metikobal dr hepi m

8/13/2019 Metikobal Dr Hepi m

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Methylcobalamin and Diabetic NeuropathyClinical usefulness of intrathecal injection of Methylcobalamin in patients with diabetic

neuropathy

Ide H Fujiya S Asanuma Y Tsuji M Sakai H Aishi Y! Clin Ther "#$%&'

$"(')#%*+$(

Se,en men and four women with symptomatic diabetic neuropathy were treated with

Methylcobalamin "(!-.. microrams in #. ml of saline' injected intrathecally/ Treatmentwas beun when patients had ood metabolic control! as determined by measurements of

plasma lucose and hemolobin! and was repeated se,eral times with a one+month

inter,al between injections/ Three patients were re+treated one year after the lastintrathecal injection/ Symptoms in the les! such as paresthesia! burnin pains! and

hea,iness! dramatically impro,ed/ The effect appeared within a few hours to one week

and lasted from se,eral months to four years/ The mean peroneal motor+ner,e conduction,elocity did not chane sinificantly/ The mean "01+ S2' concentration of

Methylcobalamin in spinal fluid was ##3 01+ *( p1ml before intrathecal injection "n 4 -'and 3!&-( 01+ (!-.3 p1ml one month after intrathecal Methylcobalamin treatment "n 4

##'/ Methylcobalamin caused no side effects with respect to subjecti,e symptoms orcharacteristics of spinal fluid/ These findins suest that a hih concentration of

Methylcobalamin in spinal fluid is hihly effecti,e and safe for treatin the symptoms of

diabetic neuropathy/

METHYLCOBALAMIN

Methylcobalamin is the neuroloically acti,e form of ,itamin 5#(/ The li,er does not

con,ert cyanocobalamin! the commonly a,ailable form of ,itamin 5#(! into ade6uate

amounts of methylcobalamin! which the body uses to treat or correct neuroloicaldefects/ Animal studies ha,e shown that hih doses of methylcobalamin are effecti,e inneuron reeneration and that there is no known to7icity at these doses/

Those who ha,e low le,els of ,itamin 5#( in the blood ha,e lon resorted to injections

of this essential 5 ,itamin! an uncomfortable deli,ery method at best/ 8ew e,idencesuests that oral 5#( works as well as injections! accordin to a study published in the

journal 5lood +but hih doses must be taken/ This ,erifies reports from Sweden datin

from the #$&.s that pernicious anemia! a disease of 5#( deficiency! can be controlledwith oral 5#(/ 9esol,in the debate o,er oral+,ersus+injections is ,ery timely! i,en that

,itamin 5#( is a homocysteine+lowerin factor/ Homocysteine has emered as a stron

and independent risk factor for heart disease and stroke! and is also connected to chronic

diseases such as arthritis! Al:heimer;s and diabetes/

Accordin to the recent data! (!... microrams1day of oral 5#( cures the symptoms of

5#( deficiency! includin ele,ated homocysteine! neuroloical problems! and ele,atedmethylmalonic acid "a marker of 5#( deficiency'/ The oral ,ersion works as well as

injections! with the added feature of maintainin hih le,els in the blood o,er time/ The

study showed that after a month! the blood le,els of the ,itamin in people recei,in


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injections dropped and stayed at a plateau! whereas blood le,els of those recei,in oral

5#( continued to rise/

5#( lowers homocysteine Althouh oral 5#( did not reduce homocysteine in e,ery

case! when it did! the results were dramatic/ Some of the people in the study had

homocysteine le,els as hih as #&- micromoles per liter "the optimal safe rane forhomocysteine is under


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and maintains ner,es and brain chemicals/ 9esearch shows that a lack of

methylcobalamin causes deeneration of the brain and spinal cord + a condition known as

subacute combined deeneration/ In this disease! ner,es lose their insulation and bein todeteriorate/ This process! known as demyelination! occurs in other neuroloical diseases

such as multiple sclerosis and chronic inflammatory demyelinatin polyneuropathy/

Hih doses of methylcobalamin ha,e been used to treat deenerati,e neuroloical

diseases in rodents and humans/ ?eople with amyotrophic lateral sclerosis "Bou ehri;s

disease' took (- m a day of methylcobalamin for a month/ In this disease! the neuronsthat control muscle mo,ements deteriorate/ The double+blind! controlled study showed

that methylcobalamin impro,ed muscle response after a month of treatment/

Methylcobalamin has been i,en to mice with the mouse ,ersion of muscular dystrophy/

A remarkable re,ersal of deeneratin ner,es occurred/ Methylcobalamin did not stop thedisease! but it slowed it down/

It has been documented that the le,el of 5#( decreases e,ery year with ae/ Ae+related

deficiency is associated with hearin loss! memory impairment and psychiatric disorders!alon with heart disease and stroke/ Al:heimer;s disease "A2' patients ha,e less 5#( in

their spinal fluid than people without the disease/ They also ha,e less SAMe + thesubstance re6uired to methylate cobalamin "5#(' to methylcobalamin! the acti,e form/

The failure of 5#( supplementation to impro,e A2 patients in some studies may be due

to their inability to acti,ate 5#( in the brain/ Methylcobalamin is already methylated) itdoesn;t re6uire SAMe/

Another feature of ain is the increase of free radicals/ Free radicals are ele,ated in

?arkinson;s disease "?2' and A2/ In ?2! a substance known as MA>+5 is also ele,ated/MA>+5 creates free radicals! and the MA>+5 inhibitor! seleiline! is often i,en to ?2

patients/ MA>+5 is linked to memory impairment/ In #$$( Italian researchers reported

that ele,ated MA>+5! dementia and 5#( deficiency all o toether/

B#$ Deficiency Di!ea!e!

2iet! ae and drus are the prime culprits behind 5#( deficiency/ Meat is the primary

source of ,itamin 5#(/ Strict ,eetarians + people who eat no animal products whatsoe,er

are at risk for 5#( deficiency/ "=eetarians who eat es and fish will et 5#( in their

diet/ In addition! some seaweeds contain the ,itamin! and the ut may manufacture acertain amount/' Howe,er! a meat diet doesn;t uarantee that a person won;t be 5#(

deficient/ Some elderly people! for e7ample! can eat hih 6uantities of meat but still be

5#( deficient because they don;t ha,e enouh hydrochloric acid in their stomach tomaintain intrinsic factor/ Meat+eaters takin certain drus are also at risk for 5#(

deficiency/ Cimetidine "Taamet'! omepra:ole "?rilosec'! and other drus that inhibit

astric secretion can cause 5#( deficiency/ Anyone who chronically takes drus forstomach ulcers! heartburn or astroesophaeal reflu7 may be creatin 5#( deficiency in

themsel,es/


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There appears to be somethin else causin 5#( deficiency in older people that

researchers don;t yet understand/ In a 2utch study! researchers found that about (-D of

the participants had low 5#(/ 5ut ut problems only accounted for (%D of those cases/The cause in the remainin &(D is a mystery/ 9esearchers do know that more people may

be deficient than currently appreciated/ Ehen researchers at the =eterans Administration

Hospital in >klahoma used modified criteria for 5#( deficiency "ele,ations inhomocysteine and methylmalonic acid! plus serum 5#( up to *.. p1mB+the norm is

usually (..'! they unco,ered twice as many people with 5#( deficiency than would ha,e

been detected by serum ,alues alone/

@le,ated homocysteine is found in many chronic diseases includin arthritis and

diabetes/ 9esearchers in apan ha,e disco,ered that noninsulin+dependent diabetes

patients with blood ,essel problems ha,e ele,ated homocysteine/ Ehen treated with #...microrams of ,itamin 5#( "methylcobalamin' daily for three weeks! homocysteine

le,els dropped sinificantly/ Althouh the study didn;t follow the patients lon enouh to

see the effects of lon+term treatment! the condition of the patients; blood ,essels will

likely impro,e as the le,els of homocysteine are reduced! as homocysteine is e7tremelyto7ic to blood ,essels/

B#$ and %leep

Those who can;t et to sleep at niht may need ,itamin 5#(/ Studies show that 5#(causes an earlier release of melatonin at niht which resets the sleep+wake cycle/

"Melatonin has been called the sleep hormone because of its effects on sleep'/ 5#( acts

directly on the pineal land to pro,oke a faster release of melatonin/ At the tail end! 5#(

causes melatonin to drop off faster/ 5#( helps you et to sleep earlier! and may help youwake up earlier if you lea,e a curtain open to the mornin sun/ 5#( sensiti:es you to

mornin liht! which helps you wake up/ =ery serious sleep+wake disorders ha,e been

successfully treated with ,itamin 5#( in the methylcobalamin form! althouh it may notwork for e,eryone/ Gnfortunately! the ,itamin doesn;t help people who want to cut down

on their sleep time altoether/

2urin the #$-.s! 5#( was fre6uently i,en to heart patients/ The ,itamin fell out of

,oue as drus took o,er the therapeutic picture/ 8ew findins on the connection

between homocysteine and ,ascular disease! plus the failure of drus to ha,e an impact

on the number of heart attacks and strokes! ha,e shifted the focus back to 5#( and otherhomocysteine+lowerin ,itamins/ The notion that 5#( must be injected to be effecti,e

has been dispro,en in recent studies/ Swedish e7perience shows that oral 5#( is effecti,e

for the treatment of pernicious anemia/

5#( has many benefits! includin the reduction of homocysteine! restoration of normal

sleep patterns! and mood effects/ 5#( deficiency is a fairly common deficiency in elderlypeople who fre6uently ha,e disrupted diestion/ It can cause symptoms that look e7actly

like Al:heimer;s disease! and it;s crucial for the retention of folate in cells/

Te!tin& or B#$ Deficiency


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There are se,eral tests eared towards dianosin 5#( deficiency/ Homocysteine is an

indirect test/ A more direct method is to measure methylmalonic acid which becomesele,ated in 5#( deficiency/ There are other tests which measure ut secretions or

antibodies to ut secretions/ The Schillin test can help ferret out what is causin the

deficiency! and a simple blood test can show blood le,els/

Do!a&e

The dose of oral 5#( supplements for sleep disorders is *... mc a day! while (...

mc a day has pro,en useful in lowerin homocysteine and correctin 5#( deficiency/ In

published studies! it took four weeks for the sleep effect! and four months for the

homocysteine+lowerin effect+so be patient/ ?eople with deenerati,e diseases! includinAl:heimer;s! should take ,ery hih doses in the rane of *+3... m! supplemented with

SAMe/

There is also the option of takin methylcobalamin! which is the neuroloically acti,eform of 5#(/ The potential ae+re,ersin benefits are well+worth the modest price/

Methylcobalamin is a form of 5#( that is sold as a dru in apan/ It is themethylcobalamin form of 5#( that has been used in most @uropean and apanese studies

showin efficacy aainst neuroloical disease/ The li,er con,erts about #D of inested

cyanocobalamin into methylcobalamin! but it is far more efficient to dissol,e a oodtastin methylcobalamin lo:ene in the mouth for immediately assimilation into the

brain/

Methylcobalamin: A PotentialBreakthrough in Neurological Disease

Japanese scientists have identified a form of vitamin B12that protects against

neurological disease and aging by a unique mechanism that differs from currenttherapies. Some of the disorders that may be preventable or treatable with this

natural vitamin therapy, called methylcobalamin, include chronic fatigue syndrome,

Parinson!s disease, peripheral neuropathies, "l#heimer!s disease, musculardystrophy and neurological aging. "mericans have immediate access to this unique

and new form of vitamin B12, and, unlie prescription drugs, it costs very little and isfree of side effects.

vitamin B12is a general label for a group of essential biological compounds nows ascobalamins. $he cobalamins are structurally related to hemoglobin in the blood, and

a deficiency of vitamin B12 can cause anemia. $he primary concern of conventionaldoctors is to maintain adequate cobalamin status to protect against anemia.

$he most common form of vitamin B12 is called cyanocobalamin. %owever, over thelast ten years, a number of central and peripheral neurological diseases have been

lined to a deficiency of a very specific cobalamin, the methylcobalaminform, that is
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required to protect against neurological diseases and aging. $he liver converts asmall amount of cyanocobalamin into methylcobalamin within the body, but larger

amounts of methylcobalamin are necessary to correct neurological defects andprotect against aging.

Published studies show that high doses of methylcobalaminare needed to regenerate

neurons as well as the myelin sheath that protects nerve a&ons and peripheralnerves.

CFIDS and B-!

'n the Summer 1(() issue of Healthwatch, an important research article reported afascinating new finding. *ver +- of /'0S and / patients cerebral spinal fluids

contained subnormal levels of vitamin B12. *n the other hand, vitamin B12 levels inthe blood did not significantly deviate from normal ranges.

"ccording to 0r. Paul heney!s treatment pyramid for /'0S, vitamin B12 in its noncyanocobalamin form 3the type commercially available4 is a potent deto&ifier of the

brain. 5ecent studies in 6urope suggest that it needs to be given in large doses in

the range of 1 2 mg per day, or even more. $his supplementation ofmethylcobalamin might protect the cognitive function of patients with /'0S bypreventing the death of brain cells.

*ne cause of brain cell death is glutamate to&icity. Brain cells use glutamate as aneurotransmitter, but unfortunately glutamate is a doubleedged sword in that it can

also ill brain cells. $he release of glutamate from the synapses is a usual means bywhich neurons communicate with each other.

6ffective communication means controlled release of glutamate at the right time tothe right cells, but when glutamate is released in e&cessive amounts, intercellular

communication ceases. $he flood of glutamate into the receiving neurons drivesthem into hyperactivity, and the e&cessive activity leads to cellular degradation.

$he good news is that it may now be possible to protect brain cells against glutamateto&icity by taing methylcobalamin supplementation. 'n a study in the European

Journal of Pharmacology, it was shown that methylcobalamin protected againstglutamate, aspartate and nitroprusside induced neuroto&icity in rat cortical

neurons.

5esearchers concluded that methylcobalaminprotects against neuroto&icity by

enhancing brain cell methylation. $he /'0S 7 /ibromyalgia %ealth 5esourcerecommends methylationenhancing therapies such as vitamin B+, vitamin B12, folic

acid and trimethylglycine 3$84, taen together, to protect against heart disease,stroe and other agingrelated diseases.

$he scientists who conducted the methylcobalaminstudies emphasi#e that ongoingintae of methylcobalamin is necessary to protect against neuroto&icity. $hus for

methylcobalamin to be effective in protecting against neurological disease, dailysupplementation may be required.

"n appropriate dose to protect against neurological aging might be 1 to 9 mg a daytaen under the tongue in lo#enge form.
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Slee"" recent 8erman study appearing in Neuropharmacologyshowed methylcobalamin

reduced the amount of time sub:ects slept; sleep quality was better and sub:ectsawoe feeling refreshed, with better alertness and concentration. Part of this effect

was apparently due to melatonin suppression during the daytime because morningmethylcobalamin supplementation reduces drowsiness by decreasing daytime

melatonin levels.

Multi"le Sclerosis

"ccording to a recent study at


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days suppressed liver, lung and ascites tumor growth. ice receivingmethylcobalamin survived longer than control mice did. 'n mice irradiated before

tumor cell inoculation, methylcobalamin did not improve survival.

$he effects of methylcobalaminon human immune function was investigated in theJournal of Clinical Immunology. $he study showed that methylcobalamin

demonstrated remarable $ cellenhancing effects when the $ cells were e&posed tocertain antigens.

$he scientists also showed that methylcobalamin improved the activity of $ helper

cells. $he scientists concluded that methylcobalamin could modulate lymphocytefunction by augmenting regulatory $ cell activities.

"mericans need to now about this important natural therapy that could e&tend thehealthy human life span. " search of the scientific literature reveals ??> published

studies on methylcobalamin. %owever, it would not be an e&aggeration to say thatvirtually no doctors now of it or are recommending it.

ethylcobalamin should be considered for the treatment of any neurological disease./or e&ample, based on its unique mechanisms of action, methylcobalamin could beeffective in slowing the progression of @untreatable@ diseases such as "AS 3Aou

8erhig!s disease4.

Since methylcobalaminis not a drug, there is little economic incentive to conducte&pensive clinical studies on it, so it may be a long time before we now :ust how

effective this unique form of vitamin B12 is in slowing the progression of commondiseases lie Parinson!s disease.

$he sublingual intae of methylcobalaminis an affordable and effective naturaltherapy, and has proven even safe when given in large doses.

B-! Methylcobalamin - &horne Article -

Marilyn Bachmann - March !'( !''

onograph ethylcobalamin

Introduction

ethylcobalamin is one of the two coen#yme forms of vitamin B12 3the other being

adenosylcobalamin4. 't is a cofactor in the en#yme methionine synthase whichfunctions to transfer methyl groups for the regeneration of methionine from

homocysteine.

Pharmacokinetics

6vidence indicates methylcobalamin is utili#ed more efficiently than cyanocobalaminto increase levels of one of the coen#yme forms of vitamin B12. 6&periments have
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demonstrated similar absorption of methylcobalamin following oral administration.$he quantity of cobalamin detected following a small oral dose of methylcobalamin is

similar to the amount following administration of cyanocobalamin; but significantlymore cobalamin accumulates in liver tissue following administration of

methylcobalamin. %uman urinary e&cretion of methylcobalamin is about onethirdthat of a similar dose of cyanocobalamin, indicating substantially greater tissue

retention.1

Clinical A""lications

Bell!s Palsy 6vidence suggests methylcobalamin dramatically increased the recovery

time for facial nerve function in Bell!s palsy.2

ancer ell culture and in vivo e&perimental results indicated methylcobalamininhibited the proliferation of malignant cells.? 5esearch indicated that

methylcobalamin enhanced survival time and reduced tumor growth followinginoculation of mice with 6hrlich ascites tumor cells.> ethylcobalamin has been

shown to increase survival time of leuemic mice. =nder the same e&perimental

conditions, cyanocobalamin was inactive.9 "lthough more research is required toverify findings, e&perimental evidence suggested methylcobalamin might enhancethe efficacy of methotre&ate.+

0iabetic Ceuropathy *ral administration of methylcobalamin 39 mcg three times

daily for four months4 resulted in sub:ective improvement in burning sensations,numbness, loss of sensation, and muscle cramps. "n improvement in refle&es,

vibration sense, lower motor neuron weaness, and sensitivity to pain was alsoobserved.D

6ye /unction 6&periments indicated chronic administration of methylcobalamin

protected cultured retinal neurons against Cmethyl0aspartatereceptormediated

glutamate neuroto&icity.) 0eterioration of accommodation following visual wor hasalso been shown to improve in individuals receiving methylcobalamin.(

%eart 5ate


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Sleep 0isturbances $he use of methylcobalamin in the treatment of a variety of

sleepwae disorders is very promising. "lthough the e&act mechanism of action isnot yet elucidated, it is possible that methylcobalamin is needed for the synthesis of

melatonin, since the biosynthetic formation of melatonin requires the donation of amethyl group. Supplementation appears to have a great deal of ability to modulate

melatonin secretion, enhance lightsensitivity, normali#e circadian rhythms, andnormali#e sleepwae rhythm.192

Dosage

$he dosage for clinical effect is 19+ mcg per day. Co significant therapeuticadvantage appears to occur from dosages e&ceeding this ma&imum dose.

ethylcobalamin has been administered orally, intramuscularly, and intravenously;however, positive clinical results have been reported irrespective of the method of

administration. 't is not clear whether any therapeutic advantage is gained from thenonoral methods of administration.

Sa)ety( &o*icity( and Side +))ects

ethylcobalamin has e&cellent tolerability and no nown to&icity.

What is it?Vitamin B12or cobalamin is an essential nutrient found in meat products. VitaminB12is absorbed in the small intestine and is necessary for proper nerve functionand converting food into energy. Deficiencies of vitamin B12cause anemia andneurological impairments including memory loss and disorientation.

What do people with HIV use this supplement for?To avoid deficiencyDepending on the way vitamin B12levels are measured, studies suggest thatbetween ten and 50 per cent of people living with !V"#!D$ %s' are deficientin this nutrient. (his deficiency is most li)ely due to !V*related damage to thesmall intestine that prevents the body from absorbing ade+uate amounts of B12.ertain drugs, such as #-( and the antibiotics used to treat tuberculosis, candecrease levels of vitamin B12. $everal studies suggest that deficiency in thisvitamin increases the rate at which a person becomes ill %disease progression'.!n a study conducted by Dr. #lice (ang and colleagues, serum levels of vitaminB12were measured in !V*positive people without symptoms of disease. ven

when factors such as D/ counts were considered, the team found that serumvitamin B12levels could be used to predict which subects would become ill most+uic)ly.

B12deficiency seems to be lin)ed to poor absorption most nutritionists suggesttherefore that supplements of B12be inected or ta)en sublingually %dissolvedunder the tongue'. #lthough these methods have been shown to increase serumlevels of B12in !V*positive people, no trials have been done to assess the


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impact of B12supplements on disease progression.

To prevent and treat dementia3iven that B12deficiencies are associated with confusion and memory, manyphysicians and researchers have speculated that vitamin B12might play a role in

dementia and other !V*related cognitive disorders. 4ne case report describedthe dramatic recovery of a !V*positive man suffering from dementia who wastreated with B12. linical trials have produced less impressive results and it is nowgenerally accepted that B12may be a factor in some but not all cases of !V*related dementia. B12supplements have also been useful in treating elderlypeople with B12deficiencies who showed signs of memory loss and senility.

To treat peripheral neuropathy&eripheral neuropathy is a tingling or burning in the hands and feet. !t is oftenassociated with anti*!V drugs, particularly dd, dd! and d/(. 4ne early study ofs suggested that people with low B12levels were more li)ely to eperience

neuropathy, but subse+uent studies have not confirmed this connection. B12has,however, been used successfully to treat diabetic neuropathy, a fact that arguesits case for the management of nerve damage in s.

Available forms and usage!n anada, B12is ta)en orally or by intramuscular or intravenous inections.

#lthough other forms of B12have been developed, such as nasal sprays, gelsand sublingual tablets, not all of these formulations are widely available inanada. 3iven that vitamin B12may be poorly absorbed in !V*positive people,most nutritionists and physicians recommend B12shots. (hese shots can beta)en at a doctor6s office or an !V clinic and, in most cases, they are covered by

provincial and private insurance plans. # monthly inection can be used to boosta daily oral dose of B12. !f obvious signs of B12deficiency are present, morefre+uent inections are possible %up to several times a wee)'. 4ral doses of 25 or50 mg of B12are found in B25 or B50 vitamin tablets respectively. (hese B*comple combination vitamins are described further in #(!6s supplement sheeton vitamin B*comple.

Cautions and ConcernsVitamin B12supplements are safe to use. cess amounts of the vitamin areeliminated in the urine. #t high doses, however, B 12may cause aniety in somepeople and mild diarrhea in others. $ome people are sensitive to B 12and maydevelop a s)in rash while ta)ing this supplement. $ince B*vitamins tend to wor)best together, it6s important to maintain the balance of Vitamin B12and another B*vitamin called folate %folic acid' in the body. (a)ing large doses of one B*vitaminalone is not a good idea so if you are ta)ing etra B12, you might want to ta)e aB*comple pill as well.


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Peripheral Neuropathy(polyneuropathy)

A common !ide'effect of chemotherapy''i!

there any !olution(%)MMA*Y

?eripheral neuropathy "or! polyneuropathy' is normally attributed to diabetes!

thyroid problems! alcohol abuse! and consistent e7posure to chemotherapy

treatments/ 5ut it can likewise be attributed to the use of drus other than

chemotherapy aents/ 8otwithstandin multiple statements and ad,ertisements

proclaimin that statinsare safe and ,ital to lowerin cholesterol and

pre,entin coronary e,ents! contrary e,idence e7ists that lon+term e7posure tostatins may substantially increase the risk of1induce and e7acerbate peripheral

neuropathy by #-D in the first year and (


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lenth of life+++I likewise suest that in our monthly #- minute sessions with

our doctors! they are not doin so on our behalf/

Many cancer patients are also takin a myriad of other drus! and most of us

take some statin and antianioenic aents/ Are we thus assurin that we will

suffer treatment+limitin and debilitatin "and possibly permanent' peripheralneuropathy by takin Bipitor for its cholesterol+lowerin effects! Celebre7 for

pain and antianioenesis! blood pressure medicines! and thalidomide for

antianioenesis "thalidomide is well+known for causin peripheral

neuropathy' Ehen we de,elop peripheral neuropathy! do our doctors analy:e

our medication list to assess the indi,idual and cumulati,e effects of all of our

medications "My 6uestion is ob,iously cynical and rhetorical/'

Many cancer patients who undero se,eral months of chemotherapy will

de,elop peripheral neuropathy to some e7tent/ The ner,e damain effects of

chemotherapy are cumulati,e and as the chemotherapy treatments arecontinued! the condition often becomes treatment+limitin and physically

debilitatin/ Medical science does not know of any aent to relie,e or delay the

onset of peripheral neuropathy and we are often told that ///it is just our old

friend Ta7otere///! without any analysis of the cumulati,e antianioenic

effects of our other drus as possibly contributin in a major way to our

peripheral neuropathy/

The probable side+effect of peripheral neuropathy resultin from lon+term

chemotherapy is well+known by our oncoloists! yet they ha,e no suestions

about how to alle,iate it e7cept to reduce the dose of the chemotherapy aent or

suspend treatment/ In my opinion! our doctors are not comfortable with any

aent we can buy in a dru or health food store and often just shru their

shoulders and tell us to try it if we want/ 8or do I belie,e that our doctors are

aware of the many side effects "and accumulation thereof' of the many drus

we take to support and aument our cancer treatments or alle,iate side+effects

there from/

After #& weekly Ta7otere treatments and while I was still respondin "I was

also takin 3.. m of Celebre71day 0 daily 8or,asc and Accupril for blood

pressure control'! I was forced to stop treatment due to e7treme peripheral

neuropathy and resultin onychosis (10)/ I wrote about this in Chemotherapy +

?art (/ In that paper I suested lutamine as a possible aent to relie,e or

delay peripheral neuropathy/ In subse6uent chemo treatments I continue with

daily lutamine and belie,e that it offers some relief but after (0 years of

chemotherapy! I still suffer considerable peripheral neuropathy/ Howe,er!
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below I suest other possibilities that miht partially relie,e and1or delay this

treatment+limitin side+effect of chemotherapy/

In addition to a mandatory re,iew of e,ery complementary dru we are takin

that miht ha,e any characteristics of inducin peripheral neuropathy! and

optimi:in their utili:ation in ,iew of our own concept of 6uality16uantity oflife++++ in %)MMA*Y! I suest se,eral possible solutions to alle,iate1delay

peripheral neuropathy while enaed in our saa of prostate cancer and the

treatments therefor+++with the e7ception of shakuyaku+kan:o+to! all of these

items are a,ailable in a dru1health food store)

#' lutamine at #. m J 31day as delineated in my abo,e paper/

(' Shakuyaku+kan:o+to "not a,ailable in a dru1health food store'+++an ancient

Chinese1apanese herbal concoction for muscle spasms and tinlin in the

hands and feet/

*' amma+linolenic acid "BA'!fish oil concentrate! and ascorbyl palmitate

++corrects fatty acid imbalance/

3' =itamin 5#( in the form of methylcobalmin "methl 5#(' 0 folic acid/

-' Alpha+lipoic acid 0 acety+B+carnitine 0 8+acetylcysteine 0 ,itamin C/

"8>T@) we must be coni:ant of the fact that the studies1reports of aents

effecti,e aainst peripheral neuropathy state that such aent"s' only delayorpartially mitigateperipheral neuropathy+++none proclaim topreventit+++so!

with our cancer and lon+term use of statins! antianioenic aents! and

chemotherapy! we must accept the fact that we will all suffer peripheral

neuropathy to some e7tent/'

2@FI8ITI>8S

...Neuropathyis the wastin and inflammation of ner,e tissues! often manifest

in peripheral e7tremities "hands1feet'/ Symptoms are burnin! shootin pain

possibly concurrent with a cold sensation! transient numbness! and weakness ofthe e7tremities/ The sensation"s' can be transient! mo,in from finer to

finer1toe to toe! and radiatin up the arm or le/ Symptoms usually impro,e

upon stoppin the dru! althouh impro,ement can take


15/49

aents/ (11)If peripheral neuropathy is bilateral! dru induction is usually

attributed thereto++++but if it is unilateral! there are possibly other non+dru

related problems/

+++gamma-linolenic acid (GLA)++known as the ood omea+


16/49

...sha#uya#u-#an$o-to"T+


17/49

N*,&) I am not a doctor and can not i,e medical ad,ice/ I am not a medical

researcher/ I am an unemployed prostate cancer patient in my si7th year of this

saa and I performed this laymanPs analysis for my own edification and

decision+makin purposes/ In conjunction with a competent medical team!

e,ery cancer patient must make their own decisions reardin treatment

options/ I make no claim that this analysis is definiti,e or complete and I in,ite

any and all competent suestions1corrections that will pro,ide salient

information to prostate cancer patients in our search for methods to e7tend

6uality and 6uantity of life while battlin a terminal disease/

methylcobalamin , Neuropathy

This articl s!"mitt# "$ %#li& o& 8'12'99.mail ##rss

Intern Med #$$$ un*%"


18/49

Autism 2!Understand, Act and Heal

Dr. 7eubrander is board*certified in nvironmental 8edicine with special

interests in heavy metals and B12 biochemistry. e practices in dison, 79where he dedicates :0; of his time to patients see)ing the D#7< approachto autism.

"iochemical Conte#t And Clinical $se %f&ethylcobalamin

=or years ! have prescribed vitamin B12, administered orally, sublingually, or by inection. ! haveused it for a number of disorders, none of which were autism until 1:::. !n the past ! referred to>B12> in a generic sense, assuming that there was no difference clinically between using any of

its three easily available forms? cyanocobalamin, hydroycobalamin, and methylcobalamin. 7ow,four years after beginning to treat autism with >B12> ! hold a very different view, that view beingthe methylcobalamin form of B12 holds the greatest promise for treating children on the autisticspectrum.

(hough methylcobalamin has never been studied for its effects on autism, this presentation willdemonstrate that the literature cites many studies performed on humans, animals, or in laboratorysettings that indicate positive results from several disorders that share similar symptoms orpathophysiology. (he results of my study using inectable methylcobalamin for @5 children whocarry the diagnosis of #utism, &DD, or #spergerAs syndrome will be presented. # literature reviewwill discuss the profound effects methylcobalamin has on the central and peripheral nervoussystems, the cellular and humoral immune systems, on sleep*wa)e cycles, and on detoificationbiochemistry. 8ethylcobalaminAs biochemistry and its )ey role in methylation will be discussed as

it applies to the formation of purines, pyrimidines, and nucleic acids. #n attempt will be made topresent a plausible hypothesis why >methylcobalamin loading> spares tetrahydrofolate and methylreserves, thereby resulting in increased D7# and purine synthesis and their secondarybiochemical reactions, total body transmethylation reactions, and detoification biochemistry.

The DAN movement continues to gain momentum among the scientific and lay communitiesvalidating that autism does have a strong biological component that can be manipulated for thebenefit of those afflicted.(he D#7 8anual is replete with references documenting reasons whyD#7 &ractitioners who treat children from this biological"biochemical paradigm often obtainresults. nfortunately the results reveal varying degrees of mied successes and failures. !t ispossible that our failures and"or limited degrees of success are at least partially due from the factthat we are ust now beginning to understand some of the )ey biochemical pathways involved inour childrenAs bodies. $o much more research needs to be done to predict which children mayrespond to which therapies. nfortunately none of the childrenAs bodies have read the literature orthe biochemical tetboo)scobalamin>' with its scientific conclusions shares a consensus opinion amongscientists as to its mechanism of action. B12"cobalamin has a comple ring structure with an ionof cobalt found at its core. !t can only be synthesiCed by microorganisms and would pose a


19/49

problem for vegans to avoid a deficiency condition ecept for food contamination that isubi+uitous and cannot be avoided. Dietary sources are richest in liver and yeast. # substance)nown as intrinsic factor, derived from the parietal cells in a healthy stomach, are re+uired forabsorption to ta)e place in the distal portion of the small intestine, the terminal ileum. 4nceabsorbed, (ranscobalamin !! carries cobalamin to the liver and tissues. !n the liver, cobalamin isstored by attaching to (ranscobalamin !. obalamin is uni+ue in its ability as a water*solublevitamin to be stored in the liver rather than being +uic)ly lost from the body.

(hree forms of cobalamin eist? cyanocobalamin, hydroycobalamin, and methylcobalamin. (hecyano form is the most common form, the least epensive commercially available form, but it isnot natural to the body. ydrocobalamin is primarily found in the cytoplasm where it is convertedinto its active coenCyme forms? adenosylcobalamin coenCyme %desoyadenosylcobalamincoenCyme' and methylcobalamin coenCyme. #denosylcobalamin coenCyme moves into themitochondria and remains fairly stationary in that location while methylcobalamin coenCyme is thecobalamin coenCyme form that either remains in the cytosol or is returned to the plasma fortransport to other tissues.

!n the mitochondria, adenosylcobalamin coenCyme acts in concert with the enCymemethylmalonyl*o# mutase on the substrate methylmalonic acid to form succinic acid. $uccinic

acid is an important component of the rebs cycle and gluconeogenesis. !t is plausible, thoughnot proven, that the fre+uent reports of >increased energy> clinicians hear from patients receivingB12 inections may partially be the result of this biochemical pathway. #nother possible reasoncould be the role of adenosylcobalamin coenCyme in the mitochondria and the mitochondriaAsprimary role in energy metabolism that begins with glucose and ends in the formation of #(&.=rom my study, it is possible that this glucose*inducing function supplying increased fuel to thebrain was one of the reasons parents fre+uently reported higher cognitive abilities in theirchildren.

(he hydroycobalamin"methylcobalamin coenCyme reactions are more complicated. =irst, in thepresence of ade+uate hydroycobalamin and the enCyme methyl*tetrahydrofolate reductase, themethyl group from methyl*tetrahydrofolate is transferred to hydroycobalamin to becomemethylcobalamin coenCyme. 7otice that two things are happening at once. =irst,

methylcobalamin coenCyme, in the presence of the enCyme methionine mutase, immediatelypasses its newly ac+uired one*carbon methyl group to homocysteine to regenerate the essentialamino acid methionine. 8ethionine is then +uic)ly converted to $*adenosylmethione %$#8', a)ey player in the bodyAs overall methylation biochemistry. $econd, methyl*tetrahydrofolate, bylosing its one carbon methyl group to methylcobalamin, now becomes tetrahydrofolate. !t is thisend product, tetrahydrofolate that is vital to the formation of purines, pyrimidines, and nucleicacids.

obalamin">B12> deficiency leads to three problems. =irst, when adenosylcobalamin coenCyme isdeficient, the substrate methylmalonic acid cannot be converted into succinic acid. (hereforelevels of methylmalonic acid with continue to increase and spill over into the urine, a phenomenon)nown as methylmalonic aciduria. $econd, when the methylcobalamin coenCyme is deficient, thesubstrate homocysteine cannot be converted to methionine. (herefore levels of homocysteine willcontinue to increase and may be seen in the blood or urine resulting in homocystinemia andhomocystinuria respectively. (hird, a phenomenon )nown as >folate trapping> occurs whenhydroycobalamin is deficient in the presence of ade+uate methyl*tetrahydrofolate. Ehen thissituation occurs, the methyl group on methyl*tetrahydrofolate is trapped because >it wants toleave %to become tetrahydrofolate' but canAt get away>.

Between 8ay 2002 and 8arch 200F ! obtained data on @5 children with the diagnosis of #utism,&DD, or #spergerAs syndrome. (he study was an open trial using inectable methylcobalamin.hildren ranged in age from 2 to 1: with the maority between ages F and G. (he inections werestarted when the children were stable and not ma)ing other significant changes to their therapies,


20/49

either biological or non*biological. =ollow*up was done every G wee)s with me, either in person orby telephone. &arents were instructed to write a letter describing what they saw happening withtheir children. (hese letters from parents were to be spontaneousand written >in their ownwords>. (herefore the parentAs responses were not "directed" by a uestionnaire. (he parentswere instructed that conclusions or summary statements were all right to give but only if theygave as many specific eamples as possible describing why they arrived at the conclusions thatthey did.

4f the @5 children included in the study, H1 were males and 1/ were females. =ifty*one males%H2;' and 12 %@G;' females responded. %(he number of females was probably too small for thepercentage of responders to be meaningful.' #pproimately 50; of the parents reported 15 ormore symptoms improved. $ity*seven urinary 88#As were performed of which @1; werenegative in the total group of GH and @0; were negative in the responders group. =orty*ninehomocysteine levels were performed of which :0; were negative in the total group of /: and:2; were negative in the group of responders. (herefore, it was my conclusion that the current>gold standard> lab tests documenting B12 deficiency as we presently define it has no predictivevalue as to which children may or may not respond to methylcobalamin therapy.

The "Top Ten" symptoms parents reported had improved are as follow: a) Language andCommunication !# $) Awareness % c) Cognition and Higher Levels of Cognition and'easoning &(# d) ngagement *+# e) ye Contact +# f) etter ehavior + g) -ore.ocused + h) /reater Understanding + i) 0ocali1ation + 2) Trying 3ew Things++4 4ther significant and surprising symptom improvements included many parents stating thattheir child? >Eas much happier, much more affectionate %even if her or she already wasaffectionate', much more interactive, calmer, more resilient to changes in routines had morespontaneous speech, began to use pretend play or fantasy, was able to finally sit at the table withthe family and"or sit and attend to a tas)>, etc. (here were over 100 different symptomimprovements parents reported %for a complete list, see the slide presentation in this syllabus'.$ide effects were few the primary one of hyperactivity was reported in 10;. (he second mostcommon problem was sleep disturbance, this being reported in G; of the children. 4ften giving

the inections in the morning instead of at bedtime alleviated this problem. Eith only oneeception, parents stated that the positives so far outweighed the negatives that they would dealwith the negatives, e.g. hyperactivity. (he one eception was a child who responded positively toover 20 symptoms but developed a severe sleep problem over a period of G wee)s.

Ehen first deciding to do the study, the route of administration was discussed with manycolleagues. 8y final decision, for several reasons, was to perform the original study using aninectable form. (he literature admits that the absorption of B12 is a "comple! process" involvingnumerous physiological and biochemical steps.(hese steps include binding to saliva, formationof intrinsic factor from healthy gastric parietal cells, proper stomach acid release, properpancreatic protease release, a healthy terminal ileum, the appropriate mi of intestinalmicroorganisms, enterocytes properly functioning, etc. #s ! contemplated our children, it was myconclusion that most of them chew poorly and therefore would have minimal salivary binding of

cobalamin. undreds of nutritional analyses gathered from this population have repeatedlydemonstrated poor nutritional status with inade+uate amounts of protein, carbohydrate, andessential fatty acids, the re+uired precursor building bloc)s of healthy cells. (herefore there wasno guarantee that the children would be able to meet the re+uirements necessary for >functionalrelease> of gastric acid or intrinsic factor. #lso, due to the belief shared by D#7 practitioners thatinappropriate functional release of pancreatic enCymes often eists %consider the Iepligen studyand the positive benefit of secretin in some children', there was no way to insure ade+uatedigestive enCyme function. #s previously demonstrated and"or continues to be documented bythe wor) of Ea)efield, rigsman, and Buie, the terminal ileum is fre+uently inflamed anddemonstrates varying degrees of ileitis. (his finding alone was enough to eclude the oral route


21/49

of administration as a valid >initial step> in determining the potential effectiveness ofmethylcobalamin therapy for my study. 4ther factors ! had to consider included dysbiosis and themi of microorganisms in the terminal ileum that may interfere with my ability to )now the >doseabsorbed> by the child relative to the >dose produced> by microorganisms and"or the >doseadministered> by me. (herefore, it was my strong opinion then %and even stronger now' that until !answered the first +uestion definitively Jemdash does methylcobalamin play a vital role in theautistic populationK Jemdash that these multiple variables inherent to the gastrointestinal tract,variables that were impossible to predict who suffered from them and variables that wereimpossible to consistently control due to many factors, must be bypassed by inections. !t wasalso my strong conviction that unless the dose and route of administration were fairly free ofvariables, there would be no way to interpret the data to predict optimum dosing or to evaluate achildAs response, either positive or negative.

4nce ! decided to use inectable methylcobalamin, the net dilemma that needed to be addressedwas whether to use the intramuscular intravenous or subcutaneous route of administration.!nitially ! used both the intramuscular and"or subcutaneous routes. owever, within G to @ wee)s itwas my >impression> that ! was getting a higher response rate in the group of children that wereusing the subcutaneous route of administration. ypothetically subcutaneous in#ections may

produce a "slow time$release" process allowing a "leaching effect" of the methylcobalamin. (histheoretically could allow a >relatively higher dose> of the substance to remain in the body forlonger periods of time if this was compared to the in intramuscular or intravenous routes ofadministration. 4ne reason for this is that the )idneys are )nown to +uic)ly clear any ecesscobalamin. Because cobalamin is a red substance, ! have occasionally been called by panic)ingparents reporting >red urine> in their childAs urine who were worried the child was bleeding. ! havenever seen red urine with the subcutaneous route of administration but ! have seen it infre+uentlywith intravenous and intramuscular administration. =ormal research will need to be conducted todetermine whether or not my theory is valid.

8y protocol as of early 7ovember 2002 and the techni+ues ! had the parents use can be seen indetail on the slides that follow. !t should be noted that this protocol is in a dynamic state ofchangeas ! continue to search for >the optimum dose and the ideal fre+uency of inections>.Ehen ! advised parents to give doses lower than H5 mcg per )ilogram, there was a lowerpercentage of responders and there was a different >mi> of symptoms improved. &arents nolonger seemed to report improvements from the >top 10> symptom response list thataccompanies my higher dose protocol. !nstead, there were only minor symptom improvements,e.g. >he seems to have more energy>. 8ost parents that stopped the inections because they didnot see what they believed to be significant degrees of improvement usually were on the phonewithin 2*/ wee)s begging to restart the inections because their children regressed. (he mostcommon >regressions> reported were language, awareness, and cognition Jemdash these werealso my >Big (hree> ** the symptoms most commonly reported to improve catalysis by cobalamin+dependent

en)ymes-#nnu Iev Biochem. 200FH2?20:*/H.Vitamin "/2 is a comple# organometallic cofactor associated with threesubfamilies of en)ymes> the adenosylcobalamin+dependent isomerases'the methylcobalamin+dependent methyltransferases' and thedehalogenases- =ifferent chemical aspects of the cofactor are e#ploitedduring catalysis by the isomerases and the methyltransferases- Thus' thecobalt+carbon bond ruptures homolytically in the isomerases' whereas it is
http://www.raysahelian.com/homocysteine.htmlhttp://www.raysahelian.com/homocysteine.htmlhttp://www.raysahelian.com/methyl.htmlhttp://www.raysahelian.com/sam-e.htmlhttp://www.raysahelian.com/lipoic.htmlmailto:[email protected]://www.raysahelian.com/http://www.raysahelian.com/homocysteine.htmlhttp://www.raysahelian.com/methyl.htmlhttp://www.raysahelian.com/sam-e.htmlhttp://www.raysahelian.com/lipoic.htmlmailto:[email protected]://www.raysahelian.com/


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cleaved heterolytically in the methyltransferases- The reaction mechanismof the dehalogenases' the most recently discovered class of "/2 en)ymes'is poorly understood- %ver the past decade our understanding of thereaction mechanisms of "/2 en)ymes has been greatly enhanced by theavailability of large amounts of en)yme that have afforded detailed

structure+function studies' and these recent advances are the sub,ect ofthis review-

Cobalamin+dependent methyltransferases-#cc hem Ies. 2001 #ugF/%@'?G@1*:.Cobalamin cofactors play critical roles in radical+cataly)ed rearrangementsand in methyl transfers- This Account focuses on the role ofmethylcobalamin and its structural homologues' the methylcorrinoids' asintermediaries in methyl transfer reactions' and particularly on the reactioncataly)ed by cobalamin+dependent methionine synthase- In these methyltransfer reactions' the cobalt5I6 form of the cofactor serves as the methyl

acceptor- "iological methyl donors to cobalamin include 4+methyltetrahydrofolate' other methylamines' methanol' aromatic methylethers' acetate' and dimethyl sulfide- The challenge for chemists is todetermine the en)ymatic mechanisms for activation of these unreactivemethyl donors and to mimic these ama)ing biological reactions-

1ffects of vitamin "/2 on performance and circadian rhythm in normalsub,ects-7europsychopharmacology. 1::G 7ov15%5'?/5G*G/.This preliminary study investigates effects of methyl+ and cyanocobalaminon circadian rhythms' well+being' alertness' and concentration in healthy

sub,ects- 7i# women 5mean age ! years6 and /; men 5mean age !@ years6were randomly assigned to treatment for /; days with ! mg cyano+5C"/26or methylcobalamin 5&"/26 after days of pre+treatment observation-3evels in the C"/2 group increased rapidly in the first' then slowly in thesecond treatment wee0' whereas increase in the &"/2 group was linear-$rinary a&T


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Coen)yme "/2 5cobalamin6+dependent en)ymes-ssays Biochem. 1:::F/?1F:*5/.The "/2 or cobalamin coen)ymes are comple# macrocycles whosereactivity is associated with a uni(ue cobalt+carbon bond- The twobiologically active forms are methylcobalamin and AdoCbl and their closely

related cobamide forms- &ethylcobalamin participates as the intermediatecarrier of activated methyl groups- =uring the catalytic cycle the coen)ymeshuttles between methylcobalamin and the highly nucleophilic cob5I6alaminform- 1#amples of methylcobalamin +dependent en)ymes includemethionine synthase and &e+H;+&BT> coen)yme & methyl transferase-AdoCbl functions as a source of carbon+based free radicals that areunmas0ed by homolysis of the coen)yme8s cobalt+carbon bond- The freeradicals are subse(uently used to remove non+acid hydrogen atoms fromsubstrates to facilitate a variety of reactions involving cleavage of carbon+carbon' carbon+o#ygen and carbon+nitrogen bonds- &ost reactions involve/'2 migrations of hydro#y+' amino+ and carbon+containing groups' but there

is also one class of ribonucleotide reductases that uses AdoCbl- Thestructures of two cobalamin+dependent en)ymes' methionine synthase andmethylmalonyl+CoA mutase' have been solved- In both cases the cobalt isco+ordinated by a histidine ligand from the protein- The significance of thisbinding motif is presently unclear since in other cobalamin+dependenten)ymes spectroscopic evidence suggests that the coen)yme8s nucleotide8tail8 remains co+ordinated to cobalt when bound to the protein-

8ost #mericans can6t do it

because they aren6t getting any8(LM4B#M#8!7$tress, obesity, infections, hormones, or alcoholan !7I#$ your ris) of

1.ancer2. DementiaF. Depression/. eart disease

Vitamin B*12 =olatean DI#$ your ris) of

1.ancer2. Dementia


26/49

F. Depression

/. eart disease

ou may want to get all the Vitamin "+/2 and folate you need from what you8re eating or byta0ing your multivitamin- "ut' you8re really 4%T getting what you need-

If you want to combat the ris0s of stress' obesity' infections' hormones' or alcohol' you needto learn about medical brea0throughs that ta0es you beyond homocysteine and cholesterol-They empowers you in your efforts to stay healthy- They help you ma0e the most of your od+given abilities' ma#imi)ing your performance-

8ethylcobalamin is the most potent form of Vitamin B12found in nature. Ee need methylcobalamin for thehealthy development and sustenance of our circulatory,

immune and nervous systems.

ggs, dairy products, fish and meat, especially organmeat li)e liver, are good sources of Vitamin B*12. !nfact, meals incorporating large amounts of liverrepresented the main treatment for Vitamin B*12deficiency in the past.

8ethylcobalamin is the only active form of Vitamin B*12in the brain outside the mitochondrion. (he liver mustconvert cyanocobalamin to methylcobalamin in order forVitamin B*12 to do its biochemical wor) in the brain.Ehen the comple conversion of cyanocobalamin is notcompleted, the brain is robbed of the benefits ofmethylcobalamin. yanocobalamin is a by*product of

Vitamin B*12 charcoal etraction. $cientific methods ledpeople to believe that cyanocobalamin, notmethylcobalamin was the naturally occurring form ofVitamin B*12. yanide in the charcoal replaces themethyl group in much the same way as it does in thebody of a cigarette smo)er. Vitamin B*12 re+uires the


27/49

assistance of !ntrinsic =actor to enter the body from thesmall intestine. Eithout !ntrinsic =actor, dietary VitaminB*12 or B*12*containing supplements go unabsorbed.

#utoimmune reactions and diseases sometimes destroythe stomach6s parietal cells that produce !ntrinsic =actor.&ernicious anemia results from this destructive process.8ore rarely, pernicious anemia develops when the bodyma)es antibodies against the binding site of !ntrinsic=actor. (he antibodies rob Vitamin B*12 of the binding

spot on !ntrinsic =actor as it tries to ma)e its way intothe small intestine. 8onthly inections of Vitamin B*12can correct the anemia, immune and neurologicalproblems that snea) up on people with perniciousanemia.

$urveys of depressed patients indicate nearly one*thirdof them do not receive enough folic acid or Vitamin B*

12. !t is etremely important to ta)e Vitamin B*12 whenta)ing folic acid supplements. Eithout Vitamin B*12supplementation, worse physical problems mightdevelop during folic acid supplementation.

$mall amounts of Vitamin B*12 are absorbed directlythrough the mucosal tissue of the mouth. (his discoveryled to the development of Vitamin B12 loCenges and

sprays. Ehen Vitamin B*12 is absorbed in the mouth, itgoes into the blood and then to the enCymes thatre+uire Vitamin B*12 as a coenCyme. Eith other formsof Vitamin B*12, the liver must use its enCyme systems


28/49

to produce methylcobalamin.

Eith increased availability of methylcobalamin, medical

research has shown that methylcobalamin hasimportant benefits not seen with cyanocobalamin. !t actsto reverse nerve damage and promote nerve cellregeneration.

8ethylcobalamin plays a )ey role in sleep. !t helps thebrain fill up its neurotransmitter >gas tan)> whenneurotransmitters are produced from amino acids.

$imilarly, depression also improves more +uic)ly andcompletely when patients ta)e methylcobalamin.Depression also can worsen even while usingantidepressants if a restrictive diet is started to loseweight. # diet can run the neurotransmitter >gas tan)>dry.

omocysteine has emerged on center*stage as abiochemical culprit associated with vascular and braindisease. Vitamin B*12 and folic acid are crucial to theelimination of homocysteine. Vitamin supplementationreduces the chances of building up levels ofhomocysteine associated with stress.

linical eperience and scientific research have clearly

established the importance of Vitamin B*12. (hediscovery of Vitamin B*12 was considered somonumental that the responsible researchers werehonored with the 7obel &riCe. Iecent discoveries havedemonstrated the value of using methylcobalamin for


29/49

improvement in the cardiovascular, immune andnervous systems.N

Efficacy of methylcobalamin on lo-erin& total homocy!teine pla!ma concentration! in

haemodialy!i!

patient! recei.in& hi&h'do!e folic acid !upplementation+8ephrol 2ial Transplant/ (..( May #&"-') $#G82) Hyperhomocysteinaemia! which is considered to be induced by impairment of

the

remethylation pathway in patients with chronic renal failure "C9F'! cannot be cured solely by

folic acid therapy/

In the present study! we in,estiated the additional benefit of administration of methylcobalamin!

which is a coen:yme

in the remethylation pathway! on lowerin total homocysteine "tHcy' plasma concentrations in

haemodialysis "H2' patients recei,in hih+dose folic acid supplementation/ M@TH>2S) In

order to assess theefficacy on lowerin plasma tHcy le,els "fastin concentration'! (# H2 patients! were randomly

assined andpro,ided folic acid supplementation) #- m1day orally "roup I! n 4 &' methylcobalamin -.. m

intra,enously

after each H2! in addition to folic acid "roup II! n 4 &' or ,itamin 5"


30/49

administration of methylcobalamin and supplementation of folic acid reardless of whether there

was

supplementation of ,itamin 5"


31/49

Cyanocobalamin "C8+Cbl' is the most commonly supplemented form of

,itamin 5#(! but it is present in the body in trace amounts and its biochemical

sinificance remains uncertain/ Althouh the amount of cyanide is considered

to7icoloically insinificant! humans must remo,e and deto7ify the cyanide

molecule! reduce the cobalamin to its usable 0# o7idation state! and then

en:ymatically con,ert the cobalamin into one of two metabolically acti,e

coen:yme forms/ 8utritional inade6uacies! en:yme defects! and patholoical

chanes to tissues can all contribute to a reduced ability of the body to

accomplish the synthesis of the acti,e forms of ,itamin 5#( from C8+Cbl/

The two forms of ,itamin 5#( ha,in acti,ity in 5#(+dependent en:ymes

within the human body are adenosylcobalamin "AdeCbl' and methylcobalamin

"MetCbl'/ AdeCbl is occasionally referred to as coen:yme 5#(! cobamamide!

cobinamide! or dibenco:ide/ In some biochemical or therapeutic situations! the

clinical utili:ation of either AdeCbl or MetCbl "alone or in combination' can

produce results not found with the supplementation of either C8+Cbl or

hydro7ycobalamin ">H+Cbl'/

Biochemi!try2 Metaboli!m2 and En3yme unction!

Cobalamin is a ,ery comple7 molecule! containin cobalt surrounded by fi,e

nitroen atoms/ Surroundin this central cobalt is a corrin rin! which

structurally resembles the porphyrin rin found in hemolobin! the

cytochromes! and chlorophyll/ The use of cobalt in the coen:yme forms of

cobalamin is the only known function of this metal in bioloical systems/

In humans! the cobalt in the coen:yme forms of ,itamin 5#( e7ists in a

uni,alent "0#' o7idati,e state! desinated as cob"I'alamin/ Cobalamin

molecules can also contain cobalt in a 0* "cob"III'alamin' or 0(

"cob"II'alamin' o7idati,e state howe,er! in these forms the cobalt must be

reduced prior to ha,in en:yme acti,ity/

The compound most commonly referred to as ,itamin 5#( is C8+Cbl

howe,er! this molecule does not occur naturally in plants! micro+oranisms! or

animal tissues/#C8+Cbl has a cyanide molecule at the metal+carbon position

and its cobalt atom e7ists at an o7idati,e state of 0*! not the bioloically acti,e

0# state/ In order to be utili:ed in the body! the cyanide molecule must be

remo,ed and eliminated throuh phase II deto7ification/ It is thouht that

lutathione "SH' miht be the compound performin the function of

decyanation in ,i,o! since lutathionylcobal+amin "S+Cbl' has been isolated

from mammalian tissue/(If! in fact! SH is needed as a cofactor to acti,ate


32/49

C8+Cbl to the coen:yme forms of ,itamin 5#(! clinical situations characteri:ed

by decreased tissue le,els of SH miht be e7pected to result in a functional

deficiency of ,itamin 5#(! e,en in the presence of ade6uate plasma or tissue

le,els of the cobalamin moiety "typically labs are lookin only for a cobalamin

moiety and do not differentiate between C8+Cbl and the acti,e forms of

,itamin 5#('/

Humans are incapable of synthesi:in the corrin rin structure! and so are

completely dependent upon dietary sources of ,itamin 5#(/ The ultimate

source of all ,itamin 5#( occurrin in the diet is bacteria! with animal products

pro,idin the majority of the dietary intake/ It had been proposed that humans

could absorb ,itamin 5#( formed by colonic flora howe,er! this appears to be

untrue since no sinificant amount of cobalamin can be absorbed in the colon/#

The optimal absorption of dietary ,ita+min 5#( re6uires the formation of a

comple7 between dietary cobalamins and 9+proteins! and the secretion! by thestomach parietal cells! of intrinsic factor/ The cobalamin+9+protein comple7 is

diested by pancreatic en:ymes in the small intestine! and the released

cobalamin molecule binds with intrinsic factor and is absorbed in the distal

ileum/ Cobalamin is then detached from intrinsic factor in the enterocyte cells

of the small intestine! and is bound to transcobalamin II for transport into

tissues/

Althouh the basic cobalamin molecule is only synthesi:ed by micro+

oranisms! all mammalian cells can con,ert it into the coen:ymes AdeCbl and

MetCbl/ >H+Cbl! MetCbl! and AdeCbl are the three forms of cobalamin most

fre6uently isolated from mammalian tissue/ Howe,er! only MetCbl and AdeCbl

actually function as cofactors in human en:ymes/ AdeCbl is the major form in

cellular tissues! where it is retained in the mitochondria/ MetCbl predominates

in blood plasma and certain other body fluids! such as cerebral spinal fluid! and!

in cells is found in the cytosol/*

AdeCbl functions in reactions in which hydroen roups and oranic roups

e7chane places/ In humans! AdeCbl is re6uired for the en:yme

methylmalonyl+CoA mutase which is used in the catabolic isomeri:ation of

methylmalonyl+CoA to succinyl+CoA "used in the synthesis of porphyrin' and

as an intermediate in the deradati,e pathway for ,aline! isoleucine! threonine!

methionine! thymine! odd+chain fatty acids and cholesterol/#2eficiencies in this

coen:yme form of ,itamin 5#( result in increased amounts of methylmalonyl+

CoA and enerally in an increase in lycine/


33/49

MetCbl;s only known bioloical function in humans is as a cofactor in the

en:yme methionine synthase/ The methionine synthase en:yme is located in the

cytosol of cells and participates in the transfer of methyl roups from -+

methyltetrahydrofolate to homocysteine! resultin in the subse6uent

reeneration1remethylation of methionine/

?e:acka et al ha,e proposed that at least four steps are re6uired to con,ert

supplementary C8+Cbl to the coen:yme forms of ,itamin 5#(/ These are) "i'

decyanation "ii' reduction of the 0* and 0( forms "iii' synthesis of MetCbl in

the cytosol and "i,' synthesis of AdeCbl in the mitochondria/ The initial step

of decyanation is probably dependent on SH! possibly in combination with

8A2?H and FA2/( This results in the formation of cob"III'alamin/ >H+Cbl is

also a cob"III' form but has an ad,antae o,er C8+Cbl since it bypasses the

need for decyanation/ The ne7t step re6uired is the reduction of cob"III'alamin

to cob"II'alamin/ This reduction is probably dependent upon 8A2H and

possibly either FA2 or FM8/(>nce cob"II'alamin is formed! a similar

reduction can shunt it into the formation of cob"I'alamin and subse6uently!

with AT?! AdeCbl/ An alternate pathway can! with the donation of a methyl

roup from S+adenosylmethionine "SAM'! result in the formation of MetCbl

from cob"II'alamin/ MetCbl becomes cob"I'alamin after donatin its methyl

roup howe,er! MetCbl can be reenerated! by acceptin a methyl roup from

-+methyltetrahydrofolate! for reuse in methionine synthase "see fiure #/'/

@,idence indicates alpha+tocopherol protects aainst a reduction in AdeCbl in

o7idati,ely stressed cells/3@7perimental e,idence suests alpha+tocopherol

miht be needed for formation of AdeCbl howe,er! further studies are re6uired

to clarify this relationship/ If alpha+tocopherol is used in the reducin steps! a

deficiency would be e7pected to decrease the formation of both AdeCbl and

MetCbl/-

It is important to be aware that nitrous o7ide inacti,ates the coen:yme forms of

,itamin 5#( by o7idi:in cob"I'alamin to either cob"II'alamin or

cob"III'alamin/ 8itrous o7ide also interferes with the acti,ity of methio+nine

synthase/


34/49

physioloical situations intrinsic factor probably partially protects MetCbl from

deradation/ ?aper chromatoraphy of diested ileal mucosa has demonstrated

unchaned absorption of MetCbl followin oral administration/ The 6uantity of

cobalamin detected followin a small oral dose of MetCbl is similar to the

amount followin administration of C8+Cbl but! sinificantly more cobalamin

accumulates in li,er tissue followin administration of MetCbl/ Human urinary

e7cretion of MetCbl is about one+third that of a similar dose of C8+Cbl!

indicatin substantially reater tissue retention/&

In humans! about *- percent of AdeCbl appears to be absorbed intact followin

oral administration! and about && percent of the absorbed oral dose is retained

in body tissues/ Althouh a hiher percentae of C8+Cbl appears to be

absorbed! only -. percent is retained in tissues! and assumin an ade6uate

supply of necessary cofactors is a,ailable! probably is con,erted to the

coen:yme forms of ,itamin 5#( o,er a period of #+( months/%

Althouh indi,iduals with pernicious anemia do not produce the intrinsic factor

needed for ,itamin 5#( absorption! hih doses of oral ,itamin 5#( "abo,e

#... mc' ha,e been shown to be an ade6uate treatment of 5#( deficiency and

pernicious anemia! indicatin there is some mechanism of absorption

independent of intrinsic factor/$!#.It is likely that with supra+physioloical doses

of the coen:yme forms of ,itamin 5#(! some of the absorption is also

independent of intrinsic factor/

Clinical Implication!

Anemia/The use of the coen:yme forms of ,itamin 5#( will be useful in some

types of anemia and miht offer an ad,antae o,er supplementation of the non+

bioloically acti,e forms of ,itamin 5#(/ Gnder e7perimental conditions!

poisonin of rabbits with phenylhydra:ine results in the de,elopment of

hemolytic hyperchromic anemia and impairment of hematopoiesis in the bone

marrow/ A decrease in the MetCbl content of the blood serum is obser,ed

durin spontaneous reco,ery from this e7perimentally induced anemia/

Administration of MetCbl results in a complete normali:ation of some blood

and hematopoiesis patterns! as well as a restoration of total cobalamin content!

and an impro,ed ratio of the spectrum of cobalamin forms/ AdeCbl! althouh

somewhat effecti,e! e7hibited a distinctly lower effect on the patterns studied/ ##

A -.+day treatment with a ferritin preparation combined with folinic acid and

AdeCbl was well tolerated and demonstrated efficacy in normali:in ,arious

hematoloical parameters "hemolobin! hematocrit! red cell count! mean


35/49

corpuscular ,olume! iron! and transferrin iron bindin capacity' in prenant

women/#(ranese et al similarly report a positi,e result from the

supplementation of a ferritin+AdeCbl+folinic acid preparation to 3. women

durin prenancy/ A proressi,e increase in hematoloical parameters was

demonstrated and a complete normali:ation of red cell morpholoy was

obser,ed/#*

Anore4ia/Carnitine and AdeCbl were shown to promote cerebral mass

rowth! increase neocortical layer thickness and pyramidal neuron ,olume! and

fully restore normal structure of the neocorte7 in an e7perimental model of

anore7ia ner,osa/ In patients with anore7ia ner,osa! carnitine and AdeCbl

accelerate body weiht ain and normali:ation of astrointestinal function/

Batent fatiue was reported to disappear and mental performance increase

under this treatment reimen/#3Korkina et al report the combined use of

carnitine and AdeCbl eliminate fluctuations in the work rate and impro,e the

scope and producti,ity of intellectual work in patients with anore7ia ner,osa in

the stae of cache7ia/ Batent fatiue in the population studied was not fully

remo,ed/#-

Children with infantile anore7ia were di,ided into two roups/ >ne roup of

children was i,en (... mc of AdeCbl and #... m of carnitine! while the

other roup was i,en cyproheptadine! an anti+histamine used to stimulate

appetite/ The results of usin the AdeCbl and carnitine mi7ture were juded

ood by the authors! were comparable to the effects of the pharmaceutical

aent! and were produced with no side+effects/#


36/49

It is not surprisin that MetCbl! because of its ability to donate a methyl roup

and because of its role in the reeneration of SAM! the body;s uni,ersal methyl

donor! miht be protecti,e aainst cancer/ Cell culture and in ,i,o e7perimental

results indicate MetCbl can inhibit the proliferation of malinant cells/(#

@7perimental results also indicate MetCbl can enhance sur,i,al time and

reduce tumor rowth followin inoculation of mice with @hrlich ascites tumor

cells/(( 5oth of the coen:yme forms of ,itamin 5#( ha,e been shown to

increase sur,i,al time of leukemic mice/ Gnder the same e7perimental

conditions! C8+Cbl was inacti,e/(*

Althouh more research is re6uired to ,erify findins! MetCbl miht also

enhance the efficacy of methotre7ate/ MetCbl appears to stimulate the rate of

*H+methotre7ate influ7 into tumors in e7perimental animals/ Miasishche,a et

al ha,e suested! based on kinetic analysis! a dose of ./.# m1k of MetCbl

miht be an optimal dose for impro,in the antitumor dru action of

methotre7ate/(3

Heimburer et al ha,e reported that in a preliminary study! four months;

treatment with #. m of folate plus -.. mc of >H+Cbl resulted in a reduction

of atypia in male smokers with bronchial s6uamous metaplasia/(-Since folate

and cobalamin interact in re+methylation! it is possible MetCbl would ha,e

worked as well or better than the >H+Cbl/

Diabetic Neuropathy/Ya6ub et al conducted a double+blind study on the

clinical and neurophysioloical effects of MetCbl administration in -. patients

with diabetic neuropathy/ @ach patient in the acti,e roup was i,en -.. mc

of MetCbl orally three times per day for four months/ Indi,iduals recei,in

MetCbl reported subjecti,e impro,ement in somatic and autonomic symptoms

"parasthesias! burnin sensations! numbness! loss of sensation! and muscle

cramps'! and reression of sins of diabetic neuropathy "refle7es! ,ibration

sense! lower motor neuron weakness! and sensiti,ity to pain'/ Howe,er! motor

and sensory ner,e conduction studies showed no statistical impro,ement after

four months/ MetCbl was well tolerated by the patients and no side+effects

were encountered/(


37/49

Eye function/@7periments indicate chronic administration of MetCbl protects

cultured retinal neurons aainst 8+methyl+2+aspartate+receptor+mediated

lutamate neuroto7icity/ Kikuchi et al suest the action is probably due to

alteration in the membrane properties mediated throuh methylation by SAM/

In their e7periments! an acute e7posure to MetCbl was not effecti,e in

protectin retinal neurons/(%9esults also indicate MetCbl enhances the ability

to e,oke a field potential in rat suprachiasmatic nucleus slices/ C8+Cbl had no

acti,ity in this e7perimental model/($

Iwasaki et al studied the effect of MetCbl on subjects with e7perimentally

induced deterioration of ,isual accommodation/ The authors report the

deterioration of accommodation followin ,isual work was sinificantly

impro,ed in indi,iduals recei,in MetCbl/*.

0enital')rinary/Administration of (1k of di"(+ethylhe7yl'+phthalate

"2@H?' induces se,ere testicular atrophy! reduction of testicular specificlactate dehydroenase acti,ity! and decreased :inc! manesium and potassium

concentrations in rats/ Co+administration of AdeCbl with 2@H? is reported to

pre,ent these chanes/ MetCbl! when co+administered with 2@H?! was unable

to pre,ent the testicular atrophy induced by 2@H? under similar e7perimental

conditions/*#

Thirty+nine patients with dianosed olio:oospermia were di,ided into two

roups and administered MetCbl at a dose of either < m or #( m per day for

#< weeks/ MetCbl appeared to be transported to seminal fluid ,ery efficiently!

and no dose+dependent difference between ,itamin 5#( concentrations in the

serum or seminal fluid was obser,ed between roups/ The efficacy rate for the

roup recei,in < m per day was *&/- percent and for the roup recei,in #(

m per day was *$/# percent/*(

MetCbl was administered daily "#!-.. microrams1day! for 3+(3 weeks' to (T'! serum lutamic pyru,ic transaminase

"S?T'! and alkaline phosphatase ,alues/ The AdeCbl was administered i/m/ at

a dose of # m per day for the first #( days and then orally for the ne7t #( days/

After (3 days total bilirubin was normal in #*1#%! S>T in #-1#%! S?T in

#.1#%! and alkaline phosphatase in #%1#% subjects recei,in AdeCbl/3T!

S?T! and total bilirubin ,alues in patients with a ,ariety of acute li,er

diseases/ In their study! one roup of patients recei,ed the e7tracts "@' and

another roup of patients recei,ed the e7tracts plus AdeCbl "@ 0 C'/ After (#

days of supplementation! total bilirubin! S>T and S?T were normali:ed in

#% of (. patients in the @ 0 C roup/ Correspondin ,alues in the roup

recei,in @ alone were #-1(.! #*1(.! and #(1(./3&Teti et al ha,e similarly

reported impro,ements in parameters of li,er function followin administration

of a comple7 containin * m of AdeCbl/3%

%leep Di!turbance!/The use of MetCbl in the treatment of a ,ariety of sleep+

wake disorders is ,ery promisin/ Althouh the e7act mechanism of action is

not yet elucidated! it is possible MetCbl is needed for the synthesis of

melatonin! since the biosynthetic formation of melatonin re6uires the donation

of a methyl roup/ 5ased on a,ailable information! MetCbl appears to be

capable of modulatin melatonin secretion! enhancin liht+sensiti,ity! and

normali:in circadian rhythm/


41/49

Gchiyama et al ha,e reported that intra,enous injections of MetCbl increased

rectal temperature in the later hours of the daytime and correspondinly

impro,ed alertness! as assessed with a ,isual analo scale! durin the same time

inter,al/ They suest these obser,ations were mediated by an effect of MetCbl

on the circadian clock/3$

Tomoda et al report a case of a #*+year+old male with adrenoleukodystrophy

who had de,eloped a sleep+wake disorder subse6uent to his complete loss of

,ision/ His sleep+wake cycle had been (- hours howe,er! followin

administration of MetCbl! his sleep+wake rhythm was normali:ed/ After

MetCbl therapy! circadian rhythms in his plasma melatonin and beta+endorphin

le,els appro7imated those of healthy ,olunteers! and his peak cortisol time

shifted backward/-.

Yamada et al ha,e reported the successful treatment of a *(+year+old male

patient! who had suffered from recurrent hypersomnia for #( years! withadministration of MetCbl/ 2urin this period of time! the indi,idual had

e7perienced se,eral episodes of hypersomnia! lastin a few days at a time!

reoccurrin each year/ The indi,idual had also reported the fre6uency of these

episodes had increased durin the past two years/ MetCbl was administered for

si7 months! durin which time no episodes of hypersomnia were e7perienced/

After cessation of treatment! o,er a follow+up obser,ation period of #& months!

no episodes of hypersomnia were noted/-#

>hta et al report that two adolescent patients sufferin from persistent sleep+

wake schedule disorders appear to ha,e responded to treatment with MetCbl/ In

this report! a #-+year+old irl dianosed with delayed sleep phase syndrome

"2S?S' and a #&+year+old boy with free+runnin sleep+wake rhythm

"hypernychthemeral syndrome'! had consistently complained of not bein able

to attend school despite trials of se,eral different medications/ Immediately

followin administration of * m1day of MetCbl! an impro,ement of both

sleep+wake rhythm disorders was obser,ed/ Serum concentrations of ,itamin

5#( durin treatment were in the hih rane of normal or abo,e normal/ The

duration of the sleep period of the 2S?S patient decreased radually from #.

hours to & hours! and the time of sleep onset ad,anced from ( a/m/ to midniht/The period of the sleep+wake cycle of the hypernychthemeral patient was (3/

metikobal dr hepi m

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