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The Promise & Pitfalls of Intravenous Micronutrient Therapy: From Practice to Theory, & Back Again

The Promise & Pitfalls of Intravenous Micronutrient Therapy: From Practice to Theory, & Back Again David Katz, MD, MPH, FACPM, FACP Yale Prevention Research Center Yale University School of Medicine ACAM Dallas, TX 5-4-06 www.davidkatzmd.com

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The Promise & Pitfalls of Intravenous Micronutrient Therapy: From Practice to Theory, & Back Again

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  1. The Promise & Pitfalls of Intravenous Micronutrient Therapy:From Practice to Theory, & Back Again David Katz, MD, MPH, FACPM, FACP Yale Prevention Research Center Yale University School of Medicine ACAM Dallas, TX 5-4-06 www.davidkatzmd.com

  2. History of Myers’ Cocktail(shaken, not stirred) • Treatment pioneered by John Myers – a physician from Baltimore • Myers did not leave any published or print material on the composition of the IV treatment • It appears that he used a combination of magnesium chloride, calcium gluconate, thiamine, vitamin B6, vitamin B12, calcium pantothenate, vitamin B complex, vitamin C, and dilute hydrochloric acid • Current formulations have been modified to by Dr. Alan Gaby who took over care of Dr Myers’ patients after his death in 1984

  3. Popular brew- • Members from a wide range of national medical associations report use of IVMT, including: • The American College for Advancement in Medicine (ACAM) • The American Association of Naturopathic Physicians (AANP) • The American Holistic Medical Association (AHMA) • The American Academy of Pain Management (AAPM) • The Great Lakes College of Clinical Medicine (GLCCM) and • International Society of Orthomolecular Medicine (ISOM)

  4. The Myers’ Cocktail • Myers’ Cocktail Composition- • Magnesium chloride hexahydrate (20%) 5 ml • Calcium gluconate (10%) 3 ml • Hydroxocobalamin (1,000 mcg/ml) 1 ml • Pyridoxine hydrochloride (100 mg/ml) 1 ml • Dexpanthenol (250 mg/ml) 1 ml • B-complex 100* 1 ml • Vitamin C (500 mg/ml) 5 ml • Sterile Water 20 ml

  5. Composition, cont. • B-Complex 100 contains the following per each ml: • Thiamine HCl 100mg • Riboflavin 2mg • Pyridoxine HCl 2mg • Panthenol 2mg • Niacinamide 100mg • Benxyl Alcolhol 2%

  6. Theories, at least in theory- Higher Serum Concentrations • IV administration of nutrients achieves serum concentrations much higher than those achieved by oral or IM administration • E.g. Highest serum dose achieved after oral administration of pharmacological dose of vitamin C is 9.2mg/dL. IV administration of 50 g/day of vitamin C resulted in a mean peak plasma level of 80 mg/dL

  7. Pharmacological Effects of Nutrients • Various nutrients may exert pharmacological effects only in concentrations achieved through IV administration • Eg. Antiviral effect of Vitamin C demonstrated at a concentration of 10-15 mg/dL – a level achieved through IV therapy only

  8. Correcting Intracellular Nutrient Deficits • Higher intracellular nutrient concentration necessary in some cases to maintain proper cellular function • E.g. Magnesium concentration 10 times higher in myocardial cells as compared to extra-cellular concentrations • in certain disease conditions cell membrane capacity to maintain high concentrations may be compromised • IV administration of Mg may lead to a significant though transient increase in Mg levels

  9. Therapeutic Applications of IVMT • IVMT has been effective in treating ----- Asthma ----- Migraines ----- Fatigue (including chronic fatigue syndrome) ----- Fibromyalgia ----- Acute muscle spasm ---- Upper respiratory tract infections ----- Chronic sinusitis ----- Seasonal allergic rhinitis ----- Cardiovascular disease

  10. Asthma • IV magnesium can abort acute asthma attacks • Skobeloff EM, Spivey WH, McNamara RM, Greenspon L. Intravenous magnesium sulfate for the treatment of acute asthma in the emergency department. JAMA 1989;262:1210-1213. • Bloch H, Silverman R, Mancherje N, et al. Intravenous magnesium sulfate as an adjunct in the treatment of acute asthma. Chest 1995;107:1576-1581. • Ciarallo L, Brousseau D, Reinert S. Higher-dose intravenous magnesium therapy for children with moderate to severe acute asthma. Arch Pediatr Adolesc Med 2000;154:979-983. • Ciarallo L, Sauer AH, Shannon MW. Intravenous magnesium therapy for moderate to severe pediatric asthma: results of a randomized, placebo-controlled trial. J Pediatr 1996;129:809-814. • Rowe BH, Bretzlaff JA, Bourdon C, et al. Intravenous magnesium sulfate treatment for acute asthma in the emergency department: a systematic review of the literature. Ann Emerg Med 2000;36:181-190.

  11. Migraine • Beneficial effect of IVMT in treatment of migraine has been demonstrated in some clinical trials • Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulphate relieves migraine attacks in patients with low serum ionized magnesium levels: a pilot study. Clin Sci 1995;89:633-636. • (29.) Demirkaya S, Vural O, Dora B, Topcuoglu MA. Efficacy of intravenous magnesium sulfate in the treatment of acute migraine attacks. Headache 2001;41: 171-177. • (30.) Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulfate relieves cluster headaches in patients with low serum ionized magnesium levels. Headache 1995;35:597-600.

  12. Fatigue • Duration of benefit from few days to few months • Manuel y Keenoy B, Moorkens G, Vertommen J, et al. Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium. J Am Coll Nutr 2000;19:374-382 • Howard JM, Davies S, Hunnisett A. Magnesium and chronic fatigue syndrome. Lancet 1992;340:426. • Howard JM, Davies S, Hunnisett A. Magnesium and chronic fatigue syndrome. Lancet 1992;340:426. • Clague JE, Edwards RH, Jackson MJ. Intravenous magnesium loading in chronic fatigue syndrome. Lancet 1992;340:124-125 • Ellis FR, Nasser S. A pilot study of vitamin B12 in the treatment of tiredness. Br J Nutr 1973;30:277-283.

  13. What is Fibromyalgia (FMS)? • Clinical syndrome of unknown etiology and pathogenesis • Characterized by musculoskeletal pain, non restorative sleep and fatigue, psychiatric, neurological and other symptoms

  14. Epidemiology • 3.7 million persons ages 18 older or 2% of the population affected in US • 0.5 -5% of the population affected worldwide • 4-7 times more common in adult women than men; highest prevalence in women 50-60 years of age • Ethnic, genetic, social and cultural factors may influence FMS predisposition

  15. Pathophysiology Considered- 4 theories of pathophysiology have emerged: • Neurogenic (Central Nervous System) --- generalized pain --- increase in CSF substance P --- decrease in serum and CSF serotonin --- increased central sensitization

  16. Pathophysiology, cont. • Muscle Pathology --- decreased oxygen tension and blood flow --- abnormal muscle biopsies --- weakness

  17. Pathophysiology, cont. • Psychopathology --- anxiety, depression • Immune-mediated disease --- triggered byother infections, such as Lyme disease

  18. Clinical Presentation • Pain (musculoskeletal tenderness) • Lightheadedness, dizziness, syncope • Fatigue • Chronic insomnia; sleep disturbance • Cognitive deficits/short-term memory loss • Depression/anxiety • Numbness, dysesthesia in hands and feet

  19. Diagnosis Based on the 1990 ACR classification guidelines: • 1 historical feature + 1 physical finding • Historical feature = widespread (axial) pain of 3 months or more • Physical finding = pain in at least 3 of the 4 body segments + a finding of at least 11 tender points on digital palpation of 18 designated tender points

  20. Treatment • Patient Education --- reading materials, videos, support groups • Physical Exercise --- low-grade (muscle stretches, aerobic conditioning) • Pharmacologic Therapies --- tricyclic antidepressants, NSAIDS, topical capsaicin, opioids* *Drug therapies have been used with varying degrees of success in treating fibromyalgia

  21. Treatment, cont. • Complementary Treatments --- Mind body interventions --- Homeopathy --- Acupuncture --- Nutriceuticals

  22. Practice seeking theory(cart, seeking horse…) • Myers’ cocktail has been a popular “alternative” treatment for decades • No trials for FMS have been published • The anecdotal support is strong

  23. Necessity is the mother of… investigation. • Current treatments do not adequately address FMS symptoms in most patients • The apparent promise of the Myers’ Cocktail (IVMT) called out for testing

  24. Tribulations, prior to Trial- • Lack of theoretical rationale • Empirical evidence only • Toxicity concerns • Need for IND status

  25. First RCT of IVMT for FMS(the alphabet gets a workout!) • Study Design --- Randomized, double blind, placebo controlled trial • Inclusion criteria --- Musculoskeletal pain for 3 months --- Pain in 11 of 18 tender point sites on digital palpation

  26. Methods • 40 subjects randomized to treatment or control group • Treatment 8 weekly treatments performed at one week intervals • Control Placebo / IV saline infusion • Assessments Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Index (BDI), Visual Analog Scale (VAS) and Health Status Questionnaire (HSQ 2.0)

  27. Evaluation • Primary outcome: The Tender Point Index (TPI) • The severity of pain, assessed by an algometer with a force of 4 Kg, determined by a scoring system ranging from 0 (no reported tenderness) to 4+ (severe pain). The TPI is the composite of scores at 18 tender point sites. • At baseline (following 2-week run-in period) • One-week post intervention period • 3-months following the intervention • Results are now pending; trial is nearing completion

  28. From Practice, to Theory- • Theoretical Pathway Predisposing Factor HLA Susceptibility OR Precipitating Factors (Trauma/Medical illness) --- Autoimmune Disorder: Formation of autoantibodies to surface proteins on myocytes or endothelial cells --- Deficiency in Nitric Oxide Production OR Impaired Release of, or Response to, Nitric Oxide --- Vasomotor Dysregulation --- Muscle Hypoperfusion ---Impaired intracellular energetics --- Induction of Pain • Katz DL et al. The Pain of Fibromyalgia Syndrome is due to Muscle Hypoperfusion Induced by Regional Vasomotor Dysregulation. Medical Hypotheses: In press

  29. And Theory to Practice: Arginine • Precursor to NO production • Vasodilatory influence • Ameliorates endothelial function • Also: • Promotes production of growth hormone. FM patients have an abnormal sleep pattern involving stages 3 and 4 of non REM sleep.  As GH is secreted predominantly during stages 3 and 4 of non-REM sleep, it was originally hypothesized that FM patients may have impaired GH secretion

  30. Other Nutriceuticals • Guai Theory: FMS may be caused by an excess of intracellular phosphate, and possibly oxalic acid, which build up in the cells and depress the formation of energy (ATP) in the cell's mitochondria. Based on biochemical results, guai intake results in elimination of excess phosphate and calcium from the system Dose – Determined by individual response 300 mgm to 3,600 mgm/day

  31. Other nutriceuticals, cont. Vitamin B3 and B6 Theory: FMS patients may be deficient in serotonin because the tryptophan obtained from food metabolizes into kynurenin rather than to tryptophan and 5-htp. For this reason, 5-htp is likely to be more efficient than L-tryptophan in boosting serotonin. A combination of Vitamin B3 and B6 plus tryptophan and magnesium addresses serotonin deficiency.

  32. Other nutriceuticals, cont. • Zinc and calcium supplements • Improves sleep patterns • B Complex plus Vitamin C • Improvement of overall nutritional status • Antioxidants • Theory: Inflammatory response creates damage to tissues. Antioxidants minimize the damage. • Natural carotenoids (carotenes, lycopenes and others), vitamin A (retinol), bioflavonoids like rutin, hesperidin, quercetin, catechin and the proanthocyanidins (grape seed extract, pine bark extract or pycnogenols)

  33. Other nutriceuticals, cont. • Malic acid • Theory: FMS is the result of local hypoxia to the muscles. Patients with fibromyalgia have low muscle-tissue oxygen pressure in affected muscles. Muscle biopsies from affected areas showed muscle tissue glycolysis is inhibited, reducing ATP synthesis. This stimulates the process of gluconeogenesis, which results in muscle tissue breakdown and mitochondrial damage. • Malic acid reverses hypoxia induced inhibition of glycolysis and energy production, possibly improving energy production in fibromyalgia, and reversing the negative effect of the relative hypoxia

  34. Conclusions • The needs of FMS patients are not fully met at present • CAM / Nutriceuticals show promise • Promising results from practice must be tested in trials • Practice may inform theory; theory may then serve to advance practice • If a causal pathway for FMS can be established, we can better direct our efforts at breaking the links

  35. Conclusions, cont. • IVMT appears promising for treatment of FMS sysmptoms; trial results will be available soon • Larger trial is planned for follow-up, to include assessment of mechanism • Use of IVMT/Myers’ Cocktail is justified at present, although still over the line of evidence • Future efforts will need to move further ‘upstream’

  36. Conclusions, cont. • If promise of IVMT for fibromyalgia is realized, a similar approach to other conditions will be warranted: • Delineation of theoretical causal pathways • Controlled testing of interventions • Evidence, not conviction, will best advance the cause

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  42. Thank you. David L. Katz, MD, MPH, FACPM, FACP Director, Yale Prevention Research Center 130 Division Street Derby, CT 06418 David.katz@yale.edu www.davidkatzmd.com

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