Transcript Methycobalamin by Dr Sarma

The Explosion of Knowledge
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Neurotropic Agents A Review
Dr.R.V.S.N.Sarma,
M.D., M.Sc., (Canada),
Consultant Physician,
Tiruvallur 602 001.
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Neutropic Vitamins Reviewed
 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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Neutropic Vitamins Reviewed
 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 ?
 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
 RCTClass 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
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
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
 Cyanocobalamin – CN-B12
 Hydroxycobalamin – OH-B12
 5’-Adenosylcobalamin- AS-B12
 Methylcobalamin- CH3-B12
Inactive
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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;
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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
 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
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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
 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
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Homocysteine to Methionine
Methyl melonyl CoA to Succinyl CoA
Tetrahydrofolate to Methyl Tetrahydro Folate
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SAM-e (S-Adenosyl Methionine) –powerful mood elevator
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The Vitamin B12 Family
 The Grand Parent is the CN B12
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Absorbed from gut - R factor + IF - Ileum
Transported as Transcobalamin II
Stored in liver Transcobalamin I –5 mg/ 2 μg
 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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Meet the Cobalamin Family
A
This is the Grand Parent
CN B12 is further metabolized
Cyano Cobalamin - CN B12
Boy friendship with ‘R’ factor
CN B12 + Transcobalamin I
stored in the liver and the TC II is
In the stomach
released and recycled
CN B12 + R factor combine with
CN B12 combines with Trans
cobalamin II and gets into Plasma
Intrinsic Factor from the
parietal cells of the stomach
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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Meet the Cobalamin Family
B
CN B12 when needed is
metabolized in the Liver
The Grand Parent
Inactive, a non-coenzyme form
Cyanide is stripped off from
CN B12 - Cobalamin or B12
The Parent born
Inactive, a non-coenzyme form
Lives in Liver
Hydroxyl group is added to
B12 Cobalamin – OH B12
The Parent is grown up now
Inactive, a non-coenzyme form
Gets into the plasma
(Methyl) CH3 is added to
OH B12 - CH3 B12
Adenosyl group is added to
OH B12 -AS B12
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Two Children are born
Both Active, Coenzyme forms
Both enter the cell
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C
Meet the Cobalamin Family
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
SHE lives in the Cytoplasm
Very active coenzyme
OH B12
FOLATE TRAP
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Meet the Cobalamin Family
D
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
HE lives in the Mitochondria
Very active coenzyme
Amino Acid Metabolism
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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
 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
 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
 Oral
 Transdermal
 Sublingual
 Intramuscular
 Intravenous
 Subcutaneous
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
 Intrathecal (LP)
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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
334 studies referenced on MC in various diseases
Almost all the evidence is class III or lower
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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
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Diabetic Neuropathy
 Intrathecal Injection of MC in 7 Males and 4 Females –
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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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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
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Bell’s palsy
 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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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
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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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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
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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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2.
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IgE, Histamin and IL-2, IL-4 are reduced –
This causes reduction in allergic reactions
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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
Dr.Sarma@works
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MS – ALS – MND
 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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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
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Stroke
 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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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
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Hearing Loss, ↓Visual Acuity
 Retinal glucotoxicity in DM is reduced
 Improved vision
 Senile sensori-neural deafness – some improvement
 Improves Oto-toxicity due to Gentamycin
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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
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Memory Disturbances CFIDS
 Several mgs/day of MC are required
 Cognitive function impairment disorders showed
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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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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
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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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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
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Sleep Disturbances
 Melatonin synthesis from pineal gland
 Methylcobalamin releases Melatonin early and drops its
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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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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
Dr.Sarma@works
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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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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 GI Effects
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
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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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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
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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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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
Dr.Sarma@works
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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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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
Dr.Sarma@works
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Cancer and Immune Function
 No effect on tumour cell proliferation
 T cell function improved
 T Helper function improved
 Animal studies or small human studies
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The Literature and
Methylcobalamin
 Diabetic Neuropathy
 Homocysteine excess
 Bell’s Palsy
 Sleep Disturbances
 Alzheimer's AD
 HD patients
 Parkinson's Disease PD
 Eating Disturbances
 ALS – MND
 Cardiac Rhythm
 Stroke
 Male Impotence
 Hearing Loss, Eye
 Cancer
 Memory disturbances
 HIV
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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
 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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Neutropic Vitamins Reviewed
 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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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
 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,
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infancy
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Neutropic Vitamins Reviewed
 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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Pyridoxine (vitamin B6)
C H2O H
HO
H3C
C H2O H
N
PYRIDO XINE
A pyridine derivative
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Pyridoxine
 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

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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
 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:



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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
 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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Neutropic Vitamins Reviewed
 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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Structure of ALA
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Alpha Lipoic Acid (ALA)
 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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Neutropic Vitamins Reviewed
 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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Gamma Linoliec Acid (GLA)
 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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Neutropic Vitamins Reviewed
 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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Acetyl L -Carnitine (ALC)
 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
L- Carnitine is found to improve myocardial function
and reduce oxygen demand.
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Neutropic Vitamins Reviewed
 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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Gabapentine (GBP)
 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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Neutropic Vitamins Reviewed
 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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Coenzyme Q10, NAC
 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
 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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Conclusions
 Evidence in favour of Methylcobalamin is rather soft
 However
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The day we attempt learning new things, we
Qour knowledge is !
start realizing howTHAN
inadequate
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