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IV Vitamin C: Uses in An/-‐Oxidant and Pro-‐Oxidant IV Therapy Paul S. Anderson April 2015 © PS Anderson Ascorbate safety, electrolytes and other issues
(c) PS Anderson 2015 2 Concerns with HDIVC
•  G6PD Status •  Kidney Func@on •  General Health •  Electrolytes •  Dose (c) PS Anderson 2015 3 G6PD – RBC GSH – Ascorbate - Tocopherols:
RBC
G6PDàNADPHà
GSH Reductase
GSH Cycle
Plasma &
Cytosol
ASC à DHA à ASC
(c) PS Anderson 2015 Plasma Lipids &
Cell Membranes
Tocopherol Cycle
4 The following three slides:
Livshits Z, Hoffman RS, Hymes KB, Nelson LS. If vitamins could kill: massive
hemolysis following naturopathic vitamin infusion. J Med Toxicol. 2011 Sep;7(3):
224-6.
(c) PS Anderson 2015 5 (c) PS Anderson 2015 6 (c) PS Anderson 2015 7 …
…
…
(c) PS Anderson 2015 8 So – How much IVC will oxidize?
•  A deﬁni@ve level for the threshold of oxida@on in intravenously (IV) administered ascorbate is unclear. •  Two papers [1,2] indicate that lower levels than previously considered (5-‐10 grams IVC) may cause oxida@on and another [3] disagrees. [1] Hininger I, Waters R, Osman M, et al. Prooxidant eﬀects of vitamin C in EDTA chela@on therapy and long-‐term an@oxidant beneﬁts of therapy. Free Radic Biol Med 2005;38:1565-‐1570. [2] Roussel AM, et.al. EDTA Chela@on Therapy, without Added Vitamin C, Decreases Oxida@ve DNA Damage and Lipid Peroxida@on. Altern Med Rev 2009;14(1):56-‐61 [3] Mühlhöfer A, et. al. High-‐dose intravenous vitamin C is not associated with an increase of pro-‐
oxida@ve biomarkers. Eur J Clin Nutr. 2004 Aug;58(8):1151-‐8. (Note ‘High Dose‘ was 7.4 grams). (c) PS Anderson 2015 9 A ‘safe’ Recommenda/on
•  Run pre-‐IV G6PD and hemoglobinopathy screening (CBC) for IV Ascorbate above 5-‐10 grams on repeated use: •  serial IV over several days •  Run G6PD/ hemoglobinopathy screening on any person gehng any single IVC over 10-‐15 grams (c) PS Anderson 2015 10 G6PD Tes/ng
1.  Qualita@ve (“Normal / Abnormal”) 2.  RBC-‐G6PD or Total-‐G6PD 3.  Quan@ta@ve G6PD 1.  A calculated value using both Total and RBC G6PD – considered most sensi@ve at assessing borderline cases. 2.  G6PD QUANT = {G6PD Blood / RBC G6PD} 3.  Value given in Units per Trillion RBC (U/Tril RBC) **Ul@mately, all are appropriate for screening prior to HDIVC treatment. ** A Quan@ta@ve result is most sensi@ve. (c) PS Anderson 2015 11 One view of G6PD Tes/ng Sensi/vity:
Ainoon O, et. al. Semiquan>ta>ve Screening Test for G6PD Deﬁciency Detects Severe Deﬁciency but Misses a Substan>al Propor>on of Par>ally-‐deﬁcient Females. Southeast Asian J Trop Med Public Health. Vol 34, No 2, June 2003 (c) PS Anderson 2015 12 Do an/oxidants help in Low G6PD?
(+) Chan AC, Chow CK, Chiu D. Interac@on of an@oxidants and their implica@on in gene@c anemia. Proc Soc Exp Biol Med 1999;222:274-‐82. (+) Eldamhougy S, Elhelw Z, Yamamah G, et al. The vitamin E status among glucose-‐6 phosphate dehydrogenase deﬁcient pa@ents and eﬀec@veness of oral vitamin E. Int J Vita Nutr Res 1988;58:184-‐8. (+) Hafez M, Amar ES, Zedan M, et al. Improved erythrocyte survival with combined vitamin E and selenium therapy in children with glucose-‐6-‐phosphate dehydrogenase deﬁciency and mild chronic hemolysis. J Pediatr 1986;108:558-‐561. (-‐) Johnson GJ, Vatassery GT, Finkel B, Allen DW. High-‐dose vitamin E does not decrease the rate of chronic hemolysis in glucose-‐6-‐
phosphate dehydrogenase deﬁciency. N Engl J Med 1983;308:1014-‐7. (+) Sultana N, et. al. ORAL SUPPLEMENTATION OF VITAMIN E REDUCES OSMOTIC FRAGILITY OF RBC IN HEMOLYTIC ANEMIC PATIENTS WITH G6PD DEFICIENCYPak J Physiol 2009;5(1) (c) PS Anderson 2015 13 Ascorbate IV and Labs:
•  GLUCOMETER READINGS ARE NOT VALID WHILE A PATIENT IS ON AN IVC DRIP! •  The ascorbate is read as glucose by the glucometer and glucose values will be face@ously HIGH! – This has led to the inappropriate administra@on of insulin in hypoglycemic pa@ents. (c) PS Anderson 2015 14 Ascorbate Compa@bility with natural therapies (c) PS Anderson 2015 15 Should we separate B-Vitamins from High-dose /
oxidative IVC?
The bo'om line is that while B-‐Vitamins and other an5oxidants are needed during cancer therapy, they may decrease the oxida5ve eﬀect of HDIVC if concurrently administered. Ochi M, Hetherington J, Lamson D. The Concern about B-‐Vitamins with Intravenous Ascorbate for Malignancy; Altern Med Rev 2011;16(Supp):1S-‐5S (c) PS Anderson 2015 16 Glutathione and IVC for Oxidation on the same day:
Two popular complementary, alterna@ve, and integra@ve medicine therapies, high-‐dose intravenous ascorbic acid (AA) and intravenous glutathione (GSH), are owen coadministered to cancer pa@ents with unclear eﬃcacy and drug-‐drug interac@on. Treatment in mouse pancrea@c cancer xenograws showed that intraperitoneal AA at 4g/kg daily reduced tumor volume by 42%. Addi@on of intraperitoneal GSH inhibited the AA-‐
induced tumor volume reduc@on. Although all treatments (AA, GSH, and AA+GSH) improved survival rate, AA+GSH inhibited the cytotoxic eﬀect of AA alone and failed to provide further survival beneﬁt. These data conﬁrm the pro-‐oxida@ve an@-‐cancer mechanism of pharmacologic AA and suggest that AA and GSH administered together provide no addi@onal beneﬁt compared with AA alone. There is an antagonism between ascorbate and glutathione in trea>ng cancer, and therefore iv AA and iv GSH should not be coadministered to cancer pa>ents on the same day. Chen P, Stone J, Sullivan G, Drisko JA, Chen Q. An@-‐cancer eﬀect of pharmacologic ascorbate and its interac@on with supplementary parenteral glutathione in preclinical cancer models. Free Radic Biol Med. 2011 May 30. PMID: 21672627 (c) PS Anderson 2015 17 Regarding IV Vitamin C: High and Low Dose
•  The Vitamin C IV’s are in two major categories: •  Those for general immune and an@oxidant support •  These IV’s contain support nutrients, and occasionally are given with Glutathione •  Those for purely oxida@ve purposes •  These generally only have minerals to balance blood electrolytes, and are generally not given with glutathione or other nutrients on the same day. (c) PS Anderson 2015 18 •  A deﬁni@ve level for the threshold of oxida@on in intravenously (IV) administered ascorbate is unclear. •  Two papers [1,2] indicate that lower levels than previously considered (5-‐10 grams IVC) may cause oxida@on and another [3] disagrees. •  Although lower doses of IVC can cause transient oxida@on the likelihood of use of low dose IVC as an “oxida@ve therapy” is small. •  This in no way minimizes the u@lity of lower dose IVC strategies. •  These lower dose IVC formulas can have more addi@ves and can be used for quality of life enhancement [4,5,6,7] and general nutrient support [8,9]. •  Truly “oxida@ve” IVC formulas that have a prac@cal longer term oxida@ve eﬀect in the body likely begin at 20-‐25 grams and above. •  For example the “oxida@ve” eﬀect of a 10 gram IVC is real, but highly transient. •  When employing an “oxida@ve strategy” with IVC the dose escala@on for those purposes generally starts at 25 Grams. (c) PS Anderson 2015 19 •  Dosing guidelines for IVC based on therapeu>c target: •  “Low Dose” IVC •  0.07 to 0.14 Grams per kilogram of body weight •  Quality of Life in cancer and other illnesses •  General immune and an@oxidant support •  These IV’s owen contain support nutrients, and occasionally are given with Glutathione •  “High Dose – Oxida@ve” IVC •  0.4 to 1.4 Grams per kilogram of body weight •  Those for purely oxida@ve purposes •  These generally only have minerals to balance blood electrolytes [10,11] such as magnesium, calcium and potassium in their chloride salt forms and are generally not given with glutathione or other nutrients / an@oxidants on the same day. (c) PS Anderson 2015 20 References: [1] Hininger I, Waters R, Osman M, et al. Prooxidant eﬀects of vitamin C in EDTA chela@on therapy and long-‐term an@oxidant beneﬁts of therapy. Free Radic Biol Med 2005;38:1565-‐1570. [2] Roussel AM, et.al. EDTA Chela@on Therapy, without Added Vitamin C, Decreases Oxida@ve DNA Damage and Lipid Peroxida@on. Altern Med Rev 2009;14(1):56-‐61 [3] Mühlhöfer A, et. al. High-‐dose intravenous vitamin C is not associated with an increase of pro-‐oxida@ve biomarkers. Eur J Clin Nutr. 2004 Aug;58(8):1151-‐8. (Note ‘High Dose‘ was 7.4 grams). [4] Lutsenko, E A, Carcamo J M, Golde DW. Vitamin C Prevents Gene Muta@on Induced by Oxida@ve Stress. Journal of Biological Chemistry. 277(19), May 10,2002. DOI 10.1074/jbc.M201151200 / available on line at h~p://www.jbc.org [5] Vojdani, A. Namatella, G. Enhancement of Human Natural Killer Cytotoxic Ac@vity by Vitamin C in Pure and Augmented Formula@ons. Journal of Nutri@onal and Environmental Medicine. Vol. 7, No. 3 , Pages 187-‐196. 1997. DOI: 10.1080/13590849762600 [6] Vollbracht C, et. al. Intravenous vitamin C administra@on improves quality of life in breast cancer pa@ents during chemo-‐/
radiotherapy and awercare: results of a retrospec@ve, mul@centre, epidemiological cohort study in Germany. In Vivo. 2011 Nov-‐Dec;
25(6):983-‐90. [7] Yeom CH Jung GC, Song KJ. Changes of terminal cancer pa@ents' health-‐related quality of life awer high dose vitamin C administra@on. J Korean Med Sci. 2007 Feb;22(1):7-‐11. [8] Mehrnoush Mirhosseini MD and Robin Fainsinger MD. Fast Facts Documents # 190 Parenteral Nutri@on in Advanced Cancer Pa@ents. h~p://www.eperc.mcw.edu/EPERC/FastFactsIndex/ﬀ_190.htm. Originally published October 2007. Current version re-‐copy-‐
edited in May 2009. [9] Ali A, Njike VY, Northrup V, Sabina AB, Williams AL, Liber@ LS, Perlman AI, Adelson H, Katz DL. Intravenous micronutrient therapy (Myers' Cocktail) for ﬁbromyalgia: a placebo-‐controlled pilot study. J Altern Complement Med. 2009 Mar;15(3):247-‐57. PMID: 19250003 [10] Anderson P., Naydis E., Standish L. (2011, November). High Dose IV Ascorbic Acid Therapy: the Bastyr Experience. Poster session presented at the Society for Integra@ve Oncology, Cleveland, OH. [11] Anderson P. “Intravenous Vitamin C in Naturopathic Oncology.” Scien@ﬁc Presenta@on. Oncology Associa@on of Naturopathic Physicians. Sco~sdale, Arizona. 2012. (c) PS Anderson 2015 21 Ascorbate and quality of life (c) PS Anderson 2015 22 Vitamin C Prevents Gene Muta/on Induced by Oxida/ve Stress
“High intracellular concentra>ons of vitamin C can prevent oxida>on-‐
induced muta>ons in human cells.” Lutsenko, E A, Carcamo J M, Golde DW. Vitamin C Prevents Gene Muta@on Induced by Oxida@ve Stress. Journal of Biological Chemistry. 277(19), May 10,2002. DOI 10.1074/jbc.M201151200 / available on line at h~p://
www.jbc.org (c) PS Anderson 2015 23 Low Dose Vitamin C and NK Cell Ac>vity: The an@tumor ac@vity of ascorbic acid has been reported by diﬀerent inves@gators. In this study, we determined the in vivo eﬀects of ascorbic acid and its modiﬁed formula@on (Ultra Potent-‐C) on human natural killer (NK) cell ac@vity. Twenty-‐two healthy subjects were given either ascorbic acid or Ultra Potent-‐C orally at a concentra@on of 60 mg kg -‐ 1. Vitamin C uptake was measured in the plasma and by peripheral blood lymphocytes (PBLs). The uptake of vitamin C by PBLs was maximized at 2-‐4 h and was maintained at a high level up to 24 h. At the maximal point the uptake of Ultra Potent-‐C was higher by 18-‐25% than plain ascorbic acid. In addi@on, PBL-‐NK ac@vity was measured by a 4-‐h 51Cr release assay using K562 as targets. The results demonstrated that ascorbic acid has a biphasic paaern of NK func>on; an early transient depression in NK ac>vity (29%) at 1-‐4 h that is subsequently followed by a signiﬁcant enhancement (200-‐400%) between 8 and 24 hours. However, the pa~ern of NK ac@vity in the Ultra Potent-‐C group was diﬀerent from the ascorbic acid group and the early transient depression in NK ac@vity was not observed. We conclude that ascorbic acid or its modiﬁed form is a potent immunomodulator. Vojdani, A. Namatella, G. Enhancement of Human Natural Killer Cytotoxic Ac@vity by Vitamin C in Pure and Augmented Formula@ons. Journal of Nutri@onal and Environmental Medicine. Vol. 7, No. 3 , Pages 187-‐196. 1997. DOI: 10.1080/13590849762600 (c) PS Anderson 2015 24 The Role of lower-‐dose IVC in Quality of Life (1)
Aim: The aim of the study was to evaluate under praxis condi@ons the safety and eﬃcacy of intravenous (i.v.) vitamin C administra@on in the ﬁrst postopera@ve year of women with breast cancer. PATIENTS AND METHODS: Epidemiological mul@centre cohort study, … Data from 125 breast cancer pa@ents in UICC stages IIa to IIIb were selected for the study. A total of 53 of these pa@ents were treated with i.v. vitamin C (…7.5 g) addi@onal to standard tumour therapy for at least 4 weeks (study group) and 72 without this addi@onal therapy (control group). Main outcome measures were eﬃcacy in regard to outcome and severity of disease-‐ or therapy-‐induced complaints during adjuvant chemo-‐ and radiotherapy and awercare. Vollbracht C, et. al. Intravenous vitamin C administra@on improves quality of life in breast cancer pa@ents during chemo-‐/radiotherapy and awercare: results of a retrospec@ve, mul@centre, epidemiological cohort study in Germany. In Vivo. 2011 Nov-‐Dec;25(6):
983-‐90. (c) PS Anderson 2015 25 The Role of lower-‐dose IVC in Quality of Life (2)
RESULTS: Comparison of control and study groups revealed that i.v. vitamin C administra@on resulted in a signiﬁcant reduc@on of complaints induced by the disease and chemo-‐/radiotherapy, in par@cular of nausea, loss of appe@te, fa@gue, depression, sleep disorders, dizziness and haemorrhagic diathesis. Awer adjustment for age and baseline condi@ons (intensity score before adjuvant therapy, chemotherapy, radiotherapy), the overall intensity score of symptoms during adjuvant therapy and awercare was nearly twice as high in the control group compared to the study group. No side-‐eﬀects of the i.v. vitamin C administra@on were documented. DISCUSSION: Oxida@ve stress and vitamin C deﬁciency play an important role in the e@ology of adverse eﬀects of guideline-‐based adjuvant chemo-‐/radiotherapy. Restoring an>oxida>ve capacity by complementary i.v. vitamin C administra>on helps to prevent or reduce disease-‐, or therapy-‐induced complaints in breast cancer pa>ents. Vollbracht C, et. al. (c) PS Anderson 2015 26 Changes of Terminal Cancer Pa/ents’ Health-‐related Quality of Life (1)
Over the years there has been a great deal of controversy on the eﬀect of vitamin C on cancer. To inves@gate the eﬀects of vitamin C on cancer pa@ents’ health-‐related quality of life, we prospec@vely studied 39 terminal cancer pa@ents. All pa@ents were given an intravenous administra@on of 10 g vitamin C twice with a 3-‐day interval and an oral intake of 4 g vitamin C daily for a week. And then we inves@gated demographic data and assessed changes in pa@ents’ quality of life awer administra@on of vitamin C. Quality of life was assessed with EORTC QLQ-‐C30. Yeom CH Jung GC, Song KJ. Changes of terminal cancer pa@ents' health-‐related quality of life awer high dose vitamin C administra@on. J Korean Med Sci. 2007 Feb;22(1):7-‐11. (c) PS Anderson 2015 27 Changes of Terminal Cancer Pa/ents’ Health-‐related QOL (2)
In the global health/quality of life scale, health score improved from 36+/-‐18 to 55 +/-‐ 16 awer administra@on of vitamin C (p=0.001). In func@onal scale, the pa@ents reported signiﬁcantly higher scores for physical, role, emo@onal, and cogni@ve func@on awer administra@on of vitamin C (p<0.05). In symptom scale, the pa@ents reported signiﬁcantly lower scores for fa@gue, nausea/vomi@ng, pain, and appe@te loss awer administra@on of vitamin C (p<0.005). The other func@on and symptom scales were not signiﬁcantly changed awer administra@on of vitamin C. In terminal cancer pa>ents, the quality of life is as important as cure. Although there is s@ll controversy regarding an@cancer eﬀects of vitamin C, the use of vitamin C is considered a safe and eﬀec@ve therapy to improve the quality of life of terminal cancer pa@ents. Yeom CH Jung GC, Song KJ. (c) PS Anderson 2015 28 (c) PS Anderson 2015 29 (c) PS Anderson 2015 30 Guidelines for the U/liza/on of IV Vitamin C in the Suppor/ve Care of Pa/ents with Advanced Malignancies: SIO Poster Presenta/on, 2012 Authors: Eiko Klimant MD, Heather Wright ND, Hadassah Hilewitz ND
Conclusion: •  The use of IVC in suppor@ve care for pa@ents with advanced malignancies is controversial. •  According to the literature there may be clinical beneﬁt from low dose IV vitamin C in suppor@ve care of pa@ents with advanced malignancies. •  Our guideline for low dose IV vitamin C is a step towards evidence-‐
based prac@ce of integra@ve oncology. •  Further studies looking at Low dose versus High dose IV vitamin C in suppor@ve care of cancer pa@ents are warranted. (c) PS Anderson 2015 31 Guidelines for the U/liza/on of IV Vitamin C in the Suppor/ve Care of Pa/ents with Advanced Malignancies: SIO Poster Presenta/on, 2012 Authors: Eiko Klimant MD, Heather Wright ND, Hadassah Hilewitz ND
i Padya~y SJ, Sun H, Wang Y, Riordan HD, Hewi~ SM, Katz A, Wesley RA, Levine M: Vitamin C Pharmacokine@cs: Implica@ons for Oral and Intravenous Use. Annals of Internal Medicine; 2004; 140; 533-‐573. iiCameron E, Pauling L: Supplemental ascorbate in the suppor@ve treatment of cancer: Prolonga@on of survival @mes in terminal human cancer. Proc Natl Acad Sci USA 1976; 73:3685-‐3689. iii Murata A, Morishige F, Yamaguchi H; Prolonga@on of survival @mes of terminal cancer pa@ents by administra@on of large doses of ascorbate; Int J Vitam Nutr Res Suppl; 1982; 23:103-‐113. Iv Yeom CH, Jung GC, Song KJ: Changes of terminal cancer pa@ents’ health related quality of life awer high dose vitamin C administra@on. J Korean Med Sci 2007; 22:7-‐11. v Vollbracht C, Schneider B, Van Leendert, Weiss G, Auerbach L, Beuth J; Intravenous Vitamin C Administra@on Improves Quality of Life in Breast. Cancer Pa@ents during Chemo-‐/Radiotherapy and Awercare: Results of a Retrospec@ve, Mul@centre Epidemiological Cohort Study in Germany. In Vivo 25: 983-‐990 (2011). vi Ichim TE, Minev B, Braciak T, Luna B, Hunninghake R, Mikirova NA, Jackson JA, Gonzalez MJ, Miranda-‐Massari JR, Alexandrescu DT, Dasanu CA, Bogin V, Ancans J, Stevens RB, Markosian B, Koropatnick J, Chen CS, Riordan NH; Intravenous ascorbic acid to prevent and treat cancer-‐
associated sepsis? J Transl Med. 2011 Mar 4;9:25. (c) PS Anderson 2015 32 Guidelines for the U/liza/on of IV Vitamin C in the Suppor/ve Care of Pa/ents with Advanced Malignancies: SIO Poster Presenta/on, 2012 Authors: Eiko Klimant MD, Heather Wright ND, Hadassah Hilewitz ND
vii Mayland CR, Benne~ MI, Allan K; Vitamin C deﬁciency in cancer pa@ents; Pallia@ve Medicine 2005;19:17-‐20. viii Hoﬀer LJ, Levine M, Assouline S, Melnychuk D, Padaya~y SJ, Rosadiuk K, Rousseau C, Robitaille L, Miller WH Jr. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol. 2008 Nov;
19(11):1969-‐74. ix Friedman GJ, Sherry S, Ralli EP; The mechanism of the excre@on of vitamin C by the human kidney at low and normal plasma levels of ascorbic acid; J Clin Inves. 1940;19:685-‐689. x Kallner A, Hartmann D, Hornig D. Steady-‐state turnover and body pool of ascorbic acid in man. Am J Clin Nutr. 1979;32:530-‐539. xiYeom CH, Jung GC, Song KJ: Changes of terminal cancer pa@ents’ health related quality of life awer high dose vitamin C administra@on. J Korean Med Sci 2007; 22:7-‐11. xii Ichim et. al. Journal of Transla@onal Medicine. 2011, 9:25. [h~p://www.transla@onal-‐medicine.com/
content/9/1/25]. xiiiGalecki P, Szemraj J, Bienkiewicz M, Florkowski A, Galecka E; Lipid peroxida@on and an@oxidant protec@on in pa@ents during acute depressive episodes and in remission awer ﬂuoxe@ne treatment. Pharmacological Reports. 2009. (61) 436-‐447. xiv Khanzode SD, Dakhale GN, Khanzode SS, Saoji A, Palasodkar R. Oxida@ve damage and major depression: the poten@al an@oxidant ac@on of selec@ve serotonin re-‐uptake inhibitors. Redox Rep. 2003; 8(6):365-‐70. xvBinfaré RW, Rosa AO, Lobato KR, Santos AR, Rodrigues AL. Ascorbic acid administra@on produces an an@depressant-‐like eﬀect: evidence for the involvement of monoaminergic neurotransmission. Prog Neuropsychopharmacol Biol Psychiatry. 2009. Apr 30;33(3): 530-‐40. (c) PS Anderson 2015 33 Examples of low dose IVC used for Rehydra/on and QOL care (c) PS Anderson 2015 34 Custom Rehydra/on / QOL Solu/ons with Nutrients
•  The following slides show examples from the BIORC / AMSA clinics of customized solu@ons used in dehydrated cancer pa@ents. •  As long as the rule of hypotonic or isotonic solu@on for rehydra@on is followed, one may compound any number of appropriate solu@ons using a hypotonic base solu@on and nutrients. •  Common addi@ves to these formulas include single amino acids, trace minerals etc. (c) PS Anderson 2015 35 Rx: Rehydration 500 mL
Total Volume: 552 mL
Osmolarity: 271 mOsm/L
500 mL
Sterile Water
1 mL Pyridoxine / B-6 (100mg)
10 mL
C-500 (5 grams)
3 mL B-100 Complex
5 mL
Calcium Chloride (6.8 mEq)
2 mL Dexpanthenol / B-5 (500mg)
10 mL
Magnesium Chloride (19.7 mEq)
3 mL
Potassium Chloride (6 mEq)
0.5
5MTHF (2.5 mg)
mL
2 mL Methyl-B12 (10 mg)
15 mL
8.4% Sodium Bicarbonate
(c) PS Anderson 2015 36 Rx: Rehydration 500 mL in 0.45% NS
Total Volume: 535 mL
Osmolarity: 325 mOsm/L
500 mL
0.45% (Half) Normal Saline
1 mL Pyridoxine / B-6 (100mg)
5 mL
C-500 (2.5 grams)
2 mL B-100 Complex
4 mL
Calcium Chloride (5.44 mEq)
2 mL Dexpanthenol / B-5 (500mg)
6 mL
Magnesium Chloride (11.82 mEq)
3 mL
Potassium Chloride (6 mEq)
0.5
5MTHF (2.5 mg)
mL
1 mL Methyl-B12 (5 mg)
10 mL
8.4% Sodium Bicarbonate
(c) PS Anderson 2015 37 Rx: Rehydration 500 mL plus Amino Acids
Total Volume: 598 mL
Osmolarity: 285 mOsm/L
500 mL
Sterile Water
1 mL
Pyridoxine / B-6 (100mg)
5 mL
C-500 (2.5 grams)
3 mL
B-100 Complex
6 mL
Calcium Chloride (8.16 mEq)
2 mL
Dexpanthenol / B-5 (500mg)
10 mL
Magnesium Chloride (19.7 mEq)
5MTHF (2.5 mg)
4 mL
Potassium Chloride (8 mEq)
0.5
mL
2 mL
15 mL
8.4% Sodium Bicarbonate
50 mL Aminosyn 8.5% Solution
(c) PS Anderson 2015 Methyl-B12 (10 mg)
38 Rx: Rehydration 1000 mL
Total Volume: 1101 mL
Osmolarity: 290 mOsm/L
1000 mL
Sterile Water
1 mL Pyridoxine / B-6 (100mg)
25 mL
C-500 (12.5 grams)
4 mL B-100 Complex
10 mL
Calcium Chloride (13.60 mEq)
4 mL Dexpanthenol / B-5 (1000mg)
20 mL
Magnesium Chloride (39.4 mEq)
8 mL
Potassium Chloride (16 mEq)
0.5
5MTHF (2.5 mg)
mL
2 mL Methyl-B12 (10 mg)
25 mL
8.4% Sodium Bicarbonate
(c) PS Anderson 2015 39 Rx: Rehydration 1000 mL plus Amino Acids
Total Volume: 1186 mL
Osmolarity: 271 mOsm/L
1000 mL
Sterile Water
1 mL
Pyridoxine / B-6 (100mg)
10 mL
C-500 (5 grams)
4 mL
B-100 Complex
10 mL
Calcium Chloride (13.60 mEq)
4 mL
20 mL
Magnesium Chloride (39.4 mEq)
Dexpanthenol / B-5
(1000mg)
0.5 mL 5MTHF (2.5 mg)
8 mL
Potassium Chloride (16 mEq)
2 mL
25 mL
8.4% Sodium Bicarbonate
100mL 8.5 % Aminosyn
(c) PS Anderson 2015 Methyl-B12 (10 mg)
40 Ascorbate High Dose IVC used for Oxida/ve Therapy (c) PS Anderson 2015 41 Pro-‐oxidant Mechanism Of Ac/on
(c) PS Anderson 2015 42 The cell paradox: Does the ASC need to enter the tumor cell? – No.
“Extracellular but not intracellular ascorbate mediated cell death, which occurred by apoptosis and pyknosis/necrosis. Cell death was independent of metal chelators and absolutely dependent on H(2)O(2) forma@on. Cell death from H(2)O(2) added to cells was iden@cal to that found when H(2)O(2) was generated by ascorbate treatment… Taken together, these data indicate that ascorbate at concentra@ons achieved only by i.v. administra@on may be a pro-‐drug for forma@on of H(2)O(2), and that blood can be a delivery system of the pro-‐drug to @ssues. These ﬁndings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implica@ons for treatment of infec@ons where H(2)O(2) may be beneﬁcial.” Chen Q, et.al. Pharmacologic ascorbic acid concentra@ons selec@vely kill cancer cells: ac@on as a pro-‐drug to deliver hydrogen peroxide to @ssues. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13604-‐9. Epub 2005 Sep 12. (c) PS Anderson 2015 43 Where does this MOA work? The Ques/on and Answer:
•  Where does the H2O2 need to be to have a poten@al an@-‐cancer eﬀect? •  As opposed to former thought, data presented during the past decade shown below is clear that the H2O2 surge is outside rather than inside the cell. The an@-‐oncologic poten@al eﬀects then cascade from the H2O2 genera@on. (c) PS Anderson 2015 44 Human pharmacokine>cs data indicate that i.v. ascorbic acid (ascorbate) in pharmacologic concentra>ons could have an unan>cipated role in cancer treatment. … Extracellular but not intracellular ascorbate mediated cell death, which occurred by apoptosis and pyknosis/necrosis. Cell death was independent of metal chelators and absolutely dependent on H(2)O(2) forma>on. Cell death from H(2)O(2) added to cells was iden>cal to that found when H(2)O(2) was generated by ascorbate treatment… Taken together, these data indicate that ascorbate at concentra>ons achieved only by i.v. administra>on may be a pro-‐drug for forma>on of H(2)O(2), and that blood can be a delivery system of the pro-‐drug to >ssues. These ﬁndings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implica>ons for treatment of infec>ons where H(2)O(2) may be beneﬁcial. Chen Q, et.al. Pharmacologic ascorbic acid concentra>ons selec>vely kill cancer cells: ac>on as a pro-‐drug to deliver hydrogen peroxide to >ssues.Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13604-‐9. Epub 2005 Sep 12. (c) PS Anderson 2015 45 Chen Q, Espey, MG, and Sun AY, et al. Ascorbate in
pharmacologic concentrations selectively generates
ascorbate radical and hydrogen peroxide in
extracellular fluid in vivo. Proc Natl Acad Sci U S A.
2007; 104(21):8749-54. PMID: 17502596. www.pnas.orgcgidoi10.1073pnas.0702854104 © 2007 by The Na>onal Academy of Sciences of the USA (The following three slides and images are from this paper) (c) PS Anderson 2015 46 Abstract: (c) PS Anderson 2015 47 As ASC Plasma concentrations rise, ECF ASC concentrations rise. ASC is then
radicalized in the presence of Fe causing a peroxide surge. In catalase/GSH
deficient tissues the peroxide surge creates potential cell damage.
IMAGE: © 2007 by The Na@onal Academy of Sciences of the USA (c) PS Anderson 2015 48 Proposed mechanism of injury in CA / Virally infected cells via high ASC
concentrations.
IMAGE: © 2007 by The Na@onal Academy of Sciences of the USA
(c) PS Anderson 2015 49 What poten/al mechanisms can the H2O2 generated by the ASC (as well as the metabolism of the ASC itself) have in the damage and death of a cancer cell?
•  Pharmacologic ascorbic acid concentra@ons produce extracellular H2O2, which can diﬀuse into cells, deplete ATP in sensi@ve cells, and thereby cause cell death. ATP may be depleted by three mechanisms. (i) DNA damage induced by H2O2 ac@vates PARP. Ac@vated PARP catabolizes NAD+, thereby deple@ng substrate for NADH forma@on and consequent ATP synthesis. (ii) H2O2 is catabolized by concurrent oxida@on of GSH to GSSG. To reduce GSSG back to GSH, GSH reductase u@lizes NADPH, which is provided by the pentose shunt from glucose. Glucose used to reduce NADP+ to NADPH cannot be used for glycolysis or NADH produc@on so that ATP genera@on is decreased. (iii) H2O2 may directly damage mitochondria, especially ATP synthase, so that ATP produc@on falls. Some cancer cells rely primarily on glycolysis rather than on oxida@ve phosphoryla@on respira@on for ATP produc@on (the Warburg eﬀect). Compared with oxida@ve phosphoryla@on, ATP genera@on by glycolysis is ineﬃcient. In glycolysis-‐dependent cancer cells, decreased glycolysis may lower intracellular ATP. Cancer cells that are glycolysis-‐
dependent may be par@cularly sensi@ve to pharmacologic ascorbic acid concentra@ons, compared with cells that use oxida@ve phosphoryla@on. Chen, et.al. Ascorbate in pharmacologic concentra@ons selec@vely generates ascorbate radical and hydrogen peroxide in extracellular ﬂuid in vivo .www.pnas.org doi:10.1073:pnas.0702854104 PNAS, May 22, 2007. vol. 104. no. 21; 8749–8754 (c) PS Anderson 2015 50 High Dose IVC compared to H2O2 – Biological ac/vity: (Or: If we are genera/ng a H2O2 burst with HDIVC why not just infuse H2O2?)
(c) PS Anderson 2015 51 Biochemical diﬀerences between ASC and H2O2
ASC – High Dose IV: •  IV à ASC High Dose – “Pro-‐drug for H2O2 produc@on” •  Plasma H2O2 IV: •  IV à H2O2 •  Plasma •  ASC + Fe or Cu à H2O2 •  Some reduced by plasma catalase and GSH peroxidase •  ECF •  H2O2 –catalase/Mnà H2O+O2 àPlasma cytokine s@mula@on: •  ECF •  ASC + Fe or Cu à H2O2 •  Cell •  Cytokine release / Immune s@mula@on PLUS: •  IL-‐1, IL-‐6, IFNa, TNF, NO •  ALL H2O2 is dismutated in the venous circula>on in seconds •  No H2O2 lew But Increased Cytokine cascade à Immune s@mula@on •  No H2O2 delivered to the cells •  Normal cell: H2O2 reduced by catalase to H2O •  Abnormal cell: H2O2 à poten@al cell damage (c) PS Anderson 2015 52 References for ASC vs H2O2
•  Chen Q, Espey, MG, and Sun AY, et al. Ascorbate in pharmacologic concentra@ons selec@vely generates ascorbate radical and hydrogen peroxide in extracellular ﬂuid in vivo. Proc Natl Acad Sci U S A. 2007; 104(21):8749-‐54. PMID: 17502596. •  Siwale RC, et.al. The eﬀect of intracellular an@oxidant delivery (catalase) on hydrogen peroxide and proinﬂammatory cytokine synthesis: a new therapeu@c horizon. Journal of Drug Targe@ng, Volume 17, Number 9 doi.org/10.3109/10611860903161328 •  Zadeh. et.al. Regula@on of ICAM/CD54 expression on human endothelial cells by hydrogen peroxide involves inducible NOS. J. Leukocyte Biology; 67: 327-‐334; 2000 (c) PS Anderson 2015 53 Regarding IV Vitamin C and poten/al for Oxida/on:
• The Vitamin C IV’s are in two major categories: • Those for general immune and an@oxidant support • These IV’s contain support nutrients, and occasionally are given with Glutathione • Those for purely oxida@ve purposes • These generally only have minerals to balance blood electrolytes, and are generally not given with glutathione or other nutrients on the same day. (c) PS Anderson 2015 54 So – How much IVC will oxidize?
•  A deﬁni@ve level for the threshold of oxida@on in intravenously (IV) administered ascorbate is unclear. •  Two papers [1,2] indicate that lower levels than previously considered (5-‐10 grams IVC) may cause oxida@on and another [3] disagrees. [1] Hininger I, Waters R, Osman M, et al. Prooxidant eﬀects of vitamin C in EDTA chela@on therapy and long-‐term an@oxidant beneﬁts of therapy. Free Radic Biol Med 2005;38:1565-‐1570. [2] Roussel AM, et.al. EDTA Chela@on Therapy, without Added Vitamin C, Decreases Oxida@ve DNA Damage and Lipid Peroxida@on. Altern Med Rev 2009;14(1):56-‐61 [3] Mühlhöfer A, et. al. High-‐dose intravenous vitamin C is not associated with an increase of pro-‐oxida@ve biomarkers. Eur J Clin Nutr. 2004 Aug;58(8):1151-‐8. (Note ‘High Dose‘ was 7.4 grams). (c) PS Anderson 2015 55 Oxida/on Conclusions:
•  Although lower doses of IVC can cause transient oxida@on the likelihood of use of low dose IVC as an “oxida@ve therapy” is small. •  This in no way minimizes the u@lity of lower dose IVC strategies. •  These lower dose IVC formulas can have more addi@ves and can be used for quality of life enhancement and general nutrient support. •  Truly “oxida@ve” IVC formulas that have a prac@cal longer term oxida@ve eﬀect in the body likely begin at 20-‐25 grams and above. •  For example the “oxida@ve” eﬀect of a 10 gram IVC is real, but highly transient. •  When employing an “oxida@ve strategy” with IVC the dose escala@on for those purposes generally starts at 25 Grams. (c) PS Anderson 2015 56 References: Prior sec/on
[1] Hininger I, Waters R, Osman M, et al. Prooxidant eﬀects of vitamin C in EDTA chela@on therapy and long-‐term an@oxidant beneﬁts of therapy. Free Radic Biol Med 2005;38:1565-‐1570. [2] Roussel AM, et.al. EDTA Chela@on Therapy, without Added Vitamin C, Decreases Oxida@ve DNA Damage and Lipid Peroxida@on. Altern Med Rev 2009;14(1):56-‐61 [3] Mühlhöfer A, et. al. High-‐dose intravenous vitamin C is not associated with an increase of pro-‐oxida@ve biomarkers. Eur J Clin Nutr. 2004 Aug;58(8):1151-‐8. (Note ‘High Dose‘ was 7.4 grams). [4] Lutsenko, E A, Carcamo J M, Golde DW. Vitamin C Prevents Gene Muta@on Induced by Oxida@ve Stress. Journal of Biological Chemistry. 277(19), May 10,2002. DOI 10.1074/jbc.M201151200 / available on line at h~p://www.jbc.org [5] Vojdani, A. Namatella, G. Enhancement of Human Natural Killer Cytotoxic Ac@vity by Vitamin C in Pure and Augmented Formula@ons. Journal of Nutri@onal and Environmental Medicine. Vol. 7, No. 3 , Pages 187-‐196. 1997. DOI: 10.1080/13590849762600 [6] Vollbracht C, et. al. Intravenous vitamin C administra@on improves quality of life in breast cancer pa@ents during chemo-‐/radiotherapy and awercare: results of a retrospec@ve, mul@centre, epidemiological cohort study in Germany. In Vivo. 2011 Nov-‐Dec;25(6):983-‐90. [7] Yeom CH Jung GC, Song KJ. Changes of terminal cancer pa@ents' health-‐related quality of life awer high dose vitamin C administra@on. J Korean Med Sci. 2007 Feb;22(1):7-‐11. [8] Mehrnoush Mirhosseini MD and Robin Fainsinger MD. Fast Facts Documents # 190 Parenteral Nutri@on in Advanced Cancer Pa@ents. h~p://www.eperc.mcw.edu/EPERC/FastFactsIndex/ﬀ_190.htm. Originally published October 2007. Current version re-‐copy-‐edited in May 2009. [9] Ali A, Njike VY, Northrup V, Sabina AB, Williams AL, Liber@ LS, Perlman AI, Adelson H, Katz DL. Intravenous micronutrient therapy (Myers' Cocktail) for ﬁbromyalgia: a placebo-‐controlled pilot study. J Altern Complement Med. 2009 Mar;15(3):247-‐57. PMID: 19250003 [10] Anderson P., Naydis E., Standish L. (2011, November). High Dose IV Ascorbic Acid Therapy: the Bastyr Experience. Poster session presented at the Society for Integra@ve Oncology, Cleveland, OH. [11] Anderson P. “Intravenous Vitamin C in Naturopathic Oncology.” Scien@ﬁc Presenta@on. Oncology Associa@on of Naturopathic Physicians. Sco~sdale, Arizona. 2012. (c) PS Anderson 2015 57 [Can we infuse enough Vitamin C to cause these concentra>ons?] Recently, it has been proposed that pharmacologic concentra@ons of ascorbate (vitamin C) can be reached by intravenous injec@on. Because high doses of ascorbate have been described to possess an@cancer eﬀects, the therapeu@c poten@al of these concentra@ons has been studied, both in vitro and in vivo. By using 2-‐h exposures, a protocol that mimics a parenteral use, we observed that pharmacologic concentra@ons of ascorbate killed various cancer cell lines very eﬃciently (EC(50) ranging from 3 to 7 mM, 170-‐397 mg/dL). The mechanism of cytotoxicity is based on the produc@on of extracellular hydrogen peroxide and involves intracellular transi@on metals. In agreement with what has been previously published, our in vivo results show that both intravenous and intraperitoneal administra>on of ascorbate induced pharmacologic concentra>ons (up to 20 mM, 1135 mg/dL) in blood. In contrast, the concentra@ons reached orally remained physiological. According to pharmacokine@c data, parenteral administra@on of ascorbate decreased the growth rate of a murine hepatoma, whereas oral administra@on of the same dosage did not. Verrax J, Calderon PB. Pharmacologic concentra>ons of ascorbate are achieved by parenteral administra>on and exhibit an>tumoral eﬀects. Free Radic Biol Med. 2009 Jul 1;47(1):32-‐40. Epub 2009 Feb 28. (c) PS Anderson 2015 58 Therefore doses to yield the following ranges in plasma should be suﬃcient to meet the above criteria for H2O2 produc/on and other ac/ons of ASC:
•  ASC Plasma concentra@ons of 300 to 400 mg/dl = ASC [17.04 -‐ 22.7 mMol/L] exceed the 10 mM oxida@ve threshold originally discussed [Verrax J, Calderon PB. The controversial place of vitamin C in cancer treatment. Biochemical Pharmacology 76 (2008) 1644–1652 ] and should therefore create a stead state of H2O2 produc@on in the extracellular space for an extended period of @me. (c) PS Anderson 2015 59 Dosing of IVC:
•  “Low Dose” IVC •  0.07 to 0.14 Grams per kilogram of body weight •  Quality of Life in cancer and other illnesses •  General immune and an@oxidant support •  These IV’s contain support nutrients, and occasionally are given with Glutathione •  “High Dose – Oxida@ve” IVC •  0.4 to 1.4 Grams per kilogram of body weight •  Those for purely oxida@ve purposes •  These generally only have minerals to balance blood electrolytes, and are generally not given with glutathione or other nutrients on the same day. (c) PS Anderson 2015 60 IV Vitamin C and other addi/ves
•  B-‐Vitamins and IVC: •  Glutathione and IVC: (c) PS Anderson 2015 61 Should we separate B-Vitamins from High-dose /
oxidative IVC?
The bo'om line is that while B-‐Vitamins and other an5oxidants are needed during cancer therapy, they may decrease the oxida5ve eﬀect of HDIVC if concurrently administered. Ochi M, Hetherington J, Lamson D. The Concern about B-‐Vitamins with Intravenous Ascorbate for Malignancy; Altern Med Rev 2011;16(Supp):1S-‐5S (c) PS Anderson 2015 62 Glutathione and IVC for Oxidation on the same day:
Two popular complementary, alterna@ve, and integra@ve medicine therapies, high-‐dose intravenous ascorbic acid (AA) and intravenous glutathione (GSH), are owen coadministered to cancer pa@ents with unclear eﬃcacy and drug-‐drug interac@on. Treatment in mouse pancrea@c cancer xenograws showed that intraperitoneal AA at 4g/kg daily reduced tumor volume by 42%. Addi@on of intraperitoneal GSH inhibited the AA-‐induced tumor volume reduc@on. Although all treatments (AA, GSH, and AA+GSH) improved survival rate, AA+GSH inhibited the cytotoxic eﬀect of AA alone and failed to provide further survival beneﬁt. These data conﬁrm the pro-‐oxida@ve an@-‐cancer mechanism of pharmacologic AA and suggest that AA and GSH administered together provide no addi@onal beneﬁt compared with AA alone. There is an antagonism between ascorbate and glutathione in trea>ng cancer, and therefore iv AA and iv GSH should not be coadministered to cancer pa>ents on the same day. Chen P, Stone J, Sullivan G, Drisko JA, Chen Q. An@-‐cancer eﬀect of pharmacologic ascorbate and its interac@on with supplementary parenteral glutathione in preclinical cancer models. Free Radic Biol Med. 2011 May 30. PMID: 21672627 (c) PS Anderson 2015 63 IVC – Outcomes;
The BIORC Research Trial
(c) PS Anderson 2015 64 BIORC IVC Protocol
General Schedule Tx 1-‐ 15: 2 to 3 X weekly. § Intake Visit: §  Informed Consent §  Pre-‐Tes(ng: CBC, CMP, G6PD; §  (And – per situa@on – NK Ac@vity, CTC, Tumor markers, Imaging…) § IV #1: PARQ Conference, then IVC 25 Grams § IV #2: IVC 50 Grams § IV #3: IVC 75 Grams, Then post IV (drawn directly a8er IV) Serum / Plasma ASC level §  If ASC level = > 400 mg/dL: con5nue 75 gram IVC §  If ASC level < 400 mg/dL: increase to 100 gram IVC and re test ASC level § IV #4 forward = 75 grams or higher (per tes@ng). (c) PS Anderson 2015 65 (c) PS Anderson 2015 66 Various other potential
interventions …
(c) PS Anderson 2015 67 Outcomes: End of Year One (n24)
(c) PS Anderson 2015 68 Outcomes: End of Year Two (n 35)
Deceased: >12 HDIVC = 2; <12 HDIVC = 6; Other IV = 4; QOL = 1
(c) PS Anderson 2015 69 BIORC Survival Data at Five Years:
•  Beginning data review •  Comparing matched tumor type and stage with survival data from: •  (SCCA) Sea~le Cancer Care Alliance •  (SEER) Surveillance, Epidemiology, and End Results (SEER.Cancer.gov) •  Other published survival data •  Note: “IO” = Integra@ve Oncology, “FOC” = First Oﬃce Call •  More data to come from this project! (c) PS Anderson 2015 70 Seaile Cancer Care outcome data
h~p://www.sea~lecca.org/scca-‐survival-‐rates-‐[email protected] (c) PS Anderson 2015 71
Core treatment in advanced lung cancer N = 12 stage IV lung cancer pa@ents NSCL and SCLC. IV ascorbic acid up to 100 grams per infusion twice a week for 6 weeks as ini/al course Trametes versicolor 3600 mg/day po Curcumin 3000 mg/day po Bromelain 1500 mg/day po Querce/n 2000 mg/day N-‐acetyl cysteine 300 mg bid po Nebulized glutathione and n-‐acetyl cysteine daily SCCA data 1998-‐2002 Ce@n et al 2011 Clin Epid 2011 data Lung cancer (Stage IV at FOC) Survival Rate 1 year
2 years 3 years 75%
64.3%
64.3% (c) PS Anderson 2015 72 One year BIORC outcome data for stage III ovarian cancer, 2009-‐2013 (N =11)
At 3 years 83% of stage III ovarian cancer pa@ents are alive. SEER na@onal data At 3 years 49% are s@ll alive Integra@ve Oncology may prevent (or delay) recurrence. (c) PS Anderson 2015 73 Core treatment in advanced breast cancer BIORC Protocol * Not all pa)ents received all therapies
•  IV artemisinin (Artenusate) 120 mg/infusion twice weekly •  IV ascorbic acid 50 to 100 grams infusion twice weekly •  Trametes versicolor 3600 mg/day po •  Curcumin 6000 mg/day •  Bromelain 1500 mg/day •  Querce@n 3000 mg/day •  ECGC 1600 mg/day po •  Naltrexone 3.5 mg hs •  Tetrathiomolybdate 20-‐120 mg/day po for copper chela@on (c) PS Anderson 2015 74 Later Today:
•  In the ﬁnal presenta@on today I will go through the protocols for oxida@ve IVC as well as op@mal use in the cancer popula@on. (c) PS Anderson 2015 75