wish to access

are as follows:

http://www.cfsresearch.org/cfs/

http://www.square-sun.co.uk/cfs-nim/

http://www3.sympatico.ca/me-fm.action/

References:

1. Pall ML. Elevated, sustained peroxynitrite levels as the cause of

chronic fatigue syndrome. Medical Hypotheses 2000;54:115-125. (link)

2. Pall ML. Elevated peroxynitrite as the cause of chronic fatigue

syndrome: Other inducers and mechanisms of symptom generation.

Journal of Chronic Fatigue Syndrome, 2000;7:45-58.

3. Pall ML. Cobalamin used in chronic fatigue syndrome therapy is a

nitric oxide scavenger. Journal of Chronic Fatigue Syndrome,

2001;8:39-44.

4. Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite

mechanism for the common etiology of multiple chemical sensitivity,

chronic fatigue syndrome and posttraumatic stress disorder. ls of

the New York Academy of Science, 2001;933:323-329.

5. s RS, TK, Mathers MB, RH, McGregor NR, Butt

HL. Investigation of erythrocyte oxidative damage in rheumatoid

arthritis and chronic fatigue syndrome. Journal of Chronic Fatigue

Syndrome 2000;6:37-46.

6. s RS, TK, McGregor NR, RH, Butt HL. Blood

parameters indicative of oxidative stress are associated with symptom

expression in chronic fatigue syndrome. Redox Rep 2000;5:35-41.

(link)

7. Fulle S, Mecocci P, Fano G, Vecchiet I, Vecchini A, Racciotti D,

Cherubini A, Pizzigallo E, Vecchiet L, Senin U, Beal MF. Specific

oxidative alterations in vastus lateralis muscle of patients with the

diagnosis of chronic fatigue syndrome. Free Radicals in Biology and

Medicine 2000;15:1252-1259. (link)

7A. Keenoy BM, Moorkens G, Vertommen J, DeLeeuw I. Antioxidant

strotus and lipoprotein oxidation in chronic fatigue syndrom. Life

Sciences 2001;68:2037-2049.

8. Larson AA, Giovengo SL, IJ, Michalek JE. Changes in the

concentrations of amino acids in the cerebrospinal fluid that

correlate with pain in patients with fibromyalgia: implications for

nitric oxide pathways. Pain 2000;87:201-211. (link)

9. Pall ML. Common etiology of posttraumatic stress disorder,

fibromyalgia, chronic fatigue syndrome and multiple chemical

sensitivity via elevated nitric oxide/peroxynitrite, Medical

Hypotheses, 2001;57:139-145.

 Pernicious Anemia is a rare blood disorder characterized by the

inability of the body to properly utilize vitamin B12 (a cobalamin),

which is essential for the development of red blood cells.

           The symptoms of Pernicious Anemia may include weakness,

fatigue, an upset stomach, an abnormally rapid heartbeat (tachycardia),

and/or chest pains.

           Recurring episodes of anemia (megaloblastic) and an

abnormal yellow coloration of the skin (jaundice) are also common.

           Pernicious Anemia is thought to be an autoimmune

disorder,

and certain people may have a genetic predisposition to this disorder.

           The three recognized forms of Pernicious Anemia include:

Congenital Pernicious Anemia, Juvenile Pernicious Anemia, and Adult

Onset Pernicious Anemia. The subdivisions are based on the age at onset

and the precise nature of the defect causing impaired B12 utilization

(e.g., absence of intrinsic factor).

Hypokalemia and sudden death may occur when severe megaloblastic

anemia is treated intensively. Lack of therapeutic response may be due

to infection.

Before administering vitamin B12, an intradermal test dose is

recommended for patients known to be sensitive to cobalamines.

Excessive alcohol intake for longer than 2 weeks may produce

malabsorption of vitamin B12. Doses of vitamin B12 exceeding 10 µg

daily may produce a hematologic response in patients who have a folate

deficiency.

Indiscriminate administration of vitamin B12 may mask the true

diagnosis of pernicious anemia. A dietary deficiency of only vitamin

B12 is rare. Multiple vitamin deficiency is expected in any dietary

deficiency.

In patients with ian (pernicious) anemia, parenteral therapy

with vitamin B12 is the recommended method of treatment and will be

required for the remainder of the patient's life. Oral therapy is not

dependable. Serum potassium must be watched closely the first 48 hours;

and potassium should be replaced if necessary. Reticulocyte plasma

count, vitamin B12 and folic acid levels must be obtained prior to

treatment and between the fifth and seventh day of therapy.

There is some evidence that pernicious anemia may be genetic although

its mode of inheritance is poorly documented. There is a congenital

form of pernicious anemia due to defect of intrinsic factor at birth

that is clearly inherited as an autosomal recessive trait with the

affected child having received two copies of the gene, one from each

parent. The intrinsic factor gene itself has been localized to human

chromosome 11.

Pernicious anemia probably is an autoimmune disorder with a genetic

predisposition. Pernicious anemia is more common than is expected in

families of patients with pernicious anemia, and the disease is

associated with human leucocyte antigen (HLA) types A2, A3, and B7 and

type A blood group.

Patients may report either constipation or having several semisolid

bowel movements daily. This has been attributed to megaloblastic

changes of the cells of the intestinal mucosa.

Mortality/Morbidity: The disease is called pernicious anemia because it

was fatal prior to the discovery that it was a nutritional disorder.

The megaloblastic appearance of cells led many to speculate that it was

a neoplastic disease. The response of patients to liver therapy

suggested that a nutritional deficiency was responsible for the

disorder. This became obvious in clinical trials once vitamin B-12 was

isolated. Presently, patients on appropriate treatment have a normal

lifespan.

• Nervous system: Neurological symptoms can be elicited in most

patients with pernicious anemia, and the most common symptoms are

paresthesias, weakness, clumsiness, and an unsteady gait. The 2 latter

symptoms become worse in a dark room because they reflect the loss of

proprioception in a patient who is unable to rely upon vision for

compensation. These neurological symptoms are due to myelin

degeneration and loss of nerve fibers in the dorsal and lateral columns

of the spinal cord and cerebral cortex.

â—¦ Neurological symptoms and findings may be present in the absence of

anemia; this is more common in patients taking folic acid or on a

high-folate diet.

â—¦ Patients who are older may present with symptoms suggesting senile

dementia or Alzheimer disease; memory loss, irritability, and

personality changes are commonplace. Megaloblastic madness is less

common and can be manifested by delusions, hallucinations, outbursts,

and paranoid schizophrenic ideation. Identifying the cause is important

because significant reversal of these symptoms and findings can occur

with vitamin B-12 administration

• Abnormal mentation and deterioration of vision and hearing may be

observed.

â—¦ Central nervous system: Suspect pernicious anemia in all patients

with recent loss of mental capacities. Somnolence, dementia, psychotic

depression, and frank psychosis may be observed, which can be reversed

or improved by treatment with Cbl. Perversion of taste and smell and

visual disturbances, which can progress to optic atrophy, can likewise

result from central nervous system Cbl deficiency.

â—¦ Combined system disease: A history of either paresthesias in the

fingers and toes or difficulty with gait and balance should prompt a

careful neurological examination. Loss of position sense in the second

toe and loss of vibratory sense for a 256-Hz but not a 128-Hz tuning

fork are the earliest signs of posterolateral column disease. If

untreated, this can progress to spastic ataxia from demyelinization of

the dorsal and lateral columns of the spinal cord.

Causes: An increased incidence of pernicious anemia in families

suggests a hereditary component to the disease. Patients with

pernicious anemia have an increased incidence of autoimmune disorders

and thyroid disease, suggesting that an immunological component to the

disease exists. Children who develop Cbl deficiency usually have a

hereditary disorder, and the etiology of their Cbl deficiency is

different from the etiology observed in classic pernicious anemia.

Homocysteine is used in many of the important steps your body uses to

break down methionine into non-essential proteins. At the end of the

cycle, homocysteine is used to recombine the “leftovers†from this

process back into a little methionine. This entire process takes a lot

of energy. Your body gets this energy from vitamins and other

nutrients. If you don’t have enough nutrition, especially if you are

B-12 deficient—either because you are not getting B vitamins from the

foods you eat or because your body is not able to adequately absorb

them (which happens as we age)—the methionine is not recombined and

homocysteine escapes into your bloodstream. If it does, the

homocysteine will eventually become toxic and will damage your arteries

and brain cells.

Homocysteine is formed by the body as a naturally synthesized byproduct

of methionine ( a very important amino acid in your body) metabolism.

Like cholesterol, homocysteine performs a necessary function in the

body, after which, if the right cofactors are present, it will

eventually convert to cysteine (and this is one of the amino acids

needed to produce glutathione, which is very critical in your

detoxifications pathways.) and other beneficial compounds such as ATP,

(the energy molecule of the body)  and S-adenosylmethionine (SAM). When

left intact, it enters the bloodstream and begins attacking blood

vessel walls, laying the foundation for heart disease, stroke and other

cardiovascular diseases.

The clear message from new scientific findings is that there is no safe

" normal range " for homocysteine. While commercial laboratories state

that normal homocysteine can range from 5 to 15 micromoles per liter of

blood, epidemiological data reveal that homocysteine levels above 6.3

cause a steep, progressive risk of heart attack (the American Heart

Association's journal Circulation, Nov. 15, 1995, 2825-30). One study

found each 3-unit increase in homocysteine equals a 35% increase in

myocardial-infarction (heart-attack) risk (American Journal of

Epidemiology, 1996, 143[9]:845-59).

Many enzymes, or catalysts are involved in the complete metabolism of

homocysteine. If any of these enzymes is defective or functions

inefficiently, the body is less able to successfully process

homocysteine. Although this enzyme dysfunction  may be due to a mutated

or defective gene, ( identified by Dr. Rima Rozen at McGill University

in Montreal), more often this breakdown in metabolism is due to

deficiencies of certain nutrients. . .particularly B-6, B-12 and folic

acid. When this function is disordered, whether due to genetic defect

or nutrient deficiency, homocysteine accumulates and enters the

bloodstream where it promotes oxidation of lipids, causes platelets to

stick together, enhances the binding of lipoprotein (a) to fibrin and

promotes free radical damage to the inside of arteries.

Some have suggested that the obvious solution to reducing homocysteine

would be to restrict methionine intake by restricting foods such as

meats that are rich in methionine. Then the supermarket shelves would

be lined with low methionine and methionine-free foods. That makes

about as much sense as switching cabins on the Titanic. Methionine is a

sulfur-containing amino acid that is involved in the synthesis of

protein, important in the maintenance of cartilage, and needed for the

formation of other important amino acids such as taurine and carnitine.

Methionine is not at fault. The problem is when homocysteine cannot be

converted.

Reducing Homocysteine Levels

The good news is...elevated homocysteine levels, whether due to

nutrient deficiencies or defective genes, can easily be normalized in

virtually all cases, simply and inexpensively, using a combination of

nutritional supplements. The most effective defense against

homocysteine buildup is a combination of vitamins B-6 and B-12, folio

acid and trimethylglycine (TMG). So you have a way to naturally lower

cholesterol.

There are three biochemical pathways used by the body to reduce

homocysteine. In one pathway TMG donates a methyl group which

detoxifies homocysteine. In this reaction, TMG is reduced to DMG

(dimethylglycine), that familiar-product sold as a supplement for its

energizing effects. In the other routes, folic acid, B12 and B6 convert

homocysteine into nontoxic substances. Some people can't utilize one or

another of these pathways. That is why a combination of all these

nutrients is most effective for lowering homocysteine. In some people

vitamin B may not be efficiently converted to its active co-enzyme

form, pyridoxyl-5-phosphate. In that case supplementing with

pyridoxyl-5-phosphate would be necessary. There we go again..good

health depends on nutrition and yet many medical types insist nutrition

has nothing to do with overall health

 Trimethylglycine

Trimethylglycine (aka TMG) is the biochemical term for betaine.  TMG is

able to donate methyl groups (a methyl group is one carbon molecule and

three hydrogens..very, very important to our chemistries) to

biochemical events and in the case of  homocysteine this leads to the

increased production of S-adenosyl-methionine (SAM or sometimes it is

written SAMe) which is the bioactive form of the amino acid

methionine…also a methyl donor.  SAM has been used successfully to

treat problems such as cirrhosis of the liver, depression,

osteoarthritis and Fibromyalgia. 

Methyl groups are thought to protect cellular DNA from mutation, a

process which is also helped by good antioxidants. As people age, they

often do not have enough available methyl groups to safeguard DNA.

Abnormal methylation patterns are found in many people with cancer.

Eating foods that contain methyl groups such as beets, green leafy

vegetables and legumes is helpful, but these must be eaten in

relatively large quantities several times a week. Therefore, dietary

supplements such as TMG may often be necessary to provide the body with

sufficient protective methyl groups.

Betaine comes from beet sugar and is extracted through a very complex

process.  Don’t think the betaine HCL you see in digestive supports is

the same thing..it isn’t.  It has not been shown that betaine HCL is a

methyl donator..although it may be..it is very acidic and for long term

use, would not be a good plan.

There are essentially two ways to lower homocysteine levels.  One, the

most common, would be to add methyl groups to it to convert it to

methionine or SAMe.

This is accomplished, as mentioned, through TMG (which as its name

suggests, has three methyl groups on each glycine molecule – glycine is

another amino acid.  They are transferred to homocysteine, but need the

help of folic acid, vitamin B12, and zinc.

Another methyl donor of importance is choline and this remethylation of

homocysteine does NOT need co-factors.  One hitch, though, is that this

process is only active in the liver and kidneys..so to protect the

whole body, in particular the brain one should be sure to take a

complex with all factors present.

The second pathway to lower homocysteine involves converting it into

cysteine (an very important amino acid), which then through a cascade

of chemistry becomes glutathione.  This pathway is dependent on vitamin

B6 and the exact amount needed to lower homocysteine from person to

person can vary greatly.  It is only the amino acid methionine which

can create homocysteine and the amount of that in someone’s diet,

really depends on the individual’s diet.  One higher in red meat and

chicken would be higher in methionine and so this person would need

more B6 (and the other co-factors for that matter) to ensure the

clearing of homocysteine.

Elevated homocysteine can also be caused by a genetic defect that

blocks the trans-sulfuration pathway (the path which ultimately changes

it to glutathione) by inducing a deficiency of the vitamin B6-dependent

enzyme cystathionine-B-synthase. In this case, high doses of vitamin B6

are required to suppress excessive homocysteine accumulation. Since one

would not want to take excessive doses of vitamin B6 (greater than 300

to 500 mg a day for a long time period), a homocysteine blood test can

help determine whether you are taking enough vitamin B6 to keep

homocysteine levels in a safe range. There are some people who lack an

enzyme to convert vitamin B6 into its biologically active form,

pyridoxal-5-phosphate. In this case, if low-cost vitamin B6 supplements

do not sufficiently lower homocysteine levels, then a high-cost

pyridoxal-5-phosphate supplement may be required. I generally suggest

to my patients to take the bio-active form without thinking about the

cheaper brands. 

For many people, the daily intake of 500 mg of TMG, 800 mcg of folic

acid, 1000 mcg of vitamin B12, 250 mg of choline, 250 mg of inositol,

30 mg of zinc, and 100 mg of vitamin B6 will keep homocysteine levels

in a safe range. But the only way to really know is to have your blood

tested to make sure your homocysteine levels are under 7. If

homocysteine levels are too high, then up to 6 grams of TMG may be

needed along with higher amounts of other remethylation cofactors. Some

people with cystathione-B synthase deficiencies will require 500 mg a

day or more of vitamin B6 to reduce homocysteine to a safe level. For

the prevention of cardiovascular disease, you would want your

homocysteine blood level to be under 7. For the prevention of aging,

some people have suggested that an even lower level is desirable, but

more research needs to be done before any scientific conclusions can be

reached.

A Life Extension article (July, 1997), sites these cases of people with

problems in these pathways. “People with these disorders frequently die

of cardiovascular disease before reaching adulthood. In one case

history report, a 16-year-old Japanese girl was unable to walk with or

without support, and had severe peripheral neuropathy, muscle weakness

and convulsions. Her vascular system was on the verge of collapse. B6

or B12 didn't help. Folic acid lowered homocysteine, but didn't improve

her symptoms. Two months after adding TMG to the regimen, her

homocysteine level dropped and she was able to walk with support.

Seventeen months later, she was free from convulsions and able to walk

normally again.

This case history demonstrates the seesaw relationship between

homocysteine and SAM. The girls SAM levels went from undetectable to

near normal after the first two months of treatment while her

homocysteine levels fell dramatically. If these nutrients can overcome

a genetic disorder, consider how powerful they can be in reducing the

risks associated with elevated homocysteine in the general population.

Some people who have been taking this homocysteine lowering nutrient

combination for more than a decade reported many benefits including

fewer colds, more energy, increased endurance and lower blood sugar

levels.â€

Methylation/Homocysteine and Other Disease

I cannot speak enough of the importance of the process of methylation

to our health and functions. For one, it is essential to DNA repair,

which if not repaired will result in breaks and mutation.  This in turn

leads to accelerated aging because of larger amounts of “half-baked†or

even dangerous proteins being produced. In fact, in a journal  Medical

Hypothesis (1998, 51[3]:179-221), it was suggested that aging, period,

could be a result of cellular demethylation, or in other words, a

slowing of “re-methylation†needed to maintain and repair DNA.  

Methylation is a key process in the liver with respect to its ability

to detoxify our bodies.  It is needed for the growth of new cells,

nerve sheath production (myelination) and a whole host of other

critical processes.  

 Homocysteine is a “biggy†for interfering with the whole methylation

pathway. High homocysteine speaks to us of poor methylation in a

patient.  Homocysteine may also be causing damage through oxidative

stress (free radical formation).  This is the reason I use a good

antioxidant with most protocols such as Metagenic’s Oxygenics or

Naturpharm’s Super A/O. 

Many studies have been done on the relationship between homocysteine

levels and dementia, and while research does not conclusively prove the

relationship, it strongly suggests that homocysteine directly promotes

the development of dementia and Alzheimer’s disease.

Vitamin B12:

Surprising New Findings

by: Terri

Page 1 of 4

For years, vitamin B12 languished as the vitamin that cures anemia.

Hardly any research was done into what this vitamin could do for

non-anemic people. It turns out that it may do a lot. New studies show

that the right amount of B12 can protect against dementia, boost immune

function, maintain nerves, regenerate cells and more. B12 is in the

news because it lowers homocysteine and protects against

atherosclerosis. It’s also vital for maintaining methylation reactions

that repair DNA and prevent cancer. One of the crucial areas for B12 is

the brain.

It’s not surprising that people with B12 deficiency develop mental

disorders. The vitamin is crucial for the synthesis or utilization of

important neuro-factors including monoamines, melatonin and serotonin.

In addition, B12 is absolutely critical for the function and

maintenance of nerves themselves. B12 is needed for methylation

reactions that maintain these cells, and enable them to function. For

this reason, the methylated form of B12, methylcobalamin, may be

superior to other forms of the vitamin. Methylcobalamin is considered

“bioactiveâ€, which means that it doesn’t have to undergo any chemical

reactions in the body before it starts working.

B12 contributes to brain function by lowering homocysteine.

Homocysteine is a toxic by-product of methionine metabolism that can

damage neurons. Importantly, homocysteine interferes with the

methylation reactions critical for brain function. Studies show that

people with elevated homocysteine can’t think.

I can’t remember

B12-deficiency can cause a dementia that looks exactly like Alzheimer’s

disease. And Alzheimer’s disease itself is characterized by brain

deficiencies of both vitamin B12 and the methylating factor,

S-adenosylmethionine (SAMe). A new study from Germany correlates B12

deficiency in Alzheimer’s patients with two personality

changes—irritability and disturbed behavior.

The connection between B12 deficiency and mental illness has been

documented repeatedly. According to the latest research, as much as 30%

of hospitalized mental patients may be deficient in the vitamin. And

what’s disturbing is that studies repeatedly show that the deficiency

is frequently missed by standard blood tests. For example, a recent

study from Germany shows that out of 67 hemodialysis patients who were

B12-deficient by the measurement of methylmalonic acid (it goes up when

B12 goes down), only two of them were deficient by a standard blood

test. Looking at the data, one can’t help but wonder how many people

with B12 deficiency get treated for mental illness when what they

should get is a vitamin!

B12 and folate

Folate deficiency can also produce mental symptoms, although it is less

common. Folate and vitamin B12 are both required for biochemical

reactions that occur in the brain. One won’t work without the other: a

deficiency in one produces a deficiency in the other.

Should a folate deficiency be suspected, both folate and vitamin B12

should be taken. This is because the deficiencies look so similar. If

the deficiency is, in fact, B12 instead of folate, folate will appear

to correct it in blood cells (where deficiencies are measured). But

folate will not correct a B12 deficiency in the brain. Permanent brain

damage can result if B12 deficiency is treated with folate. For years,

this problem has caused the government to resist supplementing the food

supply with significant amounts of folate. Be aware, also, that high

amounts of folate in the absence of adequate B12 can provoke or worsen

neurological conditions. It’s important to get adequate amounts of both

of these vitamins simultaneously.

Aging

Many studies have been done on the issue of whether B12 deficiency

relates to age-related cognitive decline in normal people. Results have

been mixed. One of the problems is getting an accurate reading on B12

levels. Blood levels don’t necessarily reflect tissue levels. Another

problem is that folate deficiency can complicate the picture. A study

in people 65+ found that folate levels significantly correlate with

cognitive function, but B12 did not. Another study published at the

same time (but using a different kind of evaluation) found that

supplemental B12 improves cognition, notably, a person’s ability to

remember words.

Protect your nerves

Methylcobalamin is terrific for protecting neurons. It saves the brain

from the damaging effects of glutamate, nitric oxide, low blood sugar

and low oxygen. Low oxygen occurs during stroke or heart attack. Low

blood sugar is a chronic problem in diabetes. Glutamate and nitric

oxide toxicity are features of Alzheimer’s and Parkinson’s diseases.

Taking methylcobalamin everyday may provide immediate protection should

a person be suddenly injured or have a stroke. Researchers in Japan

demonstrated that chronic application of methylcobalamin to neurons

protects them, but in order for the vitamin to work, it has to be ready

and available before the injury occurs.

The supplement-of-choice

Vitamin B12 is the only vitamin that is part mineral. The scientific

name for B12 is cobalamin. Cobalamin contains cobalt, a mineral that

stimulates the production of red blood cells. The most common forms of

supplemental B12 are cyanocobalamin or hydroxycobalamin. The natural

form of B12 found in food is methylcobalamin (or a similar form,

adenosylocobalamin). The structure of B12 is very complex, with

numerous methyl groups attached. Methyl groups (CH3) are used in

beneficial methylation reactions, such as those that reduce

homocysteine.

Methylcobalamin is the supplement-of-choice in Japan where it’s

approved to treat anemia. This form may have advantages over the cyano

form. In a study on sleep patterns, methylcobalamin seemed to work

better than cyanocobalamin. And this form is the B12 used in neuron

protection studies.

Myelin sheath, the “insulation†around nerve cells, is critical for

nerve conduction. Degeneration of this protein causes serious

neurological diseases. Myelin is created and maintained by methylation

reactions that depend on vitamin B12.

Recently, researchers in France succeeded in creating for the first

time a model of vitamin B12 deficiency in oligodendrocytes, the cells

that produce myelin sheath. This will enable the in-depth study of the

effects of vitamin B12 on the synthesis of myelin for the first time.

Data from this new model could lead to new insight into muscular

dystrophy, amyotrophic lateral sclerosis, subacute combined

degeneration of the spinal cord, multiple sclerosis and other

neuro-degenerative diseases.

Methylcobalamin has been used in animal studies on neurodegenerative

diseases. The methyl form of vitamin B12 clearly promotes nerve

regeneration and slows the progression of neurodegenerative diseases.

Neuropathies are strange and sometimes painful sensations caused by

degeneration of nerves. Methylcobalamin is effective for this

condition. In a study on diabetic rats, methylcobalamin reduced

demyelination. In a study on humans undergoing hemodialysis, 500

micrograms of methylcobalamin by injection three times a week, lessened

neuropathies.

Heart attack and stroke

Vitamin B12 has an important role in reducing levels of homocysteine to

prevent heart attack and stroke. Homocysteine is a by-product of

methionine metabolism that can damage blood vessels. B12 and folate are

critical for the production of the tongue-twisting enzyme,

methylenetetrahydrofolatereductase, which helps convert homocysteine to

methionine. Dozens of studies show that the most common cause of

elevated homocysteine is inadequate folate or vitamin B12.

Supplementation with these vitamins lowers homocysteine levels, but

vitamin B6 and trimethylglycine (TMG) are usually also required to

lower homocysteine to a healthy range.

Vitamin B12 deficiency has another effect on the heart as well. Turkish

researchers recently reported that people with megalobastic anemia have

abnormal electrical conductivity of the heart. The problem originates

in the nerves that control heart rate. When the anemic volunteers took

supplemental B12, heart rate returned to normal.

Cancer

Methylcobalamin (B12) and Bell's Palsy

Bell’s palsy is a temporary paralysis of the facial nerve. A person

with Bell’s palsy may not be able to open their eye or close one side

of their mouth. Since this condition involves nerves, and vitamin B12

is critical for nerves, the vitamin was tested as a treatment for this

nerve condition. Sixty people with Bell’s palsy were divided into three

groups. The first group was given standard steroid therapy. The second

group was given methylcobalamin plus steroid. The third group was given

methylcobalamin alone. It took 2-9 weeks for the drug group to recover.

The groups given methylcobalamin recovered much quicker, some within

days. The group given methylcobalamin alone recovered the quickest.

MA Jalaludin. 1995. Methylcobalamin treatment of Bell’s palsy. Methods

Find Exp Clin Pharmacol 17:539-44.

Elevated homocysteine is rightfully considered a risk factor for

cancer. High levels of homocysteine are consistently linked with DNA

damage. The connection was shown recently in a study from Australia

where the micro-nucleus index (a measure of DNA damage) increased as

levels of homocysteine increased. This held true for both younger

(18-32) and older (50-70) people.

Fifty-six percent of the men in the older bracket either tested below

par for B12 or folate, or abnormally high for homocysteine. Men with

homocysteine levels greater than 10 micromoles per liter had

significantly more DNA damage than those with lower homocysteine, even

if they had normal levels of B12 and folate. Despite no folate

deficiency, supplementation with 3.5 times the recommended allowance of

folate and B12 still significantly reduced the micronucleus index in

people where it was initially elevated above the 50th percentile.

(Note: in this study, taking 10 times the recommended amount of folate

and B12 did not have any added benefit).

One of the implications of this study is that “normal†levels of these

vitamins—standard blood levels—are probably not adequate to prevent DNA

damage. It also indicates that high homocysteine levels are a red flag

that DNA damage is occurring whether or not homocysteine-lowering

vitamins are adequate by blood measurements. Men with low, but still

“normalâ€, levels of B12 had significantly more damage. According to Dr.

Fenech, author of the study, “the accepted standard for vitamin

B12 sufficiency (i.e., plasma concentration <150 pmol/L) may not be

adequate to minimize chromosome damage rates.â€

H. Pylori and vitamin B12 deficiency

Researchers have discovered a connection between anemia, B12

deficiency, and infection with H. Pylori, the organism that causes

stomach ulcers. The study enrolled 138 people with B12 deficiency and

anemia. Fifty-six percent of them tested positive for H. Pylori. Many

had no symptoms; others had “heartburn†or other stomach problems.

When the bacteria were eradicated with antibiotics, vitamin B12 levels

returned to normal without supplementation. It took a month for this to

occur, and three to six months more for full improvement. In people

where the antibiotic treatment didn’t work, anemia and B12 levels

didn’t improve. The difference in B12 levels before and after treatment

is striking: after treatment, levels were approximately four times

higher. H. Pylori may partly explain mysterious studies showing that

elderly people are taking in enough B12, but turning up deficient

anyway. Older people are prone to atrophic gastritis, a condition where

there is not enough acid and pepsin in the stomach to properly digest

food. This creates a friendly climate for unfriendly bacteria such as

H. Pylori. It also impairs the stomach’s ability to acquire vitamin B12

from food.

People with stomach pain or “heartburn†often take antacids, including

drugs such as Prolisec or Prevacid. While these types of drugs

temporarily ease the pain, they further suppress acid necessary to

maintain B12 levels and proper stomach bacteria. If the stomach is

infected with H. Pylori or other pathogenic bacteria (overgrowth of

bacteria in the small intestine can cause similar symptoms), the answer

is to kill the bug, allow the ulcers to heal, then augment (not

suppress) stomach acid with supplements designed to maintain acidity

and discourage bacterial growth.

Oral B12 works

Despite what it says on the package insert of injectable B12, oral B12

works. For example, gastrointestinal surgery usually causes B12

depletion and anemia. Japanese researchers used 500-1500 mcg/day of

oral B12 to treat B12 deficiency after total gastrectomy. This amount

reversed the deficiency quickly and efficiently. B12 blood levels of

patients receiving 750+mcg were comparable to patients receiving 500

mcg by injection every two months. Japan has long recognized the

benefits of using the methylated form of B12, methylcobalamin. Despite

strong evidence that oral B12 is effective, physicians are slow to

recommend this form to their patients. A study published in 1998

reports that 71% of the internists surveyed don’t believe that oral B12

works as well as injections.

Widespread deficiency

A new study from Tufts University reports that B12 supplements are the

most important source of vitamin B12 for Americans. Those taking

supplements or eating cereal supplemented with B12, are half as likely

to be B12 deficient than those who don’t. Meat, the primary source of

B12 for Americans, is not as good a source. This is probably due to

problems in digestion and prescription drugs that interfere with the

absorption of B12 when it’s attached to proteins such as meat. Cooking

may also affect the vitamin B12 content of meat.

B12 deficiency has gotten so bad in America that the RDA has been

increased from 2.0 micrograms a day to 2.4. It’s not only older people

who are deficient these days. The Tufts study looked at the children of

people who took part in the original Framingham heart study. They were

stunned to see that in one generation, B12 deficiency in kids had

caught up to the generation before. Pizza, one of the foods evaluated,

is apparently not a good source of vitamin B12.

Although the body needs minute amounts of vitamin B12, Americans are

not getting enough for general health, let alone optimal DNA and heart

protection. H. Pylori infection, drugs, over-cooking meat, increased

demand and other factors may be robbing us of this highly crucial

vitamin. The mistaken belief that B12 has to be given by injection may

be keeping people from getting the extra B12 they need. High amounts of

the vitamin are not toxic; and may in fact be more beneficial than we

currently know. Evidence is stacking up that amounts of vitamin B12

above and beyond the current recommended daily allowance may help

protect nerves and protect us from cancer, infections and a host of

other adverse conditions.

Methylcobalamin (B12) and immunity

Methylcobalamin enhances the activity of natural killer and T-cells.

These immune cells are important for killing cancer and viruses.

Japanese researchers have discovered that ratio of T-helper cells to

T-suppressor cells is abnormal in people with anemia. Methylcobalamin

corrects this defect. Vegans with B12 deficiency have lowered numbers

of immune cells. People infected with HIV are more likely to get AIDS

if their B12 levels are low, irrespective of whether they take

antiviral drugs. Methylcobalamin is required for both the synthesis and

function of immune cells. In a study on people with low tissue levels

of B12, methionine synthetase activity was very low, indicating that

very few immune cells were being synthesized. Treatment with

methylcobalamin restored immunity almost immediately.

>

>

> Bleu,

>

> The only information I have found to research is the Stratton patent,

> which I wasn't able to wade thru with a good understanding. I need to

> weigh the evidence before starting anything new. Do you have a link to

> the Stratton/Wheldon protocol? does this apply to Lyme/RA?

>

> Thanks, robyn

>

> > Robin are you doing high doses of B12 as per Stratton and Weldon

> > suggests?

>

>

>

>

>

>