dr.sarma@works1 neurotropic agents - a review dr.r.v.s.n.sarma, m.d., m.sc., (canada), consultant...

Dr.Sarma@works 1

Neurotropic Agents - A Review

Dr.R.V.S.N.Sarma, M.D., M.Sc., (Canada),Consultant Physician,

Tiruvallur 602 001.

Dr.Sarma@works 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)

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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

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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

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 provingEg. Atorvastatin, Ramipril, PTCA

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Cohort studies- Class II Evidence Two or more self selected groups Prospectively followed for years Outcomes studied Conclusions drawn Good if properly designed Hypothesis testingCrash helmets, Seat belts in cars etc.,

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Case-control -Class III Evidence Cases of the disease in good number Matched controls Exposure of interest analyzed Retrospective – Problems Weaker in evidence Hypothesis generatingHiroshima Nagasaki, Bhopal gas tragedy

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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 estimatesPrevalence of obesity and Diabetes or CHD

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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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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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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 ?


Research has lookedat Methylcobalamin for many disorders

Albeit, in a weaker way !!

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You may be veryinterested in how

it could help

CAN WE TREAT NEUROPATHY AT ALL ?DOES THE NEURON REGENERATE ?


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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 Inactive

Hydroxycobalamin – OH-B12 Inactive

5’-Adenosylcobalamin- AS-B12 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

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

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

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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This is the Grand Parent

Cyano Cobalamin - CN B12

Meet the Cobalamin Family

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 + IF - Complex - Marry

Enter intestinal cells of Ileum

CN B12 + IF Complex Divorce

IF is released and recycled

CN B12 combines with Trans cobalamin II and gets into Plasma

Transcobalamin II, the Vehicle

CN B12 + Transcobalamin I stored in the liver and the TC II is released

and recycled

CN B12 is further metabolized

A

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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

B

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METHIONINE SYNTHASE Ez

CH3 –H4 FolateH4 Folate

METHYL COBALAMIN COENZYME

Of the Two Active children

First Child is - CH3 B12 SHE

lives in the Cytoplasm Very active coenzyme

Homocyst(e)ine (AA)Methionine (EAA)

Purine synthesis

MTHFR Enzyme

C

FOLIC ACID Cousin

OH B12

Purine Pyrimidine

FOLATE TRAP

↑ Homocystenemia

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METHYLMALONYL- Co A MUTASE ENZYME

ADENOSYL COBALAMIN COENZYME

Of the Two Active children

Second Child is - AS B12 HE

lives in the Mitochondria Very active coenzyme

Methylmelonyl CoASuccinyl CoA

Glycolysis cycle

D

Methylmelonic acedemia Methylmelonic aciduria

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

Feature Cyano B12 Methyl B12

IF Required RequiredAbsorption Ileum –Good Ileum - FairTissues Less retained More retainedUrinary Excre. More LessAs Cofactor Inactive ActiveEffect on Ho Cy Good Very GoodHaemopoiesis Effective No effectIn breast milk Low High concentr.

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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 goodIM inj. is not a must; works orally

Prolonged blood levels after oralS/L bypasses liver metabolism

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The Literature and Methylcobalamin

Diabetic Neuropathy Bell’s 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

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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

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

Small number of patients tried IM MC was used Improvement in tremor and rigidity Motor function less improved Needs large scale RCTs

Allergic Disorders1. IgE, Histamin and IL-2, IL-4 are reduced –2. This causes reduction in allergic reactions

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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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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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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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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

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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

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

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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N

N N

NN

H

CN

CH

H

OH

H2N

O COOH

COOH

FOLIC ACID

Also known as folacin, vitamin M, Widely available in plant foliage

pteroic acid + glutamic acid = pterylglutamic acid

Folic acid

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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

FOLIC ACID 7,8-DIHYDROFOLIC ACID (DHFA)

TETRAHYDROFOLIC ACID (THFA)N5, N10-METHYLENETETRAHYDROFOLIC ACID

N5-FORMYL TETRAHYDROFOLIC ACID (LEUCOVORIN, FOLINICACID, CITROVORUM FACTOR)

OTHER FORMS OF THFA: N 5-METHYL THFA N 5-FORMIMIDO THFA

N10-FORMYL THFAN5, N10-METHENYL 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)

N

CH2OH

CH2OHHO

H3C

PYRIDOXINE

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

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:• 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

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)

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 – KrebsALA 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

ALA to DH-LA

NAD NADH+ H+

DH-LA to ALADH Vit C

GSH - DSGSH Vit C

Vit E

ROO-

ROOH

Vit E +

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

THAN Q

dr.sarma@works1 neurotropic agents - a review dr.r.v.s.n.sarma, m.d., m.sc., (canada), consultant...

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