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. 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) Dr.Sarma@works

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 Dr.Sarma@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 Dr.Sarma@works

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 Dr.Sarma@works

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., Dr.Sarma@works

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 Dr.Sarma@works

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 Dr.Sarma@works

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 Dr.Sarma@works

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 Dr.Sarma@works

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 Dr.Sarma@works

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 Dr.Sarma@works

13. CAN WE TREAT NEUROPATHY AT ALL ?WILL THE NEURONS REGENERATE ?A SPOT LIGHT ON METHYLCOBALAMINE A special form of “New B12” may help Dr.Sarma@works

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 !! Dr.Sarma@works

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 Dr.Sarma@works

16. A Rose is Rose is a Rose But all B12 are not B12 are not B12 Dr.Sarma@works

17. The Vitamin B12 Family • Cyanocobalamin – CN-B12 Inactive • Hydroxycobalamin – OH-B12 Inactive • 5’-Adenosylcobalamin- AS-B12 Active • Methylcobalamin- CH3-B12 Active Dr.Sarma@works

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 Dr.Sarma@works

19. Dr.Sarma@works

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 Dr.Sarma@works

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 Dr.Sarma@works

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 Dr.Sarma@works

23. A Meet the Cobalamin Family 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 Dr.Sarma@works

24. 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 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 -ASB12 Dr.Sarma@works

25. 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 MTHFR Enzyme CH3 –H4 Folate Purine Pyrimidine First Child is - CH3 B12 SHE lives in the Cytoplasm Very active coenzyme METHYL COBALAMIN COENZYME OH B12 FOLATE TRAP Dr.Sarma@works

26. Meet the Cobalamin Family D Methylmelonic acedemia Methylmelonic aciduria Glycolysis cycle Succinyl CoA Methylmelonyl CoA Of the Two Active children METHYLMALONYL- Co A MUTASE ENZYME Second Child is - ASB12 HE lives in the Mitochondria Very active coenzyme ADENOSYL COBALAMIN COENZYME Amino Acid Metabolism Dr.Sarma@works

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 Dr.Sarma@works

28. 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 Dr.Sarma@works

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 Dr.Sarma@works

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!! Dr.Sarma@works

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 Dr.Sarma@works

32. Cyano B12 versus Methyl B12 Dr.Sarma@works

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 Dr.Sarma@works

34. Diabetic Neuropathy Bell’s Palsy Alzheimer's AD Parkinson's Disease PD ALS – MND Stroke Hearing Loss, Eye Memory disturbances The Literature and Methylcobalamin • 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 Dr.Sarma@works

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 Dr.Sarma@works

36. 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 Dr.Sarma@works

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 Dr.Sarma@works

38. 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 Disorders • IgE, Histamin and IL-2, IL-4 are reduced – • This causes reduction in allergic reactions Dr.Sarma@works

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 Dr.Sarma@works

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 Dr.Sarma@works

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 Dr.Sarma@works

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 Dr.Sarma@works

43. 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 Dr.Sarma@works

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 Dr.Sarma@works

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 Dr.Sarma@works

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 Dr.Sarma@works

47. 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 Dr.Sarma@works

48. Male Impotence • 6 mg per day orally for 16 weeks • Sperm count improved 37% • Motility improved by 50% Dr.Sarma@works

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 Dr.Sarma@works

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 ? Dr.Sarma@works