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Neurotropic Agents - A Review

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Title: Neurotropic Agents - A Review


1
Neurotropic Agents - A Review
  • Dr.R.V.S.N.Sarma,
  • M.D., M.Sc., (Canada),
  • Consultant Physician,
  • Tiruvallur 602 001.

2
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)

3
The Question
  • Are YOU using Methylcobalamin ?
  • Based on what sort of evidence?
  • 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

4
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

5
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

6
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.,

7
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

8
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

9
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

10
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

11
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

12
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

13
CAN WE TREAT NEUROPATHY AT ALL ?WILL THE NEURONS
REGENERATE ? A SPOT LIGHT ON METHYLCOBALAMINE
A special form of New B12 may help
14
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 !!
15
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
16
A Rose is Rose is a Rose
  • But all B12
  • are not B12
  • are not B12

17
The Vitamin B12 Family
  • Cyanocobalamin CN-B12 Inactive
  • Hydroxycobalamin OH-B12 Inactive
  • 5-Adenosylcobalamin- AS-B12 Active
  • Methylcobalamin- CH3-B12 Active

18
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

19
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20
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 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

21
Vitamin B12Biochemical 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
  • Homocysteine to Methionine
  • Methyl melonyl CoA to Succinyl CoA
  • Tetrahydrofolate to Methyl Tetrahydro Folate
  • SAM-e (S-Adenosyl Methionine) powerful mood
    elevator

22
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
  • 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

23
Meet the Cobalamin Family
A
This is the Grand Parent Cyano Cobalamin - CN
B12
CN B12 is further metabolized
CN B12 Transcobalamin I stored in the liver
and the TC II is released and recycled
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 combines with Trans cobalamin II and gets
into Plasma Transcobalamin II, the Vehicle
CN B12 IF Complex Divorce IF is released and
recycled
CN B12 IF - Complex - Marry Enter intestinal
cells of Ileum
24
Meet the Cobalamin Family
B
CN B12 when needed is metabolized in the Liver
The Grand Parent Inactive, a
non-coenzyme form
The Parent born
Inactive, a non-coenzyme form Lives in Liver
Cyanide is stripped off from CN B12 -
Cobalamin or B12
The Parent is grown up now
Inactive, a non-coenzyme form Gets into
the plasma
Hydroxyl group is added to
B12 Cobalamin OH B12
Two Children are born
Both Active, Coenzyme forms Both enter the cell
(Methyl) CH3 is added to
OH B12 - CH3 B12
Adenosyl group is added to
OH B12 -AS B12
25
Meet the Cobalamin Family
C
Purine synthesis
? Homocystenemia
Homocyst(e)ine (AA)
Methionine (EAA)
FOLIC ACID Cousin
METHIONINE SYNTHASE Ez
Of the Two Active children
CH3 H4 Folate
H4 Folate
MTHFR Enzyme
Purine Pyrimidine
First Child is - CH3 B12 SHE lives in
the Cytoplasm Very active coenzyme
METHYL COBALAMIN COENZYME
OH B12
FOLATE TRAP
26
Meet the Cobalamin Family
D
Methylmelonic acedemia Methylmelonic aciduria
Glycolysis cycle
Methylmelonyl CoA
Succinyl CoA
Of the Two Active children
METHYLMALONYL- Co A MUTASE ENZYME
Second Child is - AS B12 HE lives in
the Mitochondria Very active coenzyme
ADENOSYL COBALAMIN COENZYME
Amino Acid Metabolism
27
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

28
Diagnosis of B12 deficiency
  • Homocysteine levels (N lt 13 µmols/ l)
  • Methyl Malonic Acid (MMA) levels
  • Serum B12 levels (N 200 - 600 pg/ml)
  • IF Antibodies
  • Schilling test

29
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

30
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!!

31
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

32
Cyano B12 versus Methyl B12
Feature Cyano B12 Methyl B12
IF Required Required
Absorption Ileum Good Ileum - Fair
Tissues Less retained More retained
Urinary Excre. More Less
As Cofactor Inactive Active
Effect on Ho Cy Good Very Good
Haemopoiesis Effective No effect
In breast milk Low High concentr.
33
Routes of AdministrationMethylcobalamin
  • 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
34
The Literature and Methylcobalamin
  • Diabetic Neuropathy
  • Bells Palsy
  • Alzheimer's AD
  • Parkinson's Disease PD
  • ALS MND
  • Stroke
  • Hearing Loss, Eye
  • Memory disturbances
  • 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
35
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

36
Bells 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

37
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

38
Parkinsons Disease PD
  • Small number of patients tried
  • IM MC was used
  • Improvement in tremor and rigidity
  • Motor function less improved
  • Needs large scale RCTs
  • Allergic Disorders
  • IgE, Histamin and IL-2, IL-4 are reduced
  • This causes reduction in allergic reactions

39
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

40
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

41
Hearing Loss, ?Visual Acuity
  • Retinal glucotoxicity in DM is reduced
  • Improved vision
  • Senile sensori-neural deafness some improvement
  • Improves Oto-toxicity due to Gentamycin

42
Memory Disturbances CFIDS
  • 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

43
Hyper Homocysteinemia
  • A proved risk factor for CHD and stroke
  • Dramatic drop in HC levels
  • From 175 µmols/L to lt 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

44
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

45
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

46
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

47
Heart rate variabilty
  • MCs effect on heart rate variability
  • Effect on the Sympathetic / parasympathetic tone
    balance
  • MC found to have better effect than
    cyanocobalamine

48
Male Impotence
  • 6 mg per day orally for 16 weeks
  • Sperm count improved 37
  • Motility improved by 50

49
Cancer and Immune Function
  • No effect on tumour cell proliferation
  • T cell function improved
  • T Helper function improved
  • Animal studies or small human studies

50
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 ?

51
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

52
Folic acid
pteroic acid glutamic acid
pterylglutamic acid
Also known as folacin, vitamin M, Widely
available in plant foliage
53
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

54
Folic Acid - Biochemistry
55
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)

56
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

57
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58
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

59
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

60
Pyridoxine (vitamin B6)
A pyridine derivative
61
Pyridoxine
  • Involved in gt 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

62
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

63
Pyridoxal phosphate
  • Biochemical functions
  • 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

64
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

65
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

66
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)

67
Structure of ALA
68
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

69
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

70
Redox reactions of ALA
71
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

72
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.

73
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

74
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

75
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?

76
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

77
Cons for Methylcobalamin
  • With adequate FA intake B12 def. is rare
  • Not approved as drug by US FDA etc.,
  • Less stable than cyanocobalamin
  • We dont 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

78
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

79
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

80
THAN Q
The day we attempt learning new things, we start
realizing how inadequate our knowledge is !
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