Transcript Methycobalami by Dr Sarma for print

Neurotropic Agents A Review
Dr.R.V.S.N.Sarma,
M.D., M.Sc., (Canada),
Consultant Physician,
Tiruvallur 602 001.
Dr.Sarma@works
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Neutropic Vitamins Reviewed
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Methycobalamin (CH3 B12)
Folic Acid (FA)
Pyridoxine (Vitamin B6)
Alpha Lipoic Acid (ALA)
Gamma Linoliac Acid (GLA)
Acetyl L-Carnitine (ALC)
Gabapentine (GBP)
Coenzyme Q 10 (Ubiquinone)
NAC (N-acetyl cysteine)
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The Question
Are YOU using Methylcobalamin ?
 Based on what sort of evidence?
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Standard Medical Text
Good Review Article on it
Unbiased CME
“Experts” use it and endorse it
The Pharma companies push it
Try something because nothing works
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The Question 2
Methylcobalamin - is it a better B12 ?
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What is the quality of evidence ?
In what conditions is it useful ?
What is the dosage, route and how long ?
Biochemical basis for its use
Other agents which are co prescribed
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The Quality of Evidence
 RCT-
Class I Evidence
 Single blind, Double blind
 Placebo controlled, Comparative
 Multi-centric, Trans-national
 Large number of patient populations
 Objective assessment criteria
 Statistical evidence P value, RR, AR
 Best in rating - Hypothesis proving
Eg. Atorvastatin, Ramipril, PTCA
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The Quality of Evidence
 Cohort studies- Class II Evidence
 Two or more self selected groups
 Prospectively followed for years
 Outcomes studied
 Conclusions drawn
 Good if properly designed
 Hypothesis testing
Crash helmets, Seat belts in cars etc.,
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The Quality of Evidence
 Case-control -Class III Evidence
 Cases of the disease in good number
 Matched controls
 Exposure of interest analyzed
 Retrospective – Problems
 Weaker in evidence
 Hypothesis generating
Hiroshima Nagasaki, Bhopal gas tragedy
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The Quality of Evidence
 Cross sectional -Class IV Evidence
 One time examination of the group
 No follow up – to future time
 No retrospective – into past events
 Weakest in evidence –
 At best prevalence estimates
Prevalence of obesity and Diabetes or CHD
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The Quality of Evidence
 Case reports – No evidence status
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Isolated case studies by physicians
Dissertations, Thesis reports,
News letter reports
Out break reports
Lay press reports
At best thought provoking
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The Quality of Evidence
 Anecdotal quotes – No evidence status
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Vague claims that something works
Secretive formulae – eg. asthma cures
“My experience” tells me – things
At best some respect to the expert
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The Quality of Evidence
 International Guidelines – JNC, ADA
 Recommendations by professional bodies like WHO, AHA
 “Reputed Journal” publications- Lancet, JAMA, NEJM, Post
graduate Medicine J
 FDA like approvals for use - indications
 Pharmaceutical company trials
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Bias versus Skepticism
 Bias – constant belief that something works even though
there is no class I or II evidence
 Skepticism – brushing away something as useless without
proper knowledge on it or in spite of good evidence that it
may work.
Both are dangerous
Biochemical or patho-physiological basis may not always be
established to start with – eg. Penicillin
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CAN WE TREAT NEUROPATHY AT ALL ?
WILL THE NEURONS REGENERATE ?
A SPOT LIGHT ON METHYLCOBALAMINE
A special form of
“New B12” may help
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CAN WE TREAT NEUROPATHY AT ALL ?
DOES THE NEURON REGENERATE ?
A SPOT LIGHT ON METHYLCOBALAMINE
Research has looked
at Methylcobalamin
for many disorders
Albeit, in a weaker way !!
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CAN WE TREAT NEUROPATHY AT ALL ?
DOES THE NEURON REGENERATE ?
A SPOT LIGHT ON METHYLCOBALAMINE
You may be very
interested in how
it could help
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A Rose is Rose is a Rose
But all B12
are not B12
are not B12
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The Vitamin B12 Family
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 Cyanocobalamin – CN-B12
 Hydroxycobalamin – OH-B12
 5’-Adenosylcobalamin- AS-B12
Inactive
Inactive
Active
 Methylcobalamin- CH3-B12
Active
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Vitamin B12
 By far the most complex vitamin in structure
 Made up of a planar corrin ring (4 pyrroles) – similar to Hb; the
cobalt is attached to 4 pyrroles
 The only vitamin that possesses a metal ion (cobalt) as part of
its structure
 The major cofactor form of B12 is AS-cobalamin or 5’- deoxy
AS-cobalamin
 Small amounts of Methylcobalamin also occur
 Red in colour, Heat and light sensitive
 Body stores 5 mg - 2-3 μgs /day - sufficient for 5 years
 MC is the most abundant B12 in breast milk
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Vitamin B12
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Synthesized by bacteria and stored in animal body
Commercially available as CN B12, OH B12, CH3 B12
Stored in the liver as the Transcobalamin I
Absorbed only in the presence of the intrinsic factor (a
glycoprotein released by parietal cells)
Transported to tissues via transcobalamin II
Transcobalamin I is the storage form
Present in foods such as liver, fish, eggs, milk
Absent in vegetables and fruits
None in Vegan Vegetarian diet
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Vitamin B12
Biochemical Reactions
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Coenzyme in DNA and Serotonin synthessis
Synthesis of Purines, Pyrimidines, NA
Synthesis of RBC and Proteins
Maintains Myeline sheath of Nerve cells
3 Carbon Fatty Acid Metabolism
Methylation Reactioms
 Homocysteine to Methionine
 Methyl melonyl CoA to Succinyl CoA
 Tetrahydrofolate to Methyl Tetrahydro Folate
 SAM-e (S-Adenosyl Methionine) –powerful mood elevator
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The Vitamin B12 Family
 The Grand Parent is the CN B12
 Absorbed from gut - R factor + IF - Ileum
 Transported as Transcobalamin II
 Stored in liver Transcobalamin I –5 mg/ 2 μg
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When needed CN is stripped off – GSH
OH is added – OH B12 - plasma to cytosol
Adenosylated to AS B12 - Mitochondria
Methylated to CH3 B12 – in cytosol
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A
Meet the Cobalamin Family
This is the Grand Parent
CN B12 is further metabolized
Cyano Cobalamin - CN B12
Boy friendship with ‘R’ factor
In the stomach
CN B12 + R factor combine with
Intrinsic Factor from the parietal
cells of the stomach
CN B12 + Transcobalamin I stored
in the liver and the TC II is released
and recycled
CN B12 combines with Trans
cobalamin II and gets into Plasma
Transcobalamin II, the Vehicle
CN B12 + IF - Complex - Marry
CN B12 + IF Complex Divorce
Enter intestinal cells of Ileum
IF is released and recycled
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B
Meet the Cobalamin Family
CN B12 when needed is metabolized in
the Liver
Cyanide is stripped off from
B12 - Cobalamin or B12
Hydroxyl group is added to
B12 Cobalamin – OH B12
(Methyl) CH3 is added to
OH B12 - CH3 B12
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Adenosyl group is added to
OH B12 -AS B12
CN
The Grand Parent
Inactive, a
non-coenzyme form
The Parent born
Inactive, a non-coenzyme form
Lives in Liver
The Parent is grown up now
Inactive, a non-coenzyme form
Gets into the plasma
Two Children are born
Both Active, Coenzyme forms Both
enter the cell
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Meet the Cobalamin Family
C
Purine synthesis
↑ Homocystenemia
Methionine (EAA)
Homocyst(e)ine (AA)
FOLIC ACID Cousin
METHIONINE SYNTHASE Ez
Of the Two Active children
H4 Folate
Purine
Pyrimidine
MTHFR Enzyme
METHYL COBALAMIN
COENZYME
CH3 –H4 Folate
First Child is - CH3 B12
lives in the Cytoplasm
active coenzyme
SHE
Very
OH B12
FOLATE TRAP
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D
Meet the Cobalamin Family
Glycolysis cycle
Succinyl CoA
Methylmelonic acedemia
Methylmelonic aciduria
Methylmelonyl CoA
METHYLMALONYL- Co A
MUTASE ENZYME
ADENOSYL COBALAMIN
COENZYME
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Of the Two Active children
Second Child is - AS B12
lives in the Mitochondria
active coenzyme
Amino Acid Metabolism
HE
Very
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Causes of B12 deficiency
 Pernicious anemia (autoimmune gastritis against
parietal cells - loss of intrinsic factor)
 Rarely due dietary deficiency
 Drugs : OCP, Trimethoprim, Methotrexate, Phenytoin,
Theophyllin
 Intestinal parasites - D.latum
 Gastrectomy, Chronic gastritis, PPI, H2 Blocker
 Old age, Poor dietary Intake, Hypochlorhydria
 Malabsorption syndromes
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Diagnosis of B12 deficiency
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Homocysteine levels (N < 13 μmols/ l)
Methyl Malonic Acid (MMA) levels
Serum B12 levels (N = 200 - 600 pg/ml)
IF Antibodies
Schilling test
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Diagnosis of B12 deficiency
 Schilling test
 distinguishes deficiency caused by pernicious anemia
with that caused by malabsorption
 compares absorption in radiolabeled B12 with intrinsic
factor and radiolabeled B12 without intrinsic factor
 in pernicious anemia the B12 with intrinsic factor will be
absorbed while the B12 by itself will not
 in malabsorption neither will be absorbed
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Manifestation of B12 deficiency
 Macrocytic megaloblastic anemia
 megaloblasts are abnormal erythroid precursors in bone marrow
(most cells die in the bone marrow)
 reticulocyte index is low
 hyperchromic macrocytes appear in blood
 anemia reflects impaired DNA synthesis
 other cells involved (leukopenia, thrombocytopenia)
 Spinal cord degeneration (irreversible) SACD
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swelling, demyelination, cell death
neurological disease
results from deficient methylmalonyl-CoA mutase
this cannot be treated with folic acid!!
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Treatment of B12 deficiency
 Use IM cyanocobalamin or hydroxocobalamin
 Administer daily for 2 - 3 weeks, then every 2 - 4 weeks for life
 Monitor reticulocytosis early to assure treatment is working
(reticulocyte count should go up)
 Monitor potassium levels to ensure hypokalemia does not occur
due to excessive RBC synthesis
Neurobion-H, Macraberin forte, Vitneurin – B12 1000
Eldervit, Enerject – B12 2500
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Cyano B12 versus Methyl B12
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Feature
Cyano B12
Methyl B12
IF
Absorption
Tissues
Urinary Excre.
As Cofactor
Effect on Ho Cy
Haemopoiesis
In breast milk
Required
Ileum –Good
Less retained
More
Inactive
Good
Effective
Low
Required
Ileum - Fair
More retained
Less
Active
Very Good
No effect
High concentr.
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Routes of Administration
Methylcobalamin
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Oral
Transdermal
Sublingual
Intramuscular
Intravenous
Subcutaneous
Intrathecal (LP)
Subcutaneous route is preferred for a
slow release of the Vitamin
IM route is also good
IM inj. is not a must; works orally
Prolonged blood levels after oral
S/L bypasses liver metabolism
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The Literature and
Methylcobalamin
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Diabetic Neuropathy
Bell’s Palsy
Alzheimer's AD
Parkinson's Disease PD
ALS – MND
Stroke
Hearing Loss, Eye
Memory disturbances
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Homocysteine excess
Sleep Disturbances
HD patients
Eating disturbances
Cardiac Rhythm
Male Impotence
Cancer
HIV
334 studies referenced on MC in various diseases
Almost all the evidence is class III or lower
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Diabetic Neuropathy
 Intrathecal Injection of MC in 7 Males and 4 Females – marked
improvement
 2500 mcg of Mc in 10 ml of saline I.T
 Repeated every monthly for 4-6 months
 Improvement in a week; NCV no change
 Maintained up to 4 years; No side effects
 ALA + MC 5 mg orally daily for DM PN
 500 mcg t.i.d for 4 months orally on 50 pts of DM PN were tried
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Bell’s palsy
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Small no of subjects studied
Oral as well as IM MC tried
One group oral steroids + Electrical stimumulation
The other group, the above 2 + MC
In MC group, the recovery was faster
Needs large scale RCT
Ultra high doses (500 mcg per kg body wt) = 30 mg per day
may help in nerve regeneration
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Alzheimer's AD
Pre senile dementia
Becoming very common
Due oxidative stress and ROS
MC in 3 to 4000 mg per day is tried and found to produce some
improvement
 IV MC used on 10 patients – found useful
 In Autism found to be very useful
 Only IM MC tried on 85 children – 60% showed improvement –
speech better
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Parkinson’s Disease PD
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Small number of patients tried
IM MC was used
Improvement in tremor and rigidity
Motor function less improved
Needs large scale RCTs
Allergic Disorders
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IgE, Histamin and IL-2, IL-4 are reduced –
This causes reduction in allergic reactions
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MS – ALS – MND
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In Multiple Sclerosis visual and auditory improvement
No improvement in motor function
Massive dose of 60 mg/day for 6 months tried
Combination of high doses of MC, FA, B6
Ultra high doses like 40 mg daily S/L for MS, ALS or MND or
Toxic PN
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Stroke
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Isolated anecdotal experiences
No specific trials
Instead of conventional B12, MC was given
Transmethylation reactions in the hippocampal region of the
brain may be involved in the functional improvement after MC
in Ischemic stroke
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Hearing Loss, ↓Visual Acuity
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Retinal glucotoxicity in DM is reduced
Improved vision
Senile sensori-neural deafness – some improvement
Improves Oto-toxicity due to Gentamycin
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Memory Disturbances CFIDS
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Several mgs/day of MC are required
Cognitive function impairment disorders showed improvement
Muscular dystrophies also benefited
Glutamate is the NT in brain
Glutamate excess – Neuronal degeneration –
MC corrects the Glutamate toxicity
PSP (post synaptic potentials) amplitude is modulated
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Hyper Homocysteinemia
A proved risk factor for CHD and stroke
Dramatic drop in HC levels
From 175 μmols/L to < 6 μmols/L
Oral MC better than IM MC - found to have prolonged
effect
 IV MC works faster for severe ↑ HC
 FA + MC is the best treatment
 Oral doses of minimum 2000 mcg/day for 4 months
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Sleep Disturbances
 Melatonin synthesis from pineal gland
 Methylcobalamin releases Melatonin early and drops its levels
early
 MC amplifies Melatonin synthesis
 Sleep quality, day time concentration improved
 3000 mcg daily for 4 weeks
 1500 to 6000 mcg are tried
 safe and non toxic
 Skin rashes and diarrhea are occassional
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Haemodialysis (HD) Patients
 OH B12 passes the dialysing membrane
 Uremic and diabetic neuropathy on MHD
 9 patients on 500 mcg IV thrice a week for 6 months – some
improvement
 HD patients have high levels of HC
 Rx with MC + FA was found to be beneficial
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GI Effects
Protects against toxins
Protects from Hg toxicity
Acrylamide toxicity
Botulinum toxoid and toxins
Helps with SH transfer – detoxification by liver – 37 pts
of Viral Hepatitis studied
 Along with L-carnitine improves appetite
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Heart rate variabilty
 MC’s effect on heart rate variability
 Effect on the Sympathetic / parasympathetic tone
balance
 MC found to have better effect than cyanocobalamine
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Male Impotence
 6 mg per day orally for 16 weeks
 Sperm count improved 37%
 Motility improved by 50%
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Cancer and Immune Function
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No effect on tumour cell proliferation
T cell function improved
T Helper function improved
Animal studies or small human studies
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HIV
Inhibits infected Monocytes and Lymphocytes
May be intestinal defective absorption
T helper cells increased
CD 4 counts decreased
Dementia in HIV – some improvement
PN in HIV is due to the Rx drugs
Hypothesis – Hyper methylation may suppress the viral
replication – Is it peculiar to HIV virus ?
 Are other virus amenable ?
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Dosage
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Minimum of 1500 mcg to 6000 mcg/ day oral / IM
To be used for prolonged periods 3 to 6 months
Even larger doses are tried in refractory cases
Combination with ALA in PN
Combination with FA in ↑ HC
 Cocktail of FA + MC + B6
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Folic acid
OH
O
COOH
C
CH
N
N
N
COOH
H
N
H
H2N
N
N
FOLIC ACID
pteroic acid + glutamic acid
pterylglutamic acid
=
Also known as folacin, vitamin M,
Widely available in plant foliage
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Folic Acid
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Coenzyme for RBC and DNA synthesis
Folates are donors of 1-C units (Methyl)
Tetra Hydo Folate THF is the active form
Two reductions by DHF reductase
Folic acid deficiency in birth defects
Supplimentation of FA reduces HC levels
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Folic Acid - Biochemistry
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Folic Acid
 Absorbed by both active and passive transport
 On the average we absorb 50 -200 μg per day (about
10 -25% of dietary intake)
 Stored as 5-methyl THF (5 -20 mg)
 Found in green vegetable, dietary yeasts, liver, kidney
 Bacteria synthesize their own folic acid
(dihydropteroate synthetase)
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Folic acid
 Biochemical functions
 One carbon fragment transfer (formyl, methyl,
hydroxymethyl)
 Conversion of HC to methionine
 Conversion of serine to glycine
 Synthesis of thymidylic acid
 Synthesis of purines (de novo)
 Histdine metabolism
 Synthesis of glycine
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BIOCHEMICAL ACTIVATION OF FOLIC ACID
FO LIC AC ID
7,8-DIHYDRO FO LIC AC ID (DHFA)
N5, N10-METHYLENE
TETRAHYDRO FO LIC AC ID
TETRAHYDRO FO LIC AC ID (THFA)
N5-FO RMYL TETRAHYDRO FO LIC AC ID (LEUC O VO RIN, FO LINIC
AC ID, C ITRO VO RUM FAC TO R)
5-METHYL THFA
N
5-FO
N RMIMIDO THFA
10
N -FO RMYL THFA
N5, N10-METHENYL THFA
O THER FO RMS O F THFA:
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Deficiency of folic acid
 Inadequate intake
 Defective absorption (most common)
 sprue
 gastric resection and intestinal disorders
 acute and chronic alcoholism
 drugs (anticonvulsants and OCP)
 pregnancy
 pellagra
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Deficiency of folic acid
 Abnormal metabolism of folates
 folic acid antagonists (dihydrofolate reductase inhibibitors methotrexate, pyrimethamine, trimethoprim)
 enzyme deficiency
 vitamin B12 deficiency
 oral contraceptives
 Increased requirement
 pregnancy, infancy
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Pyridoxine (vitamin B6)
C H2O H
HO
H3C
C H2O H
N
PYRIDO XINE
A pyridine derivative
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Pyridoxine
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Involved in > 100 enzyme reaction
In CHO, Fat and Protein metabolism
Catalyzes all AA reactions –
Without this all AAs are EAAs
In Hb and neurotransmitter synthesis
Its family has got three members
 Pyridoxal, Pyridoxine, Pyridoxamine
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Pyridoxine
 Vitamin B6, anti-dermatitis factor
 Widespread occurrence
 pyridoxine: mostly in vegetable products
 pyridoxal and pyridoxamine: mostly in animal
products
 Pyridoxine is stable in acid solution, but unstable in
neutral or alkaline solutions
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Pyridoxal phosphate
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Biochemical functions:
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Decarboxylation of amino acids
Transaminase reactions
Racemization reactions
Aldol cleavage reactions
Transulfuration reactions
Conversion of tryptophan to niacin
Conversion of linoleic acid into arachidonic acid
Formation of sphingolipids
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Pyridoxine
 Deficiency:
 Difficult to produce in humans
 May be accomplished artificially with a pyridoxine
antagonist (deoxypyridoxine)
 Symptoms include: nausea and vomiting, seborrheic
dermatitis, depression and confusion, mucous membrane
lesions, peripheral neuritis, anemia
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Pyridoxine deficiency
 Can be monitored by measuring the level of xanthurenic acid in
the urine
 This is related to a decrease in kynureninase activity (pyridoxal
phosphate is the coenzyme)
 Kynurenine, a breakdown product of tryptophan is normally
converted to kynurenic acid – but in B6 deficiency it is shunted
to form xanthurenic acid
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Pyridoxine
 Requirements
 children: 0.5 – 1.2 mg
 adults: 2.0 mg
 pregnancy: 2.5 mg
 requirement for B6 is proportional to the level of protein consumption
 Therapeutic uses
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deficiency
to counteract the effects of antagonists
certain rare forms of anemia
in women taking oral contraceptives (estrogen shifts tryptophan
metabolism)
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Structure of ALA
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Alpha Lipoic Acid (ALA)
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8 C- Sulfur containing compound
Involved in metabolism as anti-oxidant
It has ring on a chain like Biotin
Lysine is the protein moiety, acyl carrier
Universal Antioxidant
Component of pyruvate and alpha ketoglutarate
dehydrogenases – Krebs
ALA 100, Lipocid 100mg cap – 300 mg/day BF
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Alpha Lipoic Acid (ALA)
 ALA neutralizes OH free radicals, Hypochlorous acid,
singlet O2 radicals
 Chelates Iron, Copper and transit metals
 It is absorbed – converted to Di Hydro LA
 DH LA is also antioxidant
 ALA is both fat and water soluble
 Active in membranes and aqueous milieu
 Protects against CVD
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Redox reactions of ALA
NADH+ H+
NAD
ROOALA to DH-LA
ROOH
DH-LA to ALA
GSH
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GSH - DS
Vit E
Vit E +
DH Vit C
Vit C
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Gamma Linoliec Acid (GLA)
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Useful in meylin synthesis
Diabetic Neropathy it is useful
Reduces the paresthaesias, burning
Available as GLA 120
One cap b.i.d to t.i.d for several weeks
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Acetyl L -Carnitine (ALC)
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Anti oxidant property similar to tocopherol
L isomer only active -D Carnitine inhibits.
Available as 500 mg cap. Carnivit, Carnitor
Dosage 1 to 2 grams daily
In primary carnitine deficiency – myopathy
Patients on HD may have deficiency
Cardiomyopathy and Ischemic heart disease
LCarnitine is found to improve myocardial function and
reduce oxygen demand.
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Gabapentine (GBP)
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Available as 300 and 400 mg caplets
Gabantine (Sun), Gabalept (Micro)
300 to 400 mg b.i.d for 3 months
In Diabetic neuropathy, Post HZ neuralgia
Class II evidence of efficacy
Costs Rs. 9/- for 300 mg caplet
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Coenzyme Q10, NAC
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Coenzyme Q 10 (Ubiquinone)
NAC (N-acetyl cysteine)
Tried in CHF, HT, PD, Anti aging
Both are claimed to help on Redox reactions
To help the antioxidant mechanism
Recycle the scavenger antioxidants
Very soft evidence – not to be tried
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Pros for Methylcobalamin
 Sound biochemical basis that it works
 Active coenzyme form - CH3 B12
 Many publications – lot of noise, there must be some
real effect
 In ↑Homcyseine and sleep disorders, there is some
what hard evidence
 In chronic neurological conditions, there is nothing
much to offer – why not try this?
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Cons for Methylcobalamin
 No RCTs of repute comparing Cyano, Methyl, Hydroxy B12
and placebo
 No prophylactic effect studied
 Subjective improvements – not objective
 Very large doses for long periods needed
 No effect on haemopoiesis demonstrated
 80% of cobalamin functions are AS B12
 Much expensive than cyanocobalamin
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Cons for Methylcobalamin
With adequate FA intake B12 def. is rare
Not approved as drug by US FDA etc.,
Less stable than cyanocobalamin
We don’t know why body is converting only small quantity of
B12 to Methylcobalamin
 May be useful in special groups like HD, AD, PD, ALS,
Autism etc., - rather uncommon
 No trials with Cyano B12 in such large doses
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Pose these questions
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Is the patient a vegan vegetarian ?
Is he having B12 diseases ?
Is having malabsorption / nutritional deficiency ?
Is he having malignancy / immunodeficiency ?
Is he on DHFR inhibitors ?
Is his Homocysteine level very high ?
Is having intractable conditions like AZ, PD, MND,
ALD, MS, Autism, MHD or cerebral dysfunction
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If the answers are ‘Yes’
He requires B12 and Folic acid supplementation
Can he managed with Folic acid alone ?
Can we not treat with simple B12 +Folic acid
If we think of Methylcobalamin give as large a dose as
the patient can afford for as long as possible
 Use oral route combining with folic acid
 Add Alpha Lipoic Acid in neuropathy
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THAN Q
The day we attempt learning new things, we start
realizing how inadequate our knowledge is !
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