Methylcobalamin and Diabetic Neuropathy

Clinical usefulness of intrathecal injection of Methylcobalamin in patients with diabetic neuropathy Ide H Fujiya S Asanuma Y Tsuji M Sakai H A ishi Y! Clin Ther "#$%&' $"(')#%*+$( Se,en men and four women with symptomatic diabetic neuropathy were treated with Methylcobalamin "(!-.. micro rams in #. ml of saline' injected intrathecally/ Treatment was be un when patients had ood metabolic control! as determined by measurements of plasma lucose and hemo lobin! and was repeated se,eral times with a one+month inter,al between injections/ Three patients were re+treated one year after the last intrathecal injection/ Symptoms in the le s! 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 chan e si nificantly/ The mean "01+ S2' concentration of Methylcobalamin in spinal fluid was ##3 01+ *( p 1ml before intrathecal injection "n 4 -' and 3!&-( 01+ (!-.3 p 1ml one month after intrathecal Methylcobalamin treatment "n 4 ##'/ Methylcobalamin caused no side effects with respect to subjecti,e symptoms or characteristics of spinal fluid/ These findin s su est that a hi h concentration of Methylcobalamin in spinal fluid is hi hly effecti,e and safe for treatin the symptoms of diabetic neuropathy/ METHYLCOBALAMIN Methylcobalamin is the neurolo ically 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 neurolo ical defects/ Animal studies ha,e shown that hi h doses of methylcobalamin are effecti,e in neuron re eneration 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,idence su ests that oral 5#( works as well as injections! accordin to a study published in the journal 5lood +but hi h doses must be taken/ This ,erifies reports from Sweden datin from the #$&.s that pernicious anemia! a disease of 5#( deficiency! can be controlled with 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 emer ed 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! (!... micro rams1day of oral 5#( cures the symptoms of 5#( deficiency! includin ele,ated homocysteine! neurolo ical problems! and ele,ated methylmalonic acid "a marker of 5#( deficiency'/ The oral ,ersion works as well as injections! with the added feature of maintainin hi h 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

injections dropped and stayed at a plateau! whereas blood le,els of those recei,in oral 5#( continued to rise/ 5#( lowers homocysteine Althou h 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 hi h as #&- micromoles per liter "the optimal safe ran e for homocysteine is under <'/ In the case of one patient! (!... micro rams of oral 5#( for four months reduced their homocysteine from ##*/3 micromoles per liter to %/(/ Injected 5#( also si nificantly reduced homocysteine + the main difference bein that the injected ,ersion worked faster/ Interestin ly! some of the patients did not respond to supplemental ,itamin 5#(/ It was disco,ered that they were also deficient in folate! and until folate was replaced! their homocysteine remained ele,ated/ =itamin 5#( and folate work syner istically in the chemical reactions that recycle homocysteine back to methionine in the methylation cycle/ It is also interestin to note that participants in the study with both 5#( and folate deficiencies were depressed! had anore7ia! and addiction to alcohol/ It is well+established that folate or 5#( deficiency causes psychiatric problems ran in from loss of memory to insanity/ This is probably due to the ,itamin;s role in methylation + a biochemical process crucial for the maintenance of brain chemistry and ner,es/ 5#( plays a role in the synthesis of serotonin! dopamine and norepinephrine/ Intrinsic factor is secreted by the stomach to help the body absorb 5#(/ >lder people produce less intrinsic factor! and are thus more ,ulnerable to 5#( deficiency/ In the study mentioned at the be innin of this article! hi h+dose oral 5#( was absorbed as well as injectable/ 8o supplemental intrinsic factor was i,en/ Intrinsic factor is usually associated with a chronic 5#( deficiency known as pernicious anemia/ ?atients with pernicious anemia lack intrinsic factor usually because of insufficient stomach acid/ >thers may ha,e antibodies to the factor + an inappropriate autoimmune response to one;s own proteins/ Injected 5#( has traditionally been used for pernicious anemia because it bypasses the absorption problem/ Howe,er! doctors are be innin to reali:e that pernicious anemia patients are not the only patients they see with 5#( deficiencies/ Anyone with ele,ated homocysteine! psychiatric disorders! eatin disorders! sleep disorders! or who is elderly is potentially 5#(+deficient/ These conditions are more likely caused by diet+induced 5#(+deficiency than a lack of intrinsic factor/ All should respond to oral 5#(/ Different orm! Of "itamin B#$ Cyanocobalamin is the usual form of 5#( sold in this country/ Hydro7ocobalamin and adenosylcobalamin are two other forms/ For the past (. years @n lish doctor Anthony A/ Freeman has been attemptin to et the cyano form of 5#( remo,ed from the market and replaced with the hydro7ocobalamin/ He points out that the cyano form is not effecti,e for certain eye de enerations caused by smokin and alcohol/ 5ut another form! methylcobalamin! may be the best of all/ 9esearch shows that this acti,e form of 5#( has the uni6ue ability to pro,oke the re eneration of ner,es without ad,erse side effects/ This is because 5#( facilitates methylation! the process that creates

and maintains ner,es and brain chemicals/ 9esearch shows that a lack of methylcobalamin causes de eneration of the brain and spinal cord + a condition known as subacute combined de eneration/ In this disease! ner,es lose their insulation and be in to deteriorate/ This process! known as demyelination! occurs in other neurolo ical diseases such as multiple sclerosis and chronic inflammatory demyelinatin polyneuropathy/ Hi h doses of methylcobalamin ha,e been used to treat de enerati,e neurolo ical diseases in rodents and humans/ ?eople with amyotrophic lateral sclerosis "Bou Aehri ;s disease' took (- m a day of methylcobalamin for a month/ In this disease! the neurons that 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 de eneratin ner,es occurred/ Methylcobalamin did not stop the disease! but it slowed it down/ It has been documented that the le,el of 5#( decreases e,ery year with a e/ A e+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 + the substance 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) it doesn;t re6uire SAMe/ Another feature of a in 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! sele iline! 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 to ether/ B#$ Deficiency Di!ea!e! 2iet! a e and dru s are the prime culprits behind 5#( deficiency/ Meat is the primary source of ,itamin 5#(/ Strict ,e etarians + people who eat no animal products whatsoe,er are at risk for 5#( deficiency/ "=e etarians who eat e s and fish will et 5#( in their diet/ In addition! some seaweeds contain the ,itamin! and the ut may manufacture a certain amount/' Howe,er! a meat diet doesn;t uarantee that a person won;t be 5#( deficient/ Some elderly people! for e7ample! can eat hi h 6uantities of meat but still be 5#( deficient because they don;t ha,e enou h hydrochloric acid in their stomach to maintain intrinsic factor/ Meat+eaters takin certain dru s are also at risk for 5#( deficiency/ Cimetidine "Ta amet'! omepra:ole "?rilosec'! and other dru s that inhibit astric secretion can cause 5#( deficiency/ Anyone who chronically takes dru s for stomach ulcers! CheartburnC or astroesopha eal reflu7 may be creatin 5#( deficiency in themsel,es/

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 in homocysteine and methylmalonic acid! plus serum 5#( up to *.. p 1mB+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 Fapan ha,e disco,ered that noninsulin+dependent diabetes patients with blood ,essel problems ha,e ele,ated homocysteine/ Ehen treated with #... micro rams of ,itamin 5#( "methylcobalamin' daily for three weeks! homocysteine le,els dropped si nificantly/ Althou h the study didn;t follow the patients lon enou h 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 e7tremely to7ic to blood ,essels/ B#$ and %leep Those who can;t et to sleep at ni ht may need ,itamin 5#(/ Studies show that 5#( causes an earlier release of melatonin at ni ht which resets the sleep+wake cycle/ "Melatonin has been called Cthe sleep hormoneC 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 you wake up earlier if you lea,e a curtain open to the mornin sun/ 5#( sensiti:es you to mornin li ht! which helps you wake up/ =ery serious sleep+wake disorders ha,e been successfully treated with ,itamin 5#( in the methylcobalamin form! althou h it may not work for e,eryone/ Gnfortunately! the ,itamin doesn;t help people who want to cut down on their sleep time alto ether/ 2urin the #$-.s! 5#( was fre6uently i,en to heart patients/ The ,itamin fell out of ,o ue as dru s took o,er the therapeutic picture/ 8ew findin s on the connection between homocysteine and ,ascular disease! plus the failure of dru s to ha,e an impact on the number of heart attacks and strokes! ha,e shifted the focus back to 5#( and other homocysteine+lowerin ,itamins/ The notion that 5#( must be injected to be effecti,e has been dispro,en in recent studies/ Swedish e7perience shows that oral 5#( is effecti,e for the treatment of pernicious anemia/ 5#( has many benefits! includin the reduction of homocysteine! restoration of normal sleep patterns! and mood effects/ 5#( deficiency is a fairly common deficiency in elderly people who fre6uently ha,e disrupted di estion/ It can cause symptoms that look e7actly like Al:heimer;s disease! and it;s crucial for the retention of folate in cells/ Te!tin& or B#$ Deficiency

There are se,eral tests eared towards dia nosin 5#( deficiency/ Homocysteine is an indirect test/ A more direct method is to measure methylmalonic acid which becomes ele,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 de enerati,e diseases! includin Al:heimer;s! should take ,ery hi h doses in the ran e of *+3... m ! supplemented with SAMe/ There is also the option of takin methylcobalamin! which is the neurolo ically acti,e form of 5#(/ The potential a e+re,ersin benefits are well+worth the modest price/ Methylcobalamin is a form of 5#( that is sold as a dru in Fapan/ It is the methylcobalamin form of 5#( that has been used in most @uropean and Fapanese studies showin efficacy a ainst neurolo ical disease/ The li,er con,erts about #D of in ested cyanocobalamin into methylcobalamin! but it is far more efficient to dissol,e a ood tastin methylcobalamin lo:en e in the mouth for immediately assimilation into the brain/

Methylcobalamin: A Potential Breakthrough in Neurological Disease

Japanese scientists have identified a form of vitamin B12 that protects against neurological disease and aging by a unique mechanism that differs from current therapies. Some of the disorders that may be preventable or treatable with this natural vitamin therapy, called methylcobalamin, include chronic fatigue syndrome, Par inson!s disease, peripheral neuropathies, "l#heimer!s disease, muscular dystrophy and neurological aging. "mericans have immediate access to this unique and new form of vitamin B12, and, unli e prescription drugs, it costs very little and is free of side effects. vitamin B12 is a general label for a group of essential biological compounds nows as cobalamins. $he cobalamins are structurally related to hemoglobin in the blood, and a deficiency of vitamin B12 can cause anemia. $he primary concern of conventional doctors is to maintain adequate cobalamin status to protect against anemia. $he most common form of vitamin B12 is called cyanocobalamin. %owever, over the last ten years, a number of central and peripheral neurological diseases have been lin ed to a deficiency of a very specific cobalamin, the methylcobalamin form, that is

required to protect against neurological diseases and aging. $he liver converts a small amount of cyanocobalamin into methylcobalamin within the body, but larger amounts of methylcobalamin are necessary to correct neurological defects and protect against aging. Published studies show that high doses of methylcobalamin are needed to regenerate neurons as well as the myelin sheath that protects nerve a&ons and peripheral nerves. CFIDS and B- ! 'n the Summer 1(() issue of Healthwatch, an important research article reported a fascinating new finding. *ver +,- of ./'0S and /1 patients cerebral spinal fluids contained subnormal levels of vitamin B12. *n the other hand, vitamin B12 levels in the blood did not significantly deviate from normal ranges. "ccording to 0r. Paul .heney!s treatment pyramid for ./'0S, vitamin B12 in its non2 cyanocobalamin 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 2, mg per day, or even more. $his supplementation of methylcobalamin might protect the cognitive function of patients with ./'0S by preventing the death of brain cells. *ne cause of brain cell death is glutamate to&icity. Brain cells use glutamate as a neurotransmitter, but unfortunately glutamate is a double2edged sword in that it can also ill brain cells. $he release of glutamate from the synapses is a usual means by which neurons communicate with each other. 6ffective communication means controlled release of glutamate at the right time to the right cells, but when glutamate is released in e&cessive amounts, intercellular communication ceases. $he flood of glutamate into the receiving neurons drives them 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 glutamate to&icity by ta ing methylcobalamin supplementation. 'n a study in the European Journal of Pharmacology, it was shown that methylcobalamin protected against glutamate2, aspartate2 and nitroprusside2 induced neuroto&icity in rat cortical neurons. 5esearchers concluded that methylcobalamin protects against neuroto&icity by enhancing brain cell methylation. $he ./'0S 7 /ibromyalgia %ealth 5esource recommends methylation2enhancing therapies such as vitamin B+, vitamin B12, folic acid and trimethylglycine 3$184, ta en together, to protect against heart disease, stro e and other aging2related diseases. $he scientists who conducted the methylcobalamin studies emphasi#e that ongoing inta e of methylcobalamin is necessary to protect against neuroto&icity. $hus for methylcobalamin to be effective in protecting against neurological disease, daily supplementation may be required. "n appropriate dose to protect against neurological aging might be 1 to 9 mg a day ta en under the tongue in lo#enge form.

Slee" " recent 8erman study appearing in Neuropharmacology showed methylcobalamin reduced the amount of time sub:ects slept; sleep quality was better and sub:ects awo e feeling refreshed, with better alertness and concentration. Part of this effect was apparently due to melatonin suppression during the daytime because morning methylcobalamin supplementation reduces drowsiness by decreasing daytime melatonin levels. Multi"le Sclerosis "ccording to a recent study at <anderbilt =niversity, chlamydia pneumoniae might lin multiple sclerosis 31S4 to ./'0S. $his ma es the published effect of methylcobalamin treatment on 1S of great importance to those who suffer from ./'0S. " study in the Journal of Internal Medicine investigated the daily administration of +, mg of methylcobalamin to patients with chronic progressive multiple sclerosis 31S4, a disease that has a poor prognosis and feature side spread demyelination in the central nervous system. "lthough motor disability did not improve, there were clinical improvements in visual and auditory 1S related disabilities. $he scientist stated that methylcobalamin might be an effective ad:unct to immunosuppressive treatment for chronic, progressive 1S. $hose with less serious forms of 1S may consider adding methylcobalamin to their daily treatment regimen. $he effects of methylcobalamin were studied on an animal model of muscular dystrophy. $his study, published in Neuroscience Letter loo ed at degeneration of a&on motor terminals. 'n mice receiving methylcobalamin, nerve sprouts were more frequently observed and regeneration of motor nerve terminals occurred in sites that had been previously degenerating. #egenerating Ner$es /ew substances have been shown to regenerate nerves in humans with peripheral neuropathies. %owever, a study in the Journal of Neurological Science postulated that methylcobalamin could increase protein synthesis and help regenerate nerves. $he scientists showed that very high doses of methylcobalamin produce nerve regeneration in laboratory rats. $he scientists stated that ultra2high doses of methylcobalamin might be of clinical use for patients with peripheral neuropathies. $he human equivalent dose the scientists used is about >, mg of sublingually administered methylcobalamin on a daily basis. $hose suffering from peripheral neuropathies often ta e alpha lipoic acid. Based on our new understanding of peripheral neuropathy, it may be prudent that anyone using alpha lipoic acid also ta e at least 9 mg a day of sublingually administered methylcobalamin to ensure that alpha lipoic acid will be bioavailable to the peripheral nerves. Cancer%Immune Function " study in the :ournal Oncology e&amined the effects of methylcobalamin on several different inds of tumors in mice. $he administration of methylcobalamin for seven

days suppressed liver, lung and ascites tumor growth. 1ice receiving methylcobalamin survived longer than control mice did. 'n mice irradiated before tumor cell inoculation, methylcobalamin did not improve survival. $he effects of methylcobalamin on human immune function was investigated in the Journal of Clinical Immunology. $he study showed that methylcobalamin demonstrated remar able $ cell2enhancing effects when the $ cells were e&posed to certain antigens. $he scientists also showed that methylcobalamin improved the activity of $ helper cells. $he scientists concluded that methylcobalamin could modulate lymphocyte function by augmenting regulatory $ cell activities. "mericans need to now about this important natural therapy that could e&tend the healthy human life span. " search of the scientific literature reveals ??> published studies on methylcobalamin. %owever, it would not be an e&aggeration to say that virtually no doctors now of it or are recommending it. 1ethylcobalamin should be considered for the treatment of any neurological disease. /or e&ample, based on its unique mechanisms of action, methylcobalamin could be effective in slowing the progression of @untreatable@ diseases such as "AS 3Aou 8erhig!s disease4. Since methylcobalamin is not a drug, there is little economic incentive to conduct e&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 common diseases li e Par inson!s disease. $he sublingual inta e of methylcobalamin is an affordable and effective natural therapy, and has proven even safe when given in large doses.

B- ! Methylcobalamin - &horne Article Marilyn Bachmann - March !'( !''

1onograph 1ethylcobalamin 22222222222222222222222222222222222222222222222222222222222222222222222222222222 Introduction 1ethylcobalamin 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 which functions to transfer methyl groups for the regeneration of methio2nine from homocysteine. 22222222222222222222222222222222222222222222222222222222222222222222222222222222 Pharmacokinetics 6vidence indicates methylco2balamin is utili#ed more efficiently than cyanocobalamin to increase levels of one of the coen#yme forms of vitamin B12. 6&periments have

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 significantly more cobalamin accumulates in liver tissue following administration of methylcobalamin. %uman urinary e&cretion of methylcobalamin is about one2third that of a similar dose of cyanocobalamin, indicating substantially greater tissue retention.1 22222222222222222222222222222222222222222222222222222222222222222222222222222222 Clinical A""lications Bell!s PalsyB 6vidence suggests methylcobalamin dramatically increased the recovery time for facial nerve function in Bell!s palsy.2 .ancerB .ell culture and in vivo e&perimental results indicated methylcobalamin inhibited the proliferation of malignant cells.? 5esearch indicated that methylcobalamin enhanced survival time and reduced tumor growth following inoculation of mice with 6hrlich ascites tumor cells.> 1ethylcobalamin has been shown to increase survival time of leu emic mice. =nder the same e&perimental conditions, cyanocobalamin was inactive.9 "lthough more research is required to verify findings, e&perimental evidence suggested methylcobalamin might enhance the efficacy of methotre&ate.+ 0iabetic CeuropathyB *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 wea ness, and sensitivity to pain was also observed.D 6ye /unctionB 6&periments indicated chronic administration of methylcobalamin protected cultured retinal neurons against C2methyl202aspartate2receptor2mediated glutamate neuroto&icity.) 0eterioration of accommodation following visual wor has also been shown to improve in individuals receiving methylcobalamin.( %eart 5ate <ariabilityB %eart rate variability is a means of detecting the relative activity and balance of the sympatheticEparasympathetic nervous systems. 1ethylcobalamin produces improvements in several components of heart rate variability, suggesting a balancing effect on the nervous system.1, %'<B =nder e&perimental conditions, methylcobalamin inhibited %'<21 infection of normal human blood monocytes and lymphocytes.11 %omocysteinemiaB 6levated levels of homocysteine can be a metabolic indication of decreased levels of the methylcobalamin form of vitamin B12. $herefore, it is not surprising that elevated homo2cysteine levels were reduced from a mean value of 1>.D to 1,.2 nmolEml following parenteral treatment with methylcobalamin.12 1ale 'mpotenceB 'n one study, methylcobalamin, at a dose of + mgEday for 1+ wee s, improved sperm count by ?D.9 percent.1? 'n a separate investigation, methylcobalamin, given at a dose of 1,9,, micrograms per day for >22> wee s, resulted in sperm concentration increases in ?) percent of cases, total sperm count increases in 9> percent of cases, and sperm motility increases in 9, percent of cases.1>

Sleep 0isturbancesB $he use of methylcobalamin in the treatment of a variety of sleep2wa e disorders is very promising. "lthough the e&act mechanism of action is not yet elucidated, it is possible that methylcobalamin is needed for the synthesis of melatonin, since the biosynthetic formation of melatonin requires the donation of a methyl group. Supplementation appears to have a great deal of ability to modulate melatonin secretion, enhance light2sensitivity, normali#e circadian rhythms, and normali#e sleep2wa e rhythm.1922, 22222222222222222222222222222222222222222222222222222222222222222222222222222222 Dosage $he dosage for clinical effect is 19,,2+,,, mcg per day. Co significant therapeutic advantage appears to occur from dosages e&ceeding this ma&imum dose. 1ethylcobalamin 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 the non2oral methods of administration. 22222222222222222222222222222222222222222222222222222222222222222222222222222222 Sa)ety( &o*icity( and Side +))ects 1ethylcobalamin has e&cellent tolerability and no nown to&icity.

What is it? Vitamin B12 or cobalamin is an essential nutrient found in meat products. Vitamin B12 is absorbed in the small intestine and is necessary for proper nerve function and converting food into energy. Deficiencies of vitamin B 12 cause anemia and neurological impairments including memory loss and disorientation. What do people with HIV use this supplement for? To avoid deficiency Depending on the way vitamin B12 levels are measured, studies suggest that between ten and 50 per cent of people living with !V"#!D$ %& #s' are deficient in this nutrient. (his deficiency is most li)ely due to !V*related damage to the small intestine that prevents the body from absorbing ade+uate amounts of B 12. ,ertain drugs, such as #-( and the antibiotics used to treat tuberculosis, can decrease levels of vitamin B12. $everal studies suggest that deficiency in this vitamin increases the rate at which a person becomes ill %disease progression'. !n a study conducted by Dr. #lice (ang and colleagues, serum levels of vitamin B12 were measured in !V*positive people without symptoms of disease. .ven when factors such as ,D/0 counts were considered, the team found that serum vitamin B12 levels could be used to predict which sub1ects would become ill most +uic)ly. B12 deficiency seems to be lin)ed to poor absorption2 most nutritionists suggest therefore that supplements of B12 be in1ected or ta)en sublingually %dissolved under the tongue'. #lthough these methods have been shown to increase serum levels of B12 in !V*positive people, no trials have been done to assess the

impact of B12 supplements on disease progression. To prevent and treat dementia 3iven that B12 deficiencies are associated with confusion and memory, many physicians and researchers have speculated that vitamin B 12 might play a role in dementia and other !V*related cognitive disorders. 4ne case report described the dramatic recovery of a !V*positive man suffering from dementia who was treated with B12. ,linical trials have produced less impressive results and it is now generally accepted that B12 may be a factor in some but not all cases of !V* related dementia. B12 supplements have also been useful in treating elderly people with B12 deficiencies 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 often associated with anti* !V drugs, particularly dd,, dd! and d/(. 4ne early study of & #s suggested that people with low B12 levels were more li)ely to e5perience neuropathy, but subse+uent studies have not confirmed this connection. B 12 has, however, been used successfully to treat diabetic neuropathy, a fact that argues its case for the management of nerve damage in & #s. Available forms and usage !n ,anada, B12 is ta)en orally or by intramuscular or intravenous in1ections. #lthough other forms of B12 have been developed, such as nasal sprays, gels and sublingual tablets, not all of these formulations are widely available in ,anada. 3iven that vitamin B12 may be poorly absorbed in !V*positive people, most nutritionists and physicians recommend B12 shots. (hese shots can be ta)en at a doctor6s office or an !V clinic and, in most cases, they are covered by provincial and private insurance plans. # monthly in1ection can be used to boost a daily oral dose of B12. !f obvious signs of B12 deficiency are present, more fre+uent in1ections are possible %up to several times a wee)'. 4ral doses of 25 or 50 mg of B12 are found in B25 or B50 vitamin tablets respectively. (hese B* comple5 combination vitamins are described further in ,#(!.6s supplement sheet on vitamin B*comple5. Cautions and Concerns Vitamin B12 supplements are safe to use. .5cess amounts of the vitamin are eliminated in the urine. #t high doses, however, B 12 may cause an5iety in some people and mild diarrhea in others. $ome people are sensitive to B 12 and may develop 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 B 12 and another B* vitamin called folate %folic acid' in the body. (a)ing large doses of one B*vitamin alone is not a good idea so if you are ta)ing e5tra B 12, you might want to ta)e a B*comple5 pill as well.

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 dru s other than chemotherapy a ents/ 8otwithstandin multiple statements and ad,ertisements proclaimin that statins are safe and ,ital to lowerin cholesterol and pre,entin coronary e,ents! contrary e,idence e7ists that lon +term e7posure to statins may substantially increase the risk of1induce and e7acerbate peripheral neuropathy by #-D in the first year and (<D for two or more years (1, 2, 3)/ Moreo,er! statins can contribute to suppression of our immune system and acti,ation of helper T+cells "lymphocyctes produced in the thymus land' (4)H likewise statins ha,e been attributed to li,er and kidney injury (5)! as well as reduction in bone mineral density and resultin osteoporosis (6)/ Contrary to some studies that report statins as reducin the risks of ad,anced prostate cancer (7)! other peer+re,iewed studies 6uestion whether lon +term use of statins actually cause cancer (8) and report findin s that statins do not pro,ide a protection a ainst breast or prostate cancer/ (9) Also! while antian io enic "retard blood ,essel rowth' dru s are in ,o ue this year "Celebre71=io77! thalidomide' and low+dose fre6uent chemotherapy is reco ni:ed as bein both cytoto7ic and antian io enic! how does the reduced blood ,essel formation from the accumulation of these ,arious antian io enic a ents affect continued health of our ner,esI I su est that lon +term use of antian io enic a ents certainly deny blood supplies to ner,es "as well as cancer and healthy tissue' and either alone or combined! certainly induce peripheral neuropathy/ Therefore! while statins are most effecti,e in pre,entin coronary e,ents! C>J+ ( inhibitors are essential for pain and antian io enesis! and thalidomide mi ht e,entually pro,e to be an effecti,e antian io enic a ent+++I su est that it is incumbent on us to analy:e our own chemical1dru cocktails and combinations in order to optimi:e the cumulati,e and combined effects on our 6uality and

len th of life+++I likewise su est 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 dru s! and most of us take some statin and antian io enic a ents/ Are we thus assurin that we will suffer treatment+limitin and debilitatin "and possibly permanent' peripheral neuropathy by takin Bipitor for its cholesterol+lowerin effects! Celebre7 for pain and antian io enesis! blood pressure medicines! and thalidomide for antian io enesis "thalidomide is well+known for causin peripheral neuropathy'I 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 medicationsI "My 6uestion is ob,iously cynical and rhetorical/' Many cancer patients who under o se,eral months of chemotherapy will de,elop peripheral neuropathy to some e7tent/ The ner,e dama in effects of chemotherapy are cumulati,e and as the chemotherapy treatments are continued! the condition often becomes treatment+limitin and physically debilitatin / Medical science does not know of any a ent to relie,e or delay the onset of peripheral neuropathy and we are often told that C///it is just our old friend Ta7otere///C! without any analysis of the cumulati,e antian io enic effects of our other dru s 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 oncolo ists! yet they ha,e no su estions about how to alle,iate it e7cept to reduce the dose of the chemotherapy a ent or suspend treatment/ In my opinion! our doctors are not comfortable with any a ent 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 dru s we take to support and au ment 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 su ested Alutamine as a possible a ent to relie,e or delay peripheral neuropathy/ In subse6uent chemo treatments I continue with daily Alutamine and belie,e that it offers some reliefH but after (0 years of chemotherapy! I still suffer considerable peripheral neuropathy/ Howe,er!

below I su est other possibilities that mi ht 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 mi ht ha,e any characteristics of inducin peripheral neuropathy! and optimi:in their utili:ation in ,iew of our own concept of 6uality16uantity of life++++ in %)MMA*Y! I su est se,eral possible solutions to alle,iate1delay peripheral neuropathy while en a ed in our sa a of prostate cancer and the treatments therefor+++with the e7ception of shakuyaku+kan:o+to! all of these items are a,ailable in a dru 1health food store) #' Alutamine at #. m J 31day as delineated in my abo,e paper/ (' Shakuyaku+kan:o+to "not a,ailable in a dru 1health food store'+++an ancient Chinese1Fapanese herbal concoction for muscle spasms and tin lin in the hands and feet/ *' Aamma+linolenic acid "ABA'! 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 co ni:ant of the fact that the studies1reports of a ents effecti,e a ainst peripheral neuropathy state that such a ent"s' only delay or partially mitigate peripheral neuropathy+++none proclaim to prevent it+++so! with our cancer and lon +term use of statins! antian io enic a ents! and chemotherapy! we must accept the fact that we will all suffer peripheral neuropathy to some e7tent/' 2@FI8ITI>8S ...Neuropathy is 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 of the e7tremities/ The sensation"s' can be transient! mo,in from fin er to fin er1toe to toe! and radiatin up the arm or le / Symptoms usually impro,e upon stoppin the dru ! althou h impro,ement can take <+% weeks and pain can worsen before it impro,es/ 8europathy is commonly caused by diabetes! fatty acid imbalance! restriction of blood supply to ner,es "could C>J+( inhibitors add to the conditionI'! nutritional deficiencies! and chemotherapy

a ents/ (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 Cthe ood ome a+<C fatH re ulates metabolic processes down to the cellular le,el+++amon se,eral e7pected effects of ABA) a cytoto7ic a ent for cancer and an arthritis relie,er/ (12). ...ascorbyl palmitate++fat+soluble form of ascorbic acid ",itamin C'H unlike ascorbic acid! which is water soluble! ascorbyl palmitate is stored in cell membranes until needed by the bodyH free+radical antio7idant/ (13) ...folic acid1folate ",itamin 5$'+++water+soluble and important in red blood cell formation! protein metabolism! rowth and cell di,ision/ (14) ...alpha-lipoic acid (ALC)+++ser,es as a coen:yme in the Krebs cycle and in the production of cellular ener y+++possibly the Cperfect and idealC antio7idant+++in Aermany it is an appro,ed treatment for peripheral neuropathyH in the GS it is sold as a dietary supplement! usually in -. m tablets/ (15) ...N-acetylcysteine (NAC)+++promotes deto7ification and acts directly as a free radical sca,en er+++protects normal cells! but not mali nant cells! from the to7ic effects of chemotherapeutic a ents and radiation+++can reduce tumor formation and pre,ent metastases! but does not interfere with cytoto7icity of chemo a ents/ (16) ...acetyl-L-carnitine (ALC) ++modulates cellular functions! includin the transfer of fatty acids for ener y production+++restores ner,e rowth factor function+++neuropathies respond to ABC (17)+++daily administration of ABC durin Ta7ol treatment completely pre,ents occurrence of neuropathy and myelosuppression (18)+++it is associated with increased ner,e conduction ,elocityH in a trial it pre,ented &*D of ner,e conduction defects and promoted1accelerated ner,e+fiber re eneration/ (11, pp. 476) ...vitamin !"+++the common form of ,itamin 5#( found in the dru store is cyanocobalamin "cyano 5#('! but this form of 5#( is inferior to methylcobalamin "methyl 5#(' as an antio7idant+++look on your 5#( bottle to see which form of the ,itamin you ha,eH and assure that you are takin the methyl form+++studies ha,e shown that methl 5#( pro,ides protection from neuroto7icity and is neurotrophic "promotes rowth of ner,e cells'! which may help re enerate peripheral ner,e dama e (19)+++methl 5#( should be taken sublin ual "under the ton ue'/

...sha#uya#u-#an$o-to "TF+<%' is an ancient oriental herbal concoction used for many ailments! includin acute muscle spasms! tin lin hands1feet! and peripheral neuropathy+++it is a blend of two crude dru s) shakuyaku "peony root' and kan:o " lycyrrhi:a root' (20)+++"note) these were amon the in redients of ?C S?@S'+++the herb is manufactured as prescription only in Fapan by TsumuraH their contact in the GS is $3$+%**+&%%(+++likewise! some men ha,e found the herbal mi7 at the Academy of >riental Medicine "-#(+*(*+ <&(.' and 8ew 5ree:e "Ken Morehead++$#$+*%3+#3*&! or kfmk@aol.com'/ Shakutaku+Kan:o+to has been reported as effecti,ely reducin the se,erity of peripheral neuropathy! arthral ia "joint pain'! and myal ia "muscular pain' in Ta7ol1Carboplatin protocols/ (21) ...statins 4 a ents capable of acceleratin the rate of secretion of a i,en hormone by the anterior pituitary land+++ cholesterol+lowerin medications known as reductase inhibitors "inhibitors of en:ymes' offerin up to *&D reduction in the risk of coronary e,ents (22, 23)+++estimates are that half of the GS population will shortly be takin a statin dru (24)++common statins are Bipitor! Locar! ?ra,achol! Bescol! and Me,acor (25)/ %P&C'('C )*%'NG AN) P+*,*C*L %-GG&%,'*N% (*+ C.&/*,.&+AP0 AN) *,.&+ )+-G(%)-'N)-C&) P&+'P.&+AL N&-+*PA,.0 #' Alutamine M #. m "about one heapin teaspoon' J 31day++++see Chemotherapy + ?art ( for lo ic and references/ (' Shakuyaku+kan:o+to M (/- m J *1day/ *' Aamma+linolenic acid "ABA' 0 fish oil concentrate 0 ascorbyl palmitateNN/ 3' =itamin 5#( "methylcobalamin' M -+3. m 1day sublin ual "under the ton ue' 0 (...+-... mc folic acidNN/ -' Alpha+lipoic acid M (-. m J (1day 0 acetyl+B+carnitine M #... m J (1day 0 8+acetylcysteine M <.. m J (1day 0 *... m ,itamin C J (1dayNN/ **(2, @ pp. 479)

Bill Ai!hman September (..(

O Copyri hted by 5ill Aishman + all ri hts reser,ed + (..(

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 sa a 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 re ardin treatment options/ I make no claim that this analysis is definiti,e or complete and I in,ite any and all competent su estions1corrections 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 )##r ss* Intern Med #$$$ FunH*%"<')3&(+Intra,enous methylcobalamin treatment for uremic and diabetic neuropathy in chronic hemodialysis patients/ Kuwabara S! 8aka:awa 9! A:uma 8! Su:uki M! Miyajima K! Fukutake T! Hattori T 2epartment of 8eurolo y! Chiba Gni,ersity School of Medicine/ QMedline record in processR >5F@CT) To study the effects of the intra,enous administration of methylcobalamin! an analo ue of ,itamin 5#(! for uremic or uremic+diabetic polyneuropathy in patients who are recei,in maintenance hemodialysis/ An ultra+hi h dose of ,itamin 5#( has been reported to promote peripheral ner,e re eneration in e7perimental neuropathy/ M@TH>2S) 8ine patients recei,ed a -.. micro methylcobalamin injection * times a week for < months/ The effects were e,aluated usin neuropathic pain radin and a ner,e conduction study/ 9@SGBTS) Serum concentrations of ,itamin 5#( were ultra+hi h durin treatment due to the lack of urinary e7cretion/ After < months of treatment! the patients; pain or paresthesia had lessened! and the ulnar motor and median sensory ner,e conduction ,elocities showed si nificant impro,ement/ There were no side effects/ C>8CBGSI>8) Intra,enous methycobalamin treatment is a safe and potentially beneficial therapy for neuropathy in chronic hemodialysis patients/

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, 79 where he dedicates :0; of his time to patients see)ing the D#7< approach to autism.

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

=or years ! have prescribed vitamin B12, administered orally, sublingually, or by in1ection. ! have used 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, hydro5ycobalamin, and methylcobalamin. 7ow, four years after beginning to treat autism with >B12> ! hold a very different view, that view being the methylcobalamin form of B12 holds the greatest promise for treating children on the autistic spectrum. (hough methylcobalamin has never been studied for its effects on autism, this presentation will demonstrate that the literature cites many studies performed on humans, animals, or in laboratory settings that indicate positive results from several disorders that share similar symptoms or pathophysiology. (he results of my study using in1ectable methylcobalamin for @5 children who carry the diagnosis of #utism, &DD, or #spergerAs syndrome will be presented. # literature review will discuss the profound effects methylcobalamin has on the central and peripheral nervous systems, the cellular and humoral immune systems, on sleep*wa)e cycles, and on deto5ification biochemistry. 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 to present a plausible hypothesis why >methylcobalamin loading> spares tetrahydrofolate and methyl reserves, thereby resulting in increased D7# and purine synthesis and their secondary biochemical reactions, total body transmethylation reactions, and deto5ification biochemistry.

The DAN movement continues to gain momentum among the scientific and lay communities validating that autism does have a strong biological component that can be manipulated for the benefit of those afflicted. (he D#7 8anual is replete with references documenting reasons why D#7 &ractitioners who treat children from this biological"biochemical paradigm often obtain results. Bnfortunately the results reveal varying degrees of mi5ed successes and failures. !t is possible that our failures and"or limited degrees of success are at least partially due from the fact that we are 1ust now beginning to understand some of the )ey biochemical pathways involved in our childrenAs bodies. $o much more research needs to be done to predict which children may respond to which therapies. Bnfortunately none of the childrenAs bodies have read the literature or the biochemical te5tboo)s< 8ethylcobalamin therapy is one such avenue that needs to be e5plored. (he biochemistry of B12 %also )nown as >cobalamin>' with its scientific conclusions shares a consensus opinion among scientists as to its mechanism of action. B12"cobalamin has a comple5 ring structure with an ion of cobalt found at its core. !t can only be synthesiCed by microorganisms and would pose a

problem for vegans to avoid a deficiency condition e5cept for food contamination that is ubi+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 for absorption to ta)e place in the distal portion of the small intestine, the terminal ileum. 4nce absorbed, (ranscobalamin !! carries cobalamin to the liver and tissues. !n the liver, cobalamin is stored by attaching to (ranscobalamin !. ,obalamin is uni+ue in its ability as a water*soluble vitamin to be stored in the liver rather than being +uic)ly lost from the body. (hree forms of cobalamin e5ist? cyanocobalamin, hydro5ycobalamin, and methylcobalamin. (he cyano form is the most common form, the least e5pensive commercially available form, but it is not natural to the body. ydro5cobalamin is primarily found in the cytoplasm where it is converted into its active coenCyme forms? adenosylcobalamin coenCyme %deso5yadenosylcobalamin coenCyme' and methylcobalamin coenCyme. #denosylcobalamin coenCyme moves into the mitochondria and remains fairly stationary in that location while methylcobalamin coenCyme is the cobalamin coenCyme form that either remains in the cytosol or is returned to the plasma for transport to other tissues. !n the mitochondria, adenosylcobalamin coenCyme acts in concert with the enCyme methylmalonyl*,o# mutase on the substrate methylmalonic acid to form succinic acid. $uccinic acid is an important component of the Drebs cycle and gluconeogenesis. !t is plausible, though not proven, that the fre+uent reports of >increased energy> clinicians hear from patients receiving B12 in1ections may partially be the result of this biochemical pathway. #nother possible reason could be the role of adenosylcobalamin coenCyme in the mitochondria and the mitochondriaAs primary 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 the brain was one of the reasons parents fre+uently reported higher cognitive abilities in their children. (he hydro5ycobalamin"methylcobalamin coenCyme reactions are more complicated. =irst, in the presence of ade+uate hydro5ycobalamin and the enCyme methyl*tetrahydrofolate reductase, the methyl group from methyl*tetrahydrofolate is transferred to hydro5ycobalamin to become methylcobalamin coenCyme. 7otice that two things are happening at once. =irst, methylcobalamin coenCyme, in the presence of the enCyme methionine mutase, immediately passes its newly ac+uired one*carbon methyl group to homocysteine to regenerate the essential amino acid methionine. 8ethionine is then +uic)ly converted to $*adenosylmethione %$#8', a )ey player in the bodyAs overall methylation biochemistry. $econd, methyl*tetrahydrofolate, by losing its one carbon methyl group to methylcobalamin, now becomes tetrahydrofolate. !t is this end product, tetrahydrofolate that is vital to the formation of purines, pyrimidines, and nucleic acids. ,obalamin">B12> deficiency leads to three problems. =irst, when adenosylcobalamin coenCyme is deficient, the substrate methylmalonic acid cannot be converted into succinic acid. (herefore levels 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, the substrate homocysteine cannot be converted to methionine. (herefore levels of homocysteine will continue to increase and may be seen in the blood or urine resulting in homocystinemia and homocystinuria respectively. (hird, a phenomenon )nown as >folate trapping> occurs when hydro5ycobalamin is deficient in the presence of ade+uate methyl*tetrahydrofolate. Ehen this situation occurs, the methyl group on methyl*tetrahydrofolate is trapped because >it wants to leave %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 in1ectable methylcobalamin. ,hildren ranged in age from 2 to 1: with the ma1ority between ages F and G. (he in1ections were started when the children were stable and not ma)ing other significant changes to their therapies,

either biological or non*biological. =ollow*up was done every G wee)s with me, either in person or by telephone. &arents were instructed to write a letter describing what they saw happening with their children. (hese letters from parents were to be spontaneous and written >in their own words>. (herefore the parentAs responses were not "directed" by a uestionnaire. (he parents were instructed that conclusions or summary statements were all right to give but only if they gave as many specific e5amples as possible describing why they arrived at the conclusions that they 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 the percentage of responders to be meaningful.' #ppro5imately 50; of the parents reported 15 or more symptoms improved. $i5ty*seven urinary 88#As were performed of which @1; were negative in the total group of GH and @0; were negative in the responders group. =orty*nine homocysteine 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 predictive value 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 and Communication !"# $) 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 that their child? >Eas much happier, much more affectionate %even if her or she already was affectionate', much more interactive, calmer, more resilient to changes in routines2 had more spontaneous speech, began to use pretend play or fantasy, was able to finally sit at the table with the family and"or sit and attend to a tas)>, etc. (here were over 100 different symptom improvements parents reported %for a complete list, see the slide presentation in this syllabus'. $ide effects were few2 the primary one of hyperactivity was reported in 10;. (he second most common problem was sleep disturbance, this being reported in G; of the children. 4ften giving the in1ections in the morning instead of at bedtime alleviated this problem. Eith only one e5ception, parents stated that the positives so far outweighed the negatives that they would deal with the negatives, e.g. hyperactivity. (he one e5ception was a child who responded positively to over 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 many colleagues. 8y final decision, for several reasons, was to perform the original study using an in1ectable form. (he literature admits that the absorption of B12 is a "comple! process" involving numerous physiological and biochemical steps. (hese steps include binding to saliva, formation of intrinsic factor from healthy gastric parietal cells, proper stomach acid release, proper pancreatic protease release, a healthy terminal ileum, the appropriate mi5 of intestinal microorganisms, enterocytes properly functioning, etc. #s ! contemplated our children, it was my conclusion that most of them chew poorly and therefore would have minimal salivary binding of cobalamin. undreds of nutritional analyses gathered from this population have repeatedly demonstrated poor nutritional status with inade+uate amounts of protein, carbohydrate, and essential fatty acids, the re+uired precursor building bloc)s of healthy cells. (herefore there was no guarantee that the children would be able to meet the re+uirements necessary for >functional release> of gastric acid or intrinsic factor. #lso, due to the belief shared by D#7 practitioners that inappropriate functional release of pancreatic enCymes often e5ists %consider the Iepligen study and the positive benefit of secretin in some children', there was no way to insure ade+uate digestive enCyme function. #s previously demonstrated and"or continues to be documented by the wor) of Ea)efield, Drigsman, and Buie, the terminal ileum is fre+uently inflamed and demonstrates varying degrees of ileitis. (his finding alone was enough to e5clude the oral route

of administration as a valid >initial step> in determining the potential effectiveness of methylcobalamin therapy for my study. 4ther factors ! had to consider included dysbiosis and the mi5 of microorganisms in the terminal ileum that may interfere with my ability to )now the >dose absorbed> by the child relative to the >dose produced> by microorganisms and"or the >dose administered> by me. (herefore, it was my strong opinion then %and even stronger now' that until ! answered the first +uestion definitively Jemdash2 does methylcobalamin play a vital role in the autistic populationK Jemdash2 that these multiple variables inherent to the gastrointestinal tract, variables that were impossible to predict who suffered from them and variables that were impossible to consistently control due to many factors, must be bypassed by in1ections. !t was also my strong conviction that unless the dose and route of administration were fairly free of variables, there would be no way to interpret the data to predict optimum dosing or to evaluate a childAs response, either positive or negative. 4nce ! decided to use in1ectable methylcobalamin, the ne5t dilemma that needed to be addressed was 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 it was my >impression> that ! was getting a higher response rate in the group of children that were using the subcutaneous route of administration. ypothetically " subcutaneous in#ections may produce a "slow time$release" process" allowing a "leaching effect" of the methylcobalamin. (his theoretically could allow a >relatively higher dose> of the substance to remain in the body for longer periods of time if this was compared to the in intramuscular or intravenous routes of administration. 4ne reason for this is that the )idneys are )nown to +uic)ly clear any e5cess cobalamin. Because cobalamin is a red substance, ! have occasionally been called by panic)ing parents reporting >red urine> in their childAs urine who were worried the child was bleeding. ! have never seen red urine with the subcutaneous route of administration but ! have seen it infre+uently with intravenous and intramuscular administration. =ormal research will need to be conducted to determine 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 in detail on the slides that follow. !t should be noted that this protocol is in a dynamic state of change as ! continue to search for >the optimum dose and the ideal fre+uency of in1ections>. Ehen ! advised parents to give doses lower than H5 mcg per )ilogram, there was a lower percentage of responders and there was a different >mi5> of symptoms improved. &arents no longer seemed to report improvements from the >top 10> symptom response list that accompanies my higher dose protocol. !nstead, there were only minor symptom improvements, e.g. >he seems to have more energy>. 8ost parents that stopped the in1ections because they did not see what they believed to be significant degrees of improvement usually were on the phone within 2*/ wee)s begging to restart the in1ections because their children regressed. (he most common >regressions> reported were language, awareness, and cognition Jemdash2 these were also my >Big (hree> ** the symptoms most commonly reported to improve<

The 5uestion arises: "6s there any research to support any of my findings or hypotheses7" .ortunately the answer is a resounding "yes" as shown from the references cited4 !t should be noted that hundreds more references are available but only those necessary to complete this presentation are listed. # few pertinent articles with )ey points are important to draw your attention to and discuss. !)eda10 demonstrated that communication' cognition and intellectual functions' and emotion in #lCheimer patients were improved in the group that achieved the highest levels of methylcobalamin and that maintained these high levels for the longest period of time. all@ discussed methylcobalamin deficiency found in early infancy shows developmental delay' hypotonia' lethargy' poor responsiveness' and fre(uent sei)ures . (wo types of treatment responses were noted? a' the first type showed slow steady psychomotor improvement over a long period of time suggesting improvement in myelination2 b' the second type showed rapid improvement within 2/*/@ hours of hypotonia, responsiveness, and lethargy.

Lamamoto/1 suggests that transmethylation by methylcobalamin may induce functional recovery from ischemia. !t should be noted that much con1ecture has occurred regarding flow*function discrepancies in the brains of autistic children. =our articles 1/, 21, 22, FH were chosen to illustrate the possible role methylcobalamin plays in protection from to#ic agents, e.g. from heavy metals, chemicals, and biological agents, possibly as they wor) through deto5ification pathways involving glutathione and sulfation. !)euchi11 concluded that methyl groups, induced only by the methylcobalamin form of B12, are re(uired for *long+lasting* postsynaptic field potential amplification. =our references1G, 21, F@, /2 are presented to illustrate that ultra+high doses of methylcobalamin' either oral or in,ectable' may result in nerve regeneration- #)ai)e1 describes chronic use of methylcobalaminAs role in the protection of cortical neurons from cytoto5icity. (hree references@, 1G, FG are cited to present the possibility of methylcobalaminAs direct and"or indirect role in protection from demyelination and.or its potential role in remyelination. 3otoAs studyH is reviewed indicating methylcobalaminAs role in the prevention of encephalopathy. =our references5, F0 F/, F5 are cited that definitively show methylcobalaminAs role in immune enhancement. (hese studies document that both the cellular and the humoral arms of the immune system are positively affected- =unadaAs studyG is reviewed indicating methylcolbalamin may downregulate allergic responses. $andbergF1 discusses that methylcobalamin is the ma,or form of "/2 present in breast mil0. MindenbaumAs study1@ discusses the vital role of methylcobalamin in rapidly dividing tissues of the body' specifically the brain. (he reference also addresses inherited errors of cobalamin metabolism and their management. Dira1G and 4hta2H report that patients who respond to therapy may have been shown to have normal lab values prior to treatment . (hree references11, 20, 2 have been selected to show that the methyl form of "/2 is the form most li0ely to result in positive responses- (wo references@, 2H show that the response to methylcobalamin therapy may be immediate- =ive references10, 1G, 21, 2H, F@ are cited indicating that high to ultra+high doses of methylcobalamin may be re(uired and"or needed to produce positive results. (hree references are cited1, 10, 1G to illustrate that long+term chronic use may be necessary to achieve or maintain positive clinical results. (wo referencesF, 10 were cited showing there were no to#ic effects or side effects' even with high dose long+term use-

%n conclusion" methylcobalamin appears to play a vital role in autistic biochemistry. % hypothesi&e that loading with high dose methylcobalamin spares the body's need to convert hydro!cobalamin into methylcobalamin by using methyl$tetrahydrofolate to regenerate tetrahydrofolate. Therefore the "additional" tetrahydrofolate is now available to be shunted to methiene$tetrahydrofolate to produce DNA( and directly or indirectly through methenyl$tetrahydrofolate to form purines. These "additional" purines are now available to participate in DNA formation" )$regulatory protein reactions" protein *inase reactions" and to enter into deto!ification pathways. % further hypothesi&e that loading with high dose methylcobalamin spares the body's limited methyl reserves that are necessary to convert homocysteine into +A, and necessary to participate in general body transmethylation reactions. -oading doses also result in more regeneration of homocysteine" a prere uisite for cysteine and deto!ification reactions.

&1TH23C%"A3A&I4
methylcobalamin research methylcobalamin for brain methylcobalamin B12

&ethylcobalamin is one of the two coen)yme forms of vitamin "/2 5cyanocobalamin6- Vitamin "/2 plays an important role in red blood cells' methylation reactions' and immune system regulation- 1vidence indicates methylcobalamin has some metabolic and therapeutic applications not shared by the other forms of vitamin "/2-

7imple &ethylcobalamin biochemistry &ethylcobalamin is the active form of vitamin "/2 that acts as a cofactor for methionine synthase in the conversion of homocysteine to methionine' thus lowering blood levels of homocysteine- &ethylcobalamin acts as a methyl donor and participates in the synthesis of 7A&+e 57+ adenosylmethionine6' a nutrient that has powerful mood elevating propertiesClinical $ses of &ethylcobalamin &ethylcobalamin supplements increase alertness and body temperature&ethylcobalamin may slightly help those with diabetic neuropathy- A better nutrient for this condition is 3ipoic Acid&ethylcobalamin has been found to be helpful in "ell8s palsy&ethylcobalamin ta0en orally is effective in the treatment of pernicious anemia' says a 9apanese study&ethylcobalamin may inhibit the ototo#ic 5hearing damage6 side effects of the antibiotic gentamicin1mail if you would li0e to receive our 7upplement :esearch $pdate newsletter emailed for free the first wee0 of each month- We email a brief abstract of ; to < studies on supplements and natural medicine topics' and their practical interpretation by =r- 7ahelianInde# of 7upplements and Herbs %ver ! listings ++ by :ay 7ahelian' &-=-

&ethylcobalamin :esearch $pdate &others with low levels of vitamin "/2 in their blood are at increased ris0 of having an infant with spina bifida ++ a birth defect in which the spinal cord fails to form properly- "ased on previous research' pregnancy guidelines recommend that women consume enough folic acid to reduce the ris0 of spina bifida and related problems- The new findings suggest that these guidelines should also include recommendations about vitamin "/2The many faces of vitamin "/2> catalysis by cobalamin+dependent en)ymes#nnu Iev Biochem. 200F2H2?20:*/H. Vitamin "/2 is a comple# organometallic cofactor associated with three subfamilies of en)ymes> the adenosylcobalamin+dependent isomerases' the methylcobalamin+dependent methyltransferases' and the dehalogenases- =ifferent chemical aspects of the cofactor are e#ploited during catalysis by the isomerases and the methyltransferases- Thus' the cobalt+carbon bond ruptures homolytically in the isomerases' whereas it is

cleaved heterolytically in the methyltransferases- The reaction mechanism of the dehalogenases' the most recently discovered class of "/2 en)ymes' is poorly understood- %ver the past decade our understanding of the reaction mechanisms of "/2 en)ymes has been greatly enhanced by the availability of large amounts of en)yme that have afforded detailed structure+function studies' and these recent advances are the sub,ect of this reviewCobalamin+dependent methyltransferases#cc ,hem Ies. 2001 #ug2F/%@'?G@1*:. Cobalamin cofactors play critical roles in radical+cataly)ed rearrangements and in methyl transfers- This Account focuses on the role of methylcobalamin and its structural homologues' the methylcorrinoids' as intermediaries in methyl transfer reactions' and particularly on the reaction cataly)ed by cobalamin+dependent methionine synthase- In these methyl transfer reactions' the cobalt5I6 form of the cofactor serves as the methyl acceptor- "iological methyl donors to cobalamin include 4?+ methyltetrahydrofolate' other methylamines' methanol' aromatic methyl ethers' acetate' and dimethyl sulfide- The challenge for chemists is to determine the en)ymatic mechanisms for activation of these unreactive methyl donors and to mimic these ama)ing biological reactions1ffects of vitamin "/2 on performance and circadian rhythm in normal sub,ects7europsychopharmacology. 1::G 7ov215%5'?/5G*G/. This preliminary study investigates effects of methyl+ and cyanocobalamin on circadian rhythms' well+being' alertness' and concentration in healthy sub,ects- 7i# women 5mean age !? years6 and /; men 5mean age !@ years6 were randomly assigned to treatment for /; days with ! mg cyano+5C"/26 or methylcobalamin 5&"/26 after A days of pre+treatment observation3evels in the C"/2 group increased rapidly in the first' then slowly in the second treatment wee0' whereas increase in the &"/2 group was linear$rinary a&T<s e#cretion was reduced by both forms of vitamin "/2 over 2; hours with a significant decrease between @ +// hours' whereas urinary e#cretion of potassium was significantly increased between @ + // hours- Activity from 2! + @ hours increased significantly under both forms of vitamin "/2- 7leep time was significantly reduced under &"/2 inta0e- In this group the change in the visual analogue scales items *sleep (uality'* *concentration'* and *feeling refreshed* between pretreatment and the first wee0 of treatment showed significant correlations with vitamin "/2 plasma levels- Cortisol e#cretion and temperature were not affected by either medication- We conclude that vitamin "/2 e#erts a direct influence on melatonin- %nly &"/2 has a positive psychotropic alerting effect with a distribution of the sleep+wa0e cycle toward sleep reduction-

Coen)yme "/2 5cobalamin6+dependent en)ymes.ssays Biochem. 1:::2F/?1F:*5/. The "/2 or cobalamin coen)ymes are comple# macrocycles whose reactivity is associated with a uni(ue cobalt+carbon bond- The two biologically active forms are methylcobalamin and AdoCbl and their closely related cobamide forms- &ethylcobalamin participates as the intermediate carrier of activated methyl groups- =uring the catalytic cycle the coen)yme shuttles between methylcobalamin and the highly nucleophilic cob5I6alamin form- 1#amples of methylcobalamin +dependent en)ymes include methionine synthase and &e+H;+&BT> coen)yme & methyl transferaseAdoCbl functions as a source of carbon+based free radicals that are unmas0ed by homolysis of the coen)yme8s cobalt+carbon bond- The free radicals are subse(uently used to remove non+acid hydrogen atoms from substrates 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- The structures of two cobalamin+dependent en)ymes' methionine synthase and methylmalonyl+CoA mutase' have been solved- In both cases the cobalt is co+ordinated by a histidine ligand from the protein- The significance of this binding motif is presently unclear since in other cobalamin+dependent en)ymes spectroscopic evidence suggests that the coen)yme8s nucleotide 8tail8 remains co+ordinated to cobalt when bound to the protein-

8ost #mericans can6t do it because they aren6t getting any 8.( LM,4B#M#8!7
$tress, obesity, infections, hormones, or alcohol ,an !7,I.#$. your ris) of 1. ,ancer 2. Dementia F. Depression /. eart disease Vitamin B*12 0 =olate ,an D.,I.#$. your ris) of 1. ,ancer 2. Dementia

F. Depression /. eart disease

2ou may want to get all the Vitamin "+/2 and folate you need from what you8re eating or by ta0ing your multivitamin- "ut' you8re really 4%T getting what you needIf you want to combat the ris0s of stress' obesity' infections' hormones' or alcohol' you need to learn about medical brea0throughs that ta0es you beyond homocysteine and cholesterolThey empowers you in your efforts to stay healthy- They help you ma0e the most of your Cod+ given abilities' ma#imi)ing your performance-

8ethylcobalamin is the most potent form of Vitamin B12 found in nature. Ee need methylcobalamin for the healthy development and sustenance of our circulatory, immune and nervous systems. .ggs, dairy products, fish and meat, especially organ meat li)e liver, are good sources of Vitamin B*12. !n fact, meals incorporating large amounts of liver represented the main treatment for Vitamin B*12 deficiency in the past. 8ethylcobalamin is the only active form of Vitamin B*12 in the brain outside the mitochondrion. (he liver must convert cyanocobalamin to methylcobalamin in order for Vitamin B*12 to do its biochemical wor) in the brain. Ehen the comple5 conversion of cyanocobalamin is not completed, the brain is robbed of the benefits of methylcobalamin. ,yanocobalamin is a by*product of Vitamin B*12 charcoal e5traction. $cientific methods led people to believe that cyanocobalamin, not methylcobalamin was the naturally occurring form of Vitamin B*12. ,yanide in the charcoal replaces the methyl group in much the same way as it does in the body of a cigarette smo)er. Vitamin B*12 re+uires the

assistance of !ntrinsic =actor to enter the body from the small intestine. Eithout !ntrinsic =actor, dietary Vitamin B*12 or B*12*containing supplements go unabsorbed. #utoimmune reactions and diseases sometimes destroy the stomach6s parietal cells that produce !ntrinsic =actor. &ernicious anemia results from this destructive process. 8ore rarely, pernicious anemia develops when the body ma)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 into the small intestine. 8onthly in1ections of Vitamin B*12 can correct the anemia, immune and neurological problems that snea) up on people with pernicious anemia. $urveys of depressed patients indicate nearly one*third of them do not receive enough folic acid or Vitamin B* 12. !t is e5tremely important to ta)e Vitamin B*12 when ta)ing folic acid supplements. Eithout Vitamin B*12 supplementation, worse physical problems might develop during folic acid supplementation. $mall amounts of Vitamin B*12 are absorbed directly through the mucosal tissue of the mouth. (his discovery led to the development of Vitamin B12 loCenges and sprays. Ehen Vitamin B*12 is absorbed in the mouth, it goes into the blood and then to the enCymes that re+uire Vitamin B*12 as a coenCyme. Eith other forms of Vitamin B*12, the liver must use its enCyme systems

to produce methylcobalamin. Eith increased availability of methylcobalamin, medical research has shown that methylcobalamin has important benefits not seen with cyanocobalamin. !t acts to reverse nerve damage and promote nerve cell regeneration. 8ethylcobalamin plays a )ey role in sleep. !t helps the brain fill up its neurotransmitter >gas tan)> when neurotransmitters are produced from amino acids. $imilarly, depression also improves more +uic)ly and completely when patients ta)e methylcobalamin. Depression also can worsen even while using antidepressants if a restrictive diet is started to lose weight. # diet can run the neurotransmitter >gas tan)> dry. omocysteine has emerged on center*stage as a biochemical culprit associated with vascular and brain disease. Vitamin B*12 and folic acid are crucial to the elimination of homocysteine. Vitamin supplementation reduces the chances of building up levels of homocysteine associated with stress. ,linical e5perience and scientific research have clearly established the importance of Vitamin B*12. (he discovery of Vitamin B*12 was considered so monumental that the responsible researchers were honored with the 7obel &riCe. Iecent discoveries have demonstrated the value of using methylcobalamin for

improvement in the cardiovascular, immune and nervous 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/ (..( MayH #&"-') $#<+((/

5ACKA9>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,esti ated 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 hi h+dose folic acid supplementation/ M@TH>2S) In order to assess the efficacy on lowerin plasma tHcy le,els "fastin concentration'! (# H2 patients! were randomly assi ned and pro,ided folic acid supplementation) #- m 1day orally " roup I! n 4 &'H methylcobalamin -.. m intra,enously after each H2! in addition to folic acid " roup II! n 4 &'H or ,itamin 5"<' "5"<''! <. m 1day orally! in addition to folic acid and methylcobalamin " roup III! n 4 &'/ All patients were treated for * weeks/Amethionine+loadin test was conducted before and after supplementation/ The followin measurements were also made before and after supplementation for each roup) serum folic acid! 5"<'! and ,itamin 5"#(' "5"#('' concentrations "includin measurement of proportion of methylcobalamin fraction'/ Twel,e H2 patients recei,in methylcobalamin alone ser,ed as the H2 control roup and se,en healthy ,olunteers ser,ed as the normal control roup for this study/ 9@SGBTS) In our randomi:ed H2 patients the proportions of methylcobalamin fraction "3%/*01+ &/-D' and plasma ,itamin 5"<' concentration "(/$01+#/# n 1ml' were si nificantly lower than in the normal controls "methylcobalamin -%/&01+(/(D! ?S./.#H 5"<' (./#01+#./% n 1ml! ?S./.#'! while folic acid and ,itamin 5"#(' were not si nificantly different from the normal controls/ Mean percenta e reduction in fastin tHcy was #&/*01+ %/3D in roup I! -&/301+#*/*D in roup II! -$/$01+-/<D in roup III! and #%/&01+&/-D in H2 controls/ The power of the test to detect a reduction of tHcy le,el was $$/<D in roup II and $$/$D in roup III when type I error le,el was set at ./.-/ Aroups II and III had normal results for the methionine+loadin test after treatment/ Treatment resulted in normali:ation of fastin tHcy le,els "S#( n 1ml' in all #3 patients treated by the combined

administration of methylcobalamin and supplementation of folic acid re ardless of whether there was supplementation of ,itamin 5"<'/ The benefit of methylcobalamin administration on lowerin plasma tHcy le,els inH2patients was remarkable/ >ur study su ested that both supplementations of hi h+dose folic acid and methylcobalamin are re6uired for the remethylation pathway to re ain its normal acti,ity/ This method could be a therapeutic strate y to combat the risk associated with atherosclerosis and cardio,ascular disease in patients with chronic renal failure/ CONCL)%ION/

The Coen:yme Forms of =itamin 5#() Toward an Gnderstandin of their Therapeutic ?otential
0re&ory 1elly2 N+D+ Ab!tract Althou h cyanocobalamin and hydro7ycobalamin are the most commonly encountered supplemental forms of ,itamin 5#(! adenosyl+ and methylcobalamin are the primary forms of ,itamin 5#( in the human body! and are the metabolically acti,e forms re6uired for 5#(+dependent en:yme function/ @,idence indicates these coen:yme forms of ,itamin 5#(! in addition to ha,in a theoretical ad,anta e o,er other forms of 5#(! actually do ha,e metabolic and therapeutic applications not shared by the other forms of ,itamin 5#(/ This article will pro,ide an o,er,iew of the metabolism and function of adenosyl+ and methylcobalamin! and will discuss the potential therapeutic rele,ance of the coen:yme forms of ,itamin 5#( in a ,ariety of clinical conditions! includin anemia! anore7ia! cancer! HI=! and li,er and sleep disorders/ "Alt Med 9e, #$$&H("-')3-$+3&#' Introduction

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 si nificance remains uncertain/ Althou h the amount of cyanide is considered to7icolo ically insi nificant! 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 patholo ical chan es 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 nitro en atoms/ Surroundin this central cobalt is a corrin rin ! which structurally resembles the porphyrin rin found in hemo lobin! the cytochromes! and chlorophyll/ The use of cobalt in the coen:yme forms of cobalamin is the only known function of this metal in biolo ical systems/ In humans! the cobalt in the coen:yme forms of ,itamin 5#( e7ists in a uni,alent "0#' o7idati,e state! desi nated as cob"I'alamin/ Cobalamin molecules can also contain cobalt in a 0* "cob"III'alamin' or 0( "cob"II'alamin' o7idati,e stateH 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+CblH howe,er! this molecule does not occur naturally in plants! micro+or anisms! 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 biolo ically acti,e 0# state/ In order to be utili:ed in the body! the cyanide molecule must be remo,ed and eliminated throu h phase II deto7ification/ It is thou ht that lutathione "ASH' mi ht be the compound performin the function of decyanation in ,i,o! since lutathionylcobal+amin "AS+Cbl' has been isolated from mammalian tissue/( If! in fact! ASH is needed as a cofactor to acti,ate

C8+Cbl to the coen:yme forms of ,itamin 5#(! clinical situations characteri:ed by decreased tissue le,els of ASH mi ht 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 floraH howe,er! this appears to be untrue since no si nificant 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 the stomach parietal cells! of intrinsic factor/ The cobalamin+9+protein comple7 is di ested 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/ Althou h the basic cobalamin molecule is only synthesi:ed by micro+ or anisms! 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 hydro en roups and or anic roups e7chan e 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 de radati,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/

MetCbl;s only known biolo ical 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 re eneration1remethylation 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' decyanationH "ii' reduction of the 0* and 0( formsH "iii' synthesis of MetCbl in the cytosolH and "i,' synthesis of AdeCbl in the mitochondria/ The initial step of decyanation is probably dependent on ASH! 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,anta e 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 roupH howe,er! MetCbl can be re enerated! by acceptin a methyl roup from -+methyltetrahydrofolate! for reuse in methionine synthase "see fi ure #/'/ @,idence indicates alpha+tocopherol protects a ainst a reduction in AdeCbl in o7idati,ely stressed cells/3 @7perimental e,idence su ests alpha+tocopherol mi ht be needed for formation of AdeCblH 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/< Ab!orption @,idence indicates cobalamin from MetCbl is utili:ed more efficiently than C8+Cbl to increase the le,els of coen:yme forms of ,itamin 5#(/ Althou h free MetCbl is not ,ery stable in the astrointestinal tract! and considerable loss of the methyl roup can take place under e7perimental conditions! in

physiolo ical situations intrinsic factor probably partially protects MetCbl from de radation/ ?aper chromato raphy of di ested ileal mucosa has demonstrated unchan ed 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+CblH but! si nificantly 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/ Althou h a hi her percenta e 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/ % Althou h indi,iduals with pernicious anemia do not produce the intrinsic factor needed for ,itamin 5#( absorption! hi h 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+physiolo ical 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 mi ht offer an ad,anta e o,er supplementation of the non+ biolo ically 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! althou h 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 hematolo ical parameters "hemo lobin! hematocrit! red cell count! mean

corpuscular ,olume! iron! and transferrin iron bindin capacity' in pre nant women/#( Aranese et al similarly report a positi,e result from the supplementation of a ferritin+AdeCbl+folinic acid preparation to 3. women durin pre nancy/ A pro ressi,e increase in hematolo ical parameters was demonstrated and a complete normali:ation of red cell morpholo y 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 wei ht ain and normali:ation of astrointestinal function/ Batent fati ue was reported to disappear and mental performance increase under this treatment re imen/#3 Korkina 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 sta e of cache7ia/ Batent fati ue 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 jud ed ood by the authors! were comparable to the effects of the pharmaceutical a ent! and were produced with no side+effects/ #< Cancer/ Ehile information is ,ery limited! both AdeCbl and MetCbl mi ht e,entually be shown to ha,e a supporti,e role in the pre,ention or treatment of cancer/ A si nificant body of e7perimental e,idence su ests a deficiency of ,itamin 5#( can enhance the acti,ity of ,arious carcino ens/ #& @7perimental results also indicate a link between alterations in the intracellular metabolism of cobalamin and the increased rowth of human melanoma cells/ #% A methyl roup+deficient diet "MA22' has been shown to result in hypomethylation of 28A and t98A! and to promote cancer in the li,er of rats in as short a period of time as one week/ 9esults of e7periments conducted by Eainfan and ?oirier support the hypothesis that intake of a MA22! by causin depletion of SAM pools! results in 28A hypomethylation! and subse6uently leads to chan es in ene e7pression/#$ Althou h many of the MA22+induced alterations in methylation and ene e7pression occur rapidly! Christman et al ha,e demonstrated they are essentially re,ersible/ (.

It is not surprisin that MetCbl! because of its ability to donate a methyl roup and because of its role in the re eneration of SAM! the body;s uni,ersal methyl donor! mi ht be protecti,e a ainst cancer/ Cell culture and in ,i,o e7perimental results indicate MetCbl can inhibit the proliferation of mali nant 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/(* Althou h more research is re6uired to ,erify findin s! MetCbl mi ht 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 su ested! based on kinetic analysis! a dose of ./.# m 1k of MetCbl mi ht be an optimal dose for impro,in the antitumor dru action of methotre7ate/(3 Heimbur er 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 neurophysiolo ical 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 re ression of si ns 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/(< ?ower spectral analysis of heart rate ,ariability is a means of detectin the relati,e acti,ity and balance of the sympathetic1parasympathetic ner,ous systems! and has been su ested to be a ood 6ualitati,e method of e,aluatin sub+clinical diabetic autonomic neuropathy/ Yoshioka et al ha,e shown for indi,iduals with 8I22M! oral administration of #-.. mc 1day of MetCbl produces impro,ements in se,eral components of heart rate ,ariability/ (&

Eye function/ @7periments indicate chronic administration of MetCbl protects cultured retinal neurons a ainst 8+methyl+2+aspartate+receptor+mediated lutamate neuroto7icity/ Kikuchi et al su est the action is probably due to alteration in the membrane properties mediated throu h 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 si nificantly 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 specific lactate dehydro enase acti,ity! and decreased :inc! ma nesium and potassium concentrations in rats/ Co+administration of AdeCbl with 2@H? is reported to pre,ent these chan es/ 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 dia nosed oli o: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 "#!-.. micro rams1day! for 3+(3 weeks' to (< infertile male patients/ ?atients with a:oospermia were e7cluded from the trial/ Sperm concentration increased in #. cases "*%/3D'! total sperm count increased in #3 cases "-*/%D'! sperm motility increased in #* cases "-./.D'! and total motile sperm count increased in #* cases "-./.D'/ Serum luteini:in hormone! follicle stimulatin hormone! and testosterone were unchan ed/ ** HI"/ It has been obser,ed that human immunodeficiency ,irus "HI=' seropositi,e indi,iduals ha,e decreased le,els of metabolites in,ol,ed in methylation! and that low serum ,itamin 5#( le,els are associated with an increased risk of pro ression to AI2SH howe,er! the effect of supplementation of coen:yme forms of ,itamin 5#( on disease pro ression is unknown/

May has proposed that the replication of HI= mi ht be! in part! modulated by 28A methylation! and has su ested hypermethylation of the HI= pro,irus mi ht suppress ,iral replication and play a role in the establishment of latency/ 5ecause of its central role in methylation! MetCbl! as well as SAM and methyltetrahydrofolate! mi ht ha,e potential as therapeutic a ents in HI=+ infected indi,iduals/*3 @,idence is be innin to su est low serum ,itamin 5#( concentrations mi ht precede disease pro ression in indi,iduals positi,e for HI=/ Tan et al ha,e reported the risk of pro ression to AI2S is increased in indi,iduals with low serum ,itamin 5+#( concentrations "9H 4 (/(#! $-D CI 4 #/#*+3/*3'/ *Eeinber et al in,esti ated cobalamins to determine their ability to modify HI=+# infection of hematopoietic cells in ,itro/ Their results indicate! under e7perimental conditions! >H+Cbl! MetCbl! and AdeCbl inhibit HI=+# infection of normal human blood monocytes and lymphocytes/ They su est that because of the relati,e ease with which hi h blood and tissue le,els of cobalamins can be achie,ed in ,i,o! these a ents Cshould be considered as potentially useful a ents for the treatment of HI=+# infection/C *< Homocy!teinemia and Methyl'malonic Acidemia/ @le,ated le,els of homocysteine and methylmalonic acid can be metabolic indications of decreased le,els of the coen:yme forms of ,itamin 5#(! or the presence of a enetic en:yme defect/ ?ropelled by e,idence that ele,ated concentrations are associated with an increased risk for a ,ariety of chronic clinical conditions! homocysteine has recei,ed a tremendous amount of emphasis in the scientific literature/ 5ecause MetCbl is a potential donor of the methyl roup re6uired to re enerate methio+ nine from homocysteine! a theoretical ar ument can be used to justify this coen:yme form of ,itamin 5#( as a part of the nutritional protocol for lowerin homocysteine/ Araki et al ha,e demonstrated that ele,ated homocysteine le,els are reduced followin parenteral treatment with MetCbl/ In their trial! ten diabetic patients with ele,ated plasma le,els of homocysteine were administered #... mc of MetCbl i/m/ daily for three weeks/ Followin treatment! the plasma le,els of homocysteine decreased from a mean ,alue of #3/& to #./( nmol1ml "? S ./.#'/*& Methylmalonic acidemia is enerally the result of an inherited metabolic defect! althou h it is possible to ha,e ele,ated le,els of this metabolite due to a functional deficiency of AdeCbl in the absence of an inherited defect/ 5hatt et al ha,e su ested a transient response to >H+Cbl mi ht be misleadin and

mi ht subse6uently impair the therapeutic response to AdeCbl/ They further su est AdeCbl be the cobalamin therapy of choice for indi,iduals with biochemically uncharacteri:ed methylmalonic acidemia/ *% Li.er Di!ea!e/ AdeCbl and MetCbl appear to offer a theoretical ad,anta e o,er either C8+Cbl or >H+Cbl in the treatment of li,er disorders/ Althou h hi h blood le,els of ,itamin 5#( ha,e been reported in patients with hepatitis! cirrhosis! and other li,er disease! it is not unusual to actually ha,e a correspondin ly low li,er tissue concentration of ,itamin 5#( and its coen:ymes/ Alass et al proposed this obser,ation mi ht be due to an impaired ability of the li,er to absorb ,itamin 5#( from the portal circulation/ *$ 5ecause a ,itamin deficiency can persist durin li,er disease despite oral ,itamin supplementation! Bee,y et al ha,e su ested the li,er;s ability to con,ert ,itamins into metabolically acti,e forms mi ht be compromised/ 3. It is possible! durin these patholo ical conditions! the li,er will not contain ade6uate supplies of the needed cofactors to optimally form coen:yme analo ues of ,itamin 5#(/ 5ecause of these factors! Iwarson et al su ested that ,itamins used in the treatment of li,er disorders should be i,en in their metabolically acti,e form! thereby eliminatin the need for con,ersion to occur in dama ed li,er cells/3# In e7perimentally induced lipid pero7idation of li,er microsomes resultin from poisonin of rabbits with phenylhydra:ine! MetCbl and AdeCbl were shown to modulate the acti,ity of the monoo7y enase system/ MetCbl appeared to induce the system! and AdeCbl seemed to repress the system/ Administration of MetCbl into poisoned rabbits stimulated the acti,ities of dimethyl aniline 8+demethylase! aniline p+hydro7ylase! 8A2?H+cytochrome ?+3-.! and 8>2H+cytochrome b- reductases as compared with normal state! while AdeCbl inhibited the reduction of all the monoo7y enase system patterns studied/ Althou h the therapeutic rele,ance of these actions of the coen:yme forms of ,itamin 5#( on the monoo7y enase system is open to debate! the authors obser,ed that both of these coen:ymes contributed to normali:ation of lipid pero7idation in li,er microsomes of poisoned rabbits/ 3( AdeCbl also e7erts hepato+protecti,e acti,ity after carbon tetrachloride+induced hepatitis in rabbits/ The normali:ation of results from the sulfobromophthalein test and the normali:ation of acti,ity of sorbitol dehydro enase and alanine aminotransferase indicate AdeCbl enhanced the reco,ery process/ 3* In an e7perimental model! a low protein choline+deficient diet! althou h it did not chan e total cobalamin content in the li,er of rats! si nificantly decreased total and non+protein sulfhydryl "SH'+ roup le,els as well as ASH transferase

acti,ity in the li,er/ MetCbl "but not AdeCbl' administration restored non+ protein SH+ roup le,els and ASH transferase acti,ity! and administration of both MetCbl and AdeCbl normali:ed total SH+ roup content/ 33 AdeCbl appears to be a useful supplement for support of patients with hepatitis A/ Two roups of patients from the same hepatitis A epidemic recei,ed either AdeCbl or >H+Cbl/ ?atients were i,en # m per day i/m/ for the first #( days and then recei,ed # m orally for the ne7t (* days/ The roup treated with AdeCbl had a 6uicker return to normal of serum aminotransferase le,els/3# Fossati reported impro,ements in body wei ht and appetite in adults with li,er disease and chronic pulmonary tuberculosis followin supplementation with < m 1day of AdeCbl for three months/3Medina et al treated *& people sufferin from ,iral hepatitis with either AdeCbl or C8+Cbl/ Their obser,ations indicate the AdeCbl was si nificantly more efficacious than C8+Cbl in normali:in total bilirubin! serum lutamic o7aloacetic transaminase "SA>T'! serum lutamic pyru,ic transaminase "SA?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#%! SA>T in #-1#%! SA?T in #.1#%! and alkaline phosphatase in #%1#% subjects recei,in AdeCbl/ 3< 9esta et al ha,e reported a combination of AdeCbl! alon with li,er e7tract! adrenal corte7 e7tract! and nucleosides! is effecti,e in normali:in SA>T! SA?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! SA>T and SA?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 / Althou h 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 li ht+sensiti,ity! and normali:in circadian rhythm/

Gchiyama et al ha,e reported that intra,enous injections of MetCbl increased rectal temperature in the later hours of the daytime and correspondin ly impro,ed alertness! as assessed with a ,isual analo scale! durin the same time inter,al/ They su est 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 (- hoursH 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! with administration 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 dia nosed 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 * m 1day of MetCbl! an impro,ement of both sleep+wake rhythm disorders was obser,ed/ Serum concentrations of ,itamin 5#( durin treatment were in the hi h ran e 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 midni ht/ The period of the sleep+wake cycle of the hypernychthemeral patient was (3/< hours before treatment and (3/. hours after treatment/ 8either of these patients had shown any laboratory or clinical e,idence su esti,e of ,itamin 5#( deficiency prior to the therapy/-( Mayer et al in,esti ated the effects of MetCbl and C8+Cbl on circadian rhythms! well+bein ! alertness! and concentration in healthy subjects/ Si7

women and #3 men were randomly assi ned to recei,e either * m of MetCbl or * m of C8+Cbl for #3 days/ All indi,iduals were initially obser,ed for nine days prior to be innin either supplementation re ime/ Acti,ity from (*..+ .&.. hours increased si nificantly with supplementation of both forms of ,itamin 5#(/ Howe,er! sleep time was only si nificantly reduced in the roup recei,in MetCbl/ In this roup! impro,ements in subjecti,e parameters of Csleep 6uality!C Cconcentration!C and Cfeelin refreshed!C as determined by a ,isual analo scale! were correlated with ,itamin 5#( plasma le,els durin the first week of MetCbl supplementation/ 8o obser,ed chan es in either cortisol e7cretion or temperature were noted in indi,iduals recei,in either form of ,itamin 5#(/ The authors concluded that! C///only methylcobalamin has a positi,e psychotropic alertin effect with a distribution of the sleep+wake cycle toward sleep reduction/C-* @i ht youn males were subjected to a sin le+blind cross+o,er test to determine the effects of MetCbl on the phase+response of the circadian melatonin rhythm to a sin le bri ht li ht e7posure/ MetCbl "./- m 1day' was injected intra,enously at #(*. hours for ## days/ Startin on day #(! this re imen was superseded by oral administration of MetCbl "( m tid' for se,en days/ The melatonin rhythm before the li ht e7posure showed a smaller amplitude in the indi,iduals treated with MetCbl than in those recei,in the placebo/ The li ht e7posure phase+ad,anced the melatonin rhythm si nificantly in the MetCbl roup! but not in the placebo roup! indicatin MetCbl enhanced the li ht+ induced phase+shift in the human circadian rhythm/ -3 Mi!cellaneou!/ A combination of a coen:yme comple7 combinin AdeCbl! pyrido7al phosphate! and phosphaden appears to be efficacious in the treatment of patients with infectious aller ic myocarditis/ Ma:urets et al report a correcti,e action of this metabolic therapy on myocardial en:ymatic status/ Antiarrhythmic and cardiotonic actions of the coen:yme comple7 were also noted/-Faludin et al included si7ty patients with 5ell;s palsy in an open randomi:ed trial/ ?atients were assi ned to one of three treatment roups) steroid! MetCbl! or MetCbl 0 steroid/ The 6uickest time re6uired for complete reco,ery of facial ner,e function occurred in the roup recei,in MetCbl alone "mean of #/$- 01+ ./-# weeks'H howe,er! the mean reco,ery time of the roup recei,in MetCbl and steroid treatment was similar "(/.- 01+ #/(* weeks'/ Indi,iduals recei,in only steroid treatment had a mean reco,ery time of $/<. 01+ &/&$ weeks'/ The authors also noted the facial ner,e score after #+* weeks of treatment was si nificantly better in indi,iduals recei,in MetCbl than in those only recei,in

steroid therapy/ The impro,ement of concomitant symptoms was also better in the roups treated with MetCbl/-< Katsuoka et al reported a case of a 3%+year+old woman with a positi,e response to MetCbl/ Her initial complaint was ait disturbanceH howe,er! by the time she was e,aluated! her symptoms had pro ressed to motor weakness! sensory disturbances in her limbs! and dementia/ She also had widespread coarse hair/ In response to injections of -.. mc of MetCbl e,ery other day! the patient;s paresthesia resol,ed! hand rip stren th impro,ed! and her dementia was e,aluated as reduced/ Her ait also impro,ed! until she was able to walk on tiptoe! and her hair te7ture returned to normal/ -& Do!a&e and To4icity A therapeutic dose for conditions re6uirin MetCbl would be a minimum of #-.. mc and a ma7imum of <... mc per day/ 8o si nificant therapeutic ad,anta e appears to occur from dosa es e7ceedin this ma7imum doseH howe,er! it is likely that beneficial physiolo ical effects occur at dosa es as low as #.. mc per day! especially if this dose is i,en repetiti,ely o,er time/ A therapeutic dose for AdeCbl is #...+<... mc per day/ Similarly! some physiolo ical benefits are likely to occur at repetiti,e doses far below this therapeutic ran e/ 5oth MetCbl and AdeCbl ha,e been administered orally! intramuscularly! and intra,enouslyH howe,er! positi,e clinical results ha,e been reported irrespecti,e of the method of administration/ It is not clear whether any therapeutic ad,anta e is ained from non+oral methods of administration/ MetCbl and AdeCbl ha,e usually been administered in di,ided doses three times daily/ These supplements ha,e e7cellent tolerability and no known to7icity/ AdeCbl has been administered safely durin pre nancy/ 8o rationale e7ists to suspect MetCbl would not also be safe durin pre nancy/ Conclu!ion AdeCbl and MetCbl are the coen:yme forms of ,itamin 5#( utili:ed in the ,itamin 5#(+dependent en:ymes in humans/ 5ecause the coen:yme forms bypass se,eral of the en:ymatic reactions re6uired for the formation of the functional forms of ,itamin 5#(! they offer a theoretical ad,anta e in

cobalamin supplementation/ 5oth AdeCbl and MetCbl are retained in the body better and increase tissue concentrations of cobalamin better than C8+Cbl/ Additionally! the coen:yme forms of ,itamin 5#( demonstrate a ran e of acti,ity and clinical results not shown by the other supplemental forms of ,itamin 5#(/ It is important to remember that circulatin le,els of ,itamin 5#( are not always a reflection of tissue le,els! and that e,en if an ade6uate supply of cobalamin appears in the circulation! a functional deficiency of the coen:yme forms mi ht coe7ist in tissues and other body fluids/ Althou h C8+Cbl will usually increase circulatin le,els of cobalamin! its ability to increase tissue le,els of the acti,e forms of ,itamin 5#( can be limited in a ran e of sub+ clinical and clinical conditions/ @,en in a best case scenario! the acti,ation of C8+Cbl to either AdeCbl or MetCbl does not occur instantly! possibly occurrin o,er #+( months! and re6uires the interaction of ASH! reducin a ents! possibly alpha+tocopherol! and in the case of MetCbl! SAM and the acti,e form of folic acid/ The use of either AdeCbl and1or MetCbl offers a si nificant biochemical and therapeutic ad,anta e o,er other e7istin forms of ,itamin 5#(! and should be considered as a first+line choice for correctin ,itamin 5#( deficiency and treatin conditions shown to benefit from cobalamin administration/ *eference! #/ Tureshi AA! 9osenblatt 2S! Cooper 5A/ Inherited disorders of cobalamin metabolism/ Crit 9e, >ncol Hematol #$$3H#&)#**+#-#/ (/ ?e:acka @! Areen 9! Facobsen 2E/ Alutathionylcobalamin as an intermediate in the formation of cobalamin coen:ymes/ 5iochem 5iophys 9es Comm #$$.H()33*+3-./ */ Cooper 5A! 9osenblatt 2S/ Inherited defects of ,itamin 5#( metabolism/ Ann 9e, 8utr #$%&H&)($#+*(./ 3/ Turley C?! 5rewster MA/ Alpha+tocopherol protects a ainst a reduction in adenosylcobalamin in o7idati,ely stressed human cells/ F 8utr #$$*H#(*)#*.-+ #*#(/

-/ ?appu AS! Fatterpaker ?! Sreni,asan A/ ?ossible interrelationship between ,itamins @ and 5#( in the disturbance in methylmalonate metabolism in ,itamin @ deficiency/ 5iochem F #$&%H#&()##-+#(#/ </ Alusker F?/ =itamin 5#( and the 5#( coen:ymes/ =itam Horm #$$-H-.)#+ &</ &/ >kuda K! Yashima K! Kita:aki T! Takara I/ Intestinal absorption and concurrent chemical chan es of methylcobalamin/ F Bab Clin Med #$&*H%#)--&+-<&/ %/ Heinrich HC! Aabbe @@/ Metabolism of the ,itamin 5#(+coen:yme in rats and man/ Ann 8Y Acad Sci #$<3H##()%&#+$.*/ $/ Bederle FA/ >ral cobalamin for pernicious anemia/ Medicines best kept secretI FAMA #$$#H(<-)$3+$-/ #./ 5erlin H! 5rante A! ?ibrant A/ =itamin 5#( body stores durin oral and parenteral treatment of pernicious anemia/ Acta Med Scand #$&%H(.3)%#+%3/ ##/ Tsukerman @S! ?omerantse,a TIa! ?o:nanskaia AA! et al/ @ffect of methyl+ cobalamin and adenosylcobalamin on the process of hematopoiesis and ,itamin 5#( e7chan e in e7perimental phenylhydra:ine+induced anemia in rabbits/ =opr Med Khim #$%$H*-)#.<+###/ QArticle in 9ussianR #(/ Fochi F! Ciampini M! Ceccarelli A/ @fficacy of iron therapy) a comparati,e e,aluation of four iron preparations administered to anaemic pre nant women/ F Int Med 9es #$%-H#*)#+##/ #*/ Aranese 2! 9etto A! Scurria B! 5or ese 9/ Associa:ione ferritina! coen:ima adenosilcobalaminico! coen:ima folico) impie o in ra,idan:a/ Min Ainecol #$%<H*%)$*+#../ QArticle in ItalianR #3/ Korkina M=! Korchak AM! Med,ede, 2I/ Clinico+e7perimental substantiation of the use of carnitine and cobalamin in the treatment of anore7ia ner,osa/ Lh 8e,ropatol ?sikhiatr #$%$H%$)%(+%&/ QArticle in 9ussianR #-/ Korkina M=! Korchak AM! Kare,a MA/ @ffects of carnitine and cobamamide on the dynamics of mental work capacity in patients with anore7ia ner,osa/ Lh 8e,ropatol ?sikhiatr Im S S Korsako,a #$$(H$()$$+#.(/ QArticle in 9ussianR

#</ Aiordano C! ?errotti A/ Clinical studies of the effects of treatment with a combination of carnitine and cobamamide in infantile anore7ia/ Clin Ter #$&$H%%)-#+<./ QArticle in ItalianR #&/ @to I! Krumdieck CB/ 9ole of ,itamin 5#( and folate deficiencies in carcino enesis/ Ad, @7p Med 5iol #$%<H(.<)*#*+**./ #%/ Biteplo 9A! Hipwell S@! 9osenblatt 2S! et al/ Chan es in cobalamin metabolism are associated with the altered methionine au7otrophy of hi hly rowth autonomous human melanoma cells/ F Cell ?hysiol #$$#H#3$)**(+**%/ #$/ Eainfan @! ?oirier BA/ Methyl roups in carcino enesis) effects on 28A methylation and ene e7pression/ Cancer 9es #$$(H-()(.&#S+(.&&S/ (./ Christman FK! Sheikhnejad A! 2i:ik M! et al/ 9e,ersibility of chan es in nucleic acid methylation and ene e7pression induced in rat li,er by se,ere dietary methyl deficiency/ Carcino enesis #$$*H#3)--#+--&/ (#/ 8ishi:awa Y! Yamamoto T! Terada 8! et al/ @ffects of methylcobalamin on the proliferation of andro en+sensiti,e or estro en+sensiti,e mali nant cells in culture and in ,i,o/ Int F =itam 8utr 9es #$$&H<&)#<3+#&./ ((/ Shimi:u 8! Hama:oe 9! Kanayama H! et al/ @7perimental study of antitumor effect of methyl+5#(/ >ncolo y #$%&H33)#<$+#&*/ (*/ Tsao CS! Myashita K/ Influence of cobalamin on the sur,i,al of mice bearin ascites tumor/ ?athobiolo y #$$*H<#)#.3+#.%/ (3/ Miasishche,a 8=! Aerasimo,a AK! Il;ina 8S! Sof;ina L?/ @ffect of methylcobalamin on methotre7ate transport in normal and tumorous tissues/ 5iull @ksp 5iol Med #$%-H$$)&*<+&*%/ QArticle in 9ussianR (-/ Heimbur er 2C! Ale7ander C5! 5irch 9! et al/ Impro,ement in bronchial s6uamous metaplasia in smokers treated with folate and ,itamin 5#(/ 9eport of a preliminary randomi:ed! double+blind inter,ention trial/ FAMA #$%%H(-$)#-(-+#-*./ (</ Ya6ub 5A! Siddi6ue A! Sulimani 9/ @ffects of methylcobalamin on diabetic neuropathy/ Clin 8eurol 8eurosur #$$(H$3)#.-+###/

(&/ Yoshioka K! Tanaka K/ @ffect of methylcobalamin on diabetic autonomic neuropathy as assessed by power spectral analysis of heart rate ,ariations/ Horm Metab 9es #$$-H(&)3*+33/ (%/ Kikuchi M! Kashii S! Honda Y! et al/ ?rotecti,e effects of methylcobalamin! a ,itamin 5#( analo ! a ainst lutamate+induced neuroto7icity in retinal cell culture/ In,est >phthalmol =is Sci #$$&H*%)%3%+ %-3/ ($/ 8ishikawa Y! Shibata S! Shima:oe T! Eatanabe S/ Methylcobalamin induces a lon +lastin enhancement of the field potential in rat suprachiasmatic nucleus slices/ 8eurosci Bett #$$<H((.)#$$+(.(/ *./ Iwasaki T! Kurimoto S/ @ffect of methylcobalamin in accommodati,e dysfunction of eye by ,isual load/ San yo Ika 2ai aku Lasshi #$%&H$)#(&+#*(/ QAbstractR *#/ >ishi S/ ?re,ention of di"(+ethylhe7yl' phthalate+induced testicular atrophy in rats by co+administration of the ,itamin 5#( deri,ati,e adenosylcobalamin/ Arch @n,iron Contam To7icol #$$3H(<)3$&+-.*/ *(/ Moriyama H! 8akamura K! Sanda 8! et al/ Studies on the usefulness of a lon +term! hi h+dose treatment of methylcobalamin in patients with oli o:oospermia/ Hinyokika Kiyo #$%&H**)#-#+#-</ QAbstractR **/ Isoyama 9! Kawai S! Shimi:u Y! et al/ Clinical e7perience with methylcobalamin "CH*+5#(' for male infertility/ Hinyokika Kiyo #$%3H*.)-%#+ -%</ QAbstractR *3/ May 5A/ A no,el anti,iral strate y for HI= infection/ Med Hypotheses #$$*H3.)$*+$3/ *-/ Tan AM! Araham 8M! Chandra 9K! Saah AF/ Bow serum ,itamin 5+#( concentrations are associated with faster human immunodeficiency ,irus type # "HI=+#' disease pro ression/ F 8utr #$$&H#(&)*3-+*-#/ *</ Eeinber F5! Sauls 2B! Misukonis MA! Shu ars 2C/ Inhibition of producti,e human immunodeficiency ,irus+# infection by cobalamins/ 5lood #$$-H%<)#(%#+#(%&/

*&/ Araki A! Sako Y! Ito H/ ?lasma homocysteine concentrations in Fapanese patients with non+insulin+dependent diabetes mellitus) effect of parenteral methylcobalamin treatment/ Atherosclerosis #$$*H#.*)#3$+#-&/ *%/ 5hatt 9H! Binnell FC! 5arltrop 2/ Treatment of hydro7ycobalamin+resistant methylmalonic acidemia with adenosylcobalamin/ Bancet #$%<H()3<-/ QBetterR *$/ Alass A5F! 5oyd BF! @bin B/ 9adioacti,e ,itamin 5#( in the li,er/ F Bab Clin Med #$-%H-()%3$+%-$/ 3./ Bee,y CM! Thompson A! 5aker H/ =itamins and li,er injury/ Am F Clin 8utr #$&.H(*)3$*+3$$/ 3#/ Iwarson S! Bindber F/ Coen:yme 5+#( therapy in acute ,iral hepatitis/ Scand F Infect 2is #$&&H$)#-&+#-%/ 3(/ Korso,a TB! Moro:o,a 8A! ?o:nanskaia AA! Kur ano, 5I/ Comparati,e study of the effect of ,itamin 5#( coen:ymes on monoo7y enase system and lipid pero7idation in the li,er of rabbits poisoned with phenylhydra:ine/ =opr Med Khim #$%$H*-)$&+#.(/ QArticle in 9ussianR 3*/ Tebenchuk AM! Bukashuk =2! Bipkan A8! Stepanenko ==/ Antito7ic action of cobamamide in e7perimental hepatitis/ Farmakol Toksikol #$%3H3&)%&+$./ QArticle in 9ussianR 33/ Tsukerman @S! Korso,a TB! ?o:nanskaia AA/ =itamin 5#( metabolism and the status of sulfhydryl roups in protein+choline deficiency in rats/ @ffects of methyl+ and adenosyl+cobalamins/ =opr ?itan #$$(H#)3.+33/ QArticle in 9ussianR 3-/ Fossati C/ >n use of cobamamide in a roup of hospitali:ed patients with pulmonary tuberculosis/ Miner,a Med #$&#H<()3<*%+3<3</ QArticle in ItalianR 3</ Medina F! =itali 2/ Controlled clinical research with cobamamide in the treatment of ,iral hepatitis/ Clin Ter #$<%H3<)#*$+#33/ QArticle in ItalianR 3&/ 9esta M! =itali 2! Medina F/ Controlled clinical trial of a li,er e7tract combined with hi h doses of nucleosides! cobamamide and adrenal corte7 e7tract in the treatment of acute li,er diseases/ Clin Ter #$&(H<()(#*+((*/ QArticle in ItalianR

3%/ Teti =! Acerbi F! 8itti A/ ?rotection of li,er by a cortico+,itamin+li,er e7tract combination and cobamamide/ Clin Ter #$&3H<%)<&+&*/ QArticle in ItalianR 3$/ Gchiyama M! Mayer A! >kawa M! Meier+@wert K/ @ffects of ,itamin 5#( on human circadian body temperature rhythm/ 8eurosci Bett #$$-H#$()#+3/ -./ Tomoda A! Miike T! Matsukura M/ Circadian rhythm abnormalities in adrenoleukodystrophy and methyl 5#( treatment/ 5rain 2e, #$$-H#&)3(%+3*#/ -#/ Yamada 8/ Treatment of recurrent hypersomnia with methylcobalamin ",itamin 5#(') a case report/ ?sychiatry Clin 8eurosci #$$-H3$)*.-+*.&/ -(/ >hta T! Ando K! Iwata T! et al/ Treatment of persistent sleep+wake schedule disorders in adolescents with methylcobalamin ",itamin 5#('/ Sleep #$$#H#3)3#3+3#%/ -*/ Mayer A! Kro er M! Meier+@wert K/ @ffects of ,itamin 5#( on performance and circadian rhythm in normal subjects/ 8europsycho+ pharmacolo y #$$<H#-)3-<+3<3/ -3/ Hashimoto S! Kohsaka M! Morita 8! et al/ =itamin 5#( enhances the phase+response of circadian melatonin rhythm to a sin le bri ht li ht e7posure in humans/ 8eurosci Bett #$$<H((.)#($+#*(/ --/ Ma:urets AF! Aure,ich MA! Kubyshkin =F! et al/ Coen:yme metabolic therapy in infectious aller ic myocarditis/ Klin Med "Mosk' #$$-H&*)3#+3*/ QArticle in 9ussianR -</ Falaludin MA/ Methylcobalamin treatment of 5ell;s palsy/ Methods Find @7p Clin ?harmacol #$$-H#&)-*$+-33/ QAbstractR -&/ Katsuoka H! Eatanabe C! Mimori Y! 8akamura S/ A case of ,itamin 5#( deficiency with broad neurolo ic disorders and canities/ 8o To Shinkei #$$&H3$)(%*+(%</ QAbstractR