Clinical experience with intravenous administration of ascorbic acid: achievable levels in blood for different states of inflammation and disease in cancer patients.
Abstract
BACKGROUND:
Ascorbic acid (vitamin C, ascorbate) is a key water soluble antioxidant that, when administered in doses well above its recommended dietary allowance, may have preventative and therapeutic value against a number of pathologies. The intravenous administration of high dose ascorbate (IVC) has increased in popularity among complementary and alternative medicine practitioners: thousands of patients received IVC, at an average dose of 0.5 g/kg, without significant side effects. While IVC may have a variety of possible applications, it has generated the most interest for its potential use in treating cancer.
METHODS:
Medical records of patients with cancer treated with IVC at the Riordan Clinic were retrospectively reviewed. Cancer patients, for whom plasma ascorbate concentration data before and after treatment were available, along with C-reactive protein (CRP) measurements, were chosen for analysis.
RESULTS:
The results of the analysis can be summarized as follows. IVC produces peak plasma ascorbate concentrations on the order of ten millimolars with lower peak plasma concentrations obtained in cancer patients as compared to healthy subjects. Cancer patients who are deficient in vitamin C prior to therapy tend to achieve lower plasma levels post infusion. High inflammation or tumor burdens, as measured by CRP or tumor antigen levels, tend to lower peak plasma ascorbate levels after IVC. When compared to patients with localized tumors, patients with metastatic tumors tend to achieve lower post infusion plasma ascorbate concentrations.
CONCLUSIONS:
The data indicate that, while potentially therapeutic plasma ascorbate concentrations can be achieved with IVC, levels attained will vary based on tumor burden and degree of inflammation (among other factors). Evidence suggests that IVC may be able to modulate inflammation, which in turn might improve outcomes for cancer patients. IVC may serve as a safe, adjunctive therapy in clinical cancer care.
J Transl Med. 2011 Mar 4;9:25. doi: 10.1186/1479-5876-9-25.
Intravenous ascorbic acid to prevent and treat cancer-associated sepsis?
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.
Source
Department of Orthomolecular Studies, Riordan Clinic, 3100 N Hillside, Wichita, Kansas 67210, USA.
Abstract
The history of ascorbic acid (AA) and cancer has been marked with controversy. Clinical studies evaluating AA in cancer outcome continue to the present day. However, the wealth of data suggesting that AA may be highly beneficial in addressing cancer-associated inflammation, particularly progression to systemic inflammatory response syndrome (SIRS) and multi organ failure (MOF), has been largely overlooked. Patients with advanced cancer are generally deficient in AA. Once these patients develop septic symptoms, a further decrease in ascorbic acid levels occurs. Given the known role of ascorbate in: a) maintaining endothelial and suppression of inflammatory markers; b) protection from sepsis in animal models; and c) direct antineoplastic effects, we propose the use of ascorbate as an adjuvant to existing modalities in the treatment and prevention of cancer-associated sepsis.
PMID: 21375761 [PubMed – indexed for MEDLINE] PMCID: PMC3061919 Free PMC Article
J Angiogenes Res. 2010 Jan 18;2:2. doi: 10.1186/2040-2384-2-2.
Ascorbate inhibition of angiogenesis in aortic rings ex vivo and subcutaneous Matrigel plugs in vivo.
Mikirova NA, Casciari JJ, Riordan NH.
Source
Bio-Communications Research Institute, Wichita, Kansas, USA.
Abstract
BACKGROUND:
Angiogenesis is critical to tumor growth and is therefore a potential target for cancer therapy. As many current inhibitors ofangiogenesis exhibit host toxicity, natural alternatives are needed. At millimolar concentrations, ascorbate (vitamin C) inhibits migration and tubule formation by mature endothelial cells and endothelial progenitors. In the present study, we examined the effects of ascorbate, at levels relevant during intravenous infusion therapy, on angiogenesis using an ex vivo an in vivo assay.
METHODS:
Two assays were used to evaluate effect of high-doses ascorbic acid on angiogenesis: ex vivo rat aortic ring explant assay in Matrigelmatrices and in vivo Matrigel plug assay. In aortic rings, we quantified microvessel growth, branching and vessel regression under different treatment conditions. In murine angiogenesis assay, male C57 mice 6-8 weeks old were treated by high-dose ascorbic acid and the number of microvessels was analyzed by histological method. To characterize the population of cells that formed capillary network and microvessels, the sections were stained by CD34 and CD31 antibodies.
RESULTS:
Results show that sprouting of endothelial tubules from aortic rings was reduced in a concentration-dependent fashion by ascorbate: while controls roughly tripled sprout densities during the study, ascorbate (1 mg/mL, 5.5 mM) actually reduced sprout density. In vivo, the ability of mice to vascularize subcutaneously implanted Matrigel plug was diminished if the mice were treated with 430 mg/kg vitamin C: numbers of vessels, and vessel densities, in plugs from treated mice were roughly 30% less than those in plugs from untreated mice.
CONCLUSIONS:
We conclude that the inhibition of angiogenesis by ascorbate suggested in vitro is confirmed in vivo, and that angiogenesis inhibitionmay be one mechanism by which intravenous ascorbate therapy shows efficacy in animal experiments and clinical case studies.
PMID: 20150992 [PubMed] PMCID: PMC2820478 Free PMC Article
J Orthomol Med. 2010;25(1):29-38.
Mitochondria, Energy and Cancer: The Relationship with Ascorbic Acid.
González MJ, Rosario-Pérez G, Guzmán AM, Miranda-Massari JR, Duconge J, Lavergne J, Fernandez N, Ortiz N, Quintero A, Mikirova N, Riordan NH, Ricart CM.
Source
School of Pharmacy, Department of Pharmacy Practice.
Abstract
Ascorbic Acid (AA) has been used in the prevention and treatment of cancer with reported effectiveness. Mitochondria may be one of the principal targets of ascorbate’s cellular activity and it may play an important role in the development and progression of cancer. Mitochondria, besides generating adenosine triphosphate (ATP), has a role in apoptosis regulation and in the production of regulatory oxidative species that may be relevant in gene expression. At higher concentrations AA may increase ATP production by increasing mitochondrial electron flux, also may induce apoptotic cell death in tumor cell lines, probably via its pro-oxidant action In contrast, at lower concentrations AA displays antioxidant properties that may prevent the activation of oxidant-induced apoptosis. These concentration dependent activities of ascorbate may explain in part the seemingly contradictory results that have been reported previously.
PMID: 23565030 [PubMed] PMCID: PMC3615720 Free PMC Article
P R Health Sci J. 2008 Mar;27(1):7-19.
Pharmacokinetics of vitamin C: insights into the oral and intravenous administration of ascorbate.
Duconge J, Miranda-Massari JR, Gonzalez MJ, Jackson JA, Warnock W, Riordan NH.
Source
Department of Pharmaceutical Sciences, Suite 413C, School of Pharmacy, Medical Sciences Campus, University of Puerto Rico, PO Box 365067, San Juan, PR 00936-5067. jduconge@rcm.upr.edu
Abstract
There is a strong advocacy movement for large doses of vitamin C. Some authors argue that the biological half-life for vitamin C at high plasma levels is about 30 minutes, but these reports are the subject of some controversy. NIH researchers established the current RDA based upon tests conducted 12 hours (24 half lives) after consumption. The dynamic flow model refutes the current low-dose recommendations for dietary intakes and links Pauling’s mega-dose suggestions with other reported effects of massive doses of ascorbate for the treatment of disease. Although, a couple of controlled clinical studies conducted at The Mayo Clinic did not support a significant benefit for terminal cancer patients after 10 grams of once-a-dayoral vitamin C, other clinical trials have demonstrated that ascorbate may indeed be effective against tumors when administered intravenously. Recent studies confirmed that plasma vitamin C concentrations vary substantially with the route of administration. Only by intravenous administration, the necessary ascorbate levels to kill cancer cells are reached in both plasma and urine. Because the efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated. One limitation of current studies is that pharmacokinetic data at high intravenous doses of vitamin C are sparse, particularly in cancer patients. This fact needs prompt attention to understand the significance of intravenous vitamin C administration. This review describes the current state-of-the-art in oral and intravenous vitamin Cpharmacokinetics. In addition, the governmental recommendations of dose and frequency of vitamin C intake will also be addressed.
PMID: 18450228 [PubMed – indexed for MEDLINE]
Ann Pharmacother. 2007 Jun;41(6):1082-3. Epub 2007 May 22.
Vitamin C pharmacokinetics after continuous infusion in a patient with prostate cancer.
Duconge J, Miranda-Massari JR, González MJ, Taylor PR, Riordan HD, Riordan NH, Casciari JJ, Alliston K.
PMID: 17519294 [PubMed – indexed for MEDLINE]
P R Health Sci J. 2005 Dec;24(4):269-76.
A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients.
Riordan HD, Casciari JJ, González MJ, Riordan NH, Miranda-Massari JR, Taylor P, Jackson JA.
Source
Biocommunication Research Institute, Center for the Improvement of Human Functioning, 3100 North Hillside Avenue, Wichita, KS 67219, USA.
Abstract
Case studies suggest that vitamin C, given intravenously at doses of 10-100 grams/day can improve patient well being and in some cases, reduce tumor size. While ascorbate is generally considered safe, clinical data on high intravenous doses is limited. Twenty-four late stage terminal cancerpatients were given continuous infusions of 150 to 710 mg/kg/day for up to eight weeks. Blood chemistry and blood count profiles were obtained at roughly one-week intervals while patient health, adverse events and tumor progression were monitored. The majority of patients were vitamin C deficient prior to treatment. Intravenous infusions increased plasma ascorbate concentrations to a mean of 1.1 mM. The most common adverse events reported were nausea, edema, and dry mouth or skin; and these were generally minor. Two Grade 3 adverse events ‘possibly related’ to the agent were reported: one patient with a history of renal calculi developed a kidney stone after thirteen days of treatment and another patient experienced hypokalemia after six weeks of treatment. White blood cell counts were stable while hemoglobin and hematocrit levels dropped slightly during treatment, consistent with trends observed prior to therapy. Blood creatinine, BUN, glucose, and uric acid concentrations decreased or remained stable during therapy, suggesting that ascorbate infusions did not adversely affect renal function. One patient had stable disease and continued the treatment for forty-eight weeks. These data suggest that intravenous vitamin C therapy for cancer is relatively safe, provided the patient does not have a history of kidney stone formation.
PMID: 16570523 [PubMed – indexed for MEDLINE]
P R Health Sci J. 2005 Jun;24(2):145-50.
Effects of high dose ascorbate administration on L-10 tumor growth in guinea pigs.
Casciari JJ, Riordan HD, Miranda-Massari JR, Gonzalez MJ.
Source
Center for the Improvement of Human Functioning, Bio-communications Research Institute, 3100 N Hillside Avenue, Wichita, KS 67219, USA.
Abstract
Sodium ascorbate is preferentially toxic to tumor cells at high concentrations. It has not been established, however, whether sufficient intra-tumorascorbate concentrations are safely achievable in vivo. We administered sodium ascorbate subcutaneously or orally for eighteen days to Sewall-Wright strain-2 guinea pigs bearing intradermal L-10 hepatocarcinoma tumors. Tumor masses and intra-tumor ascorbate concentrations were determined at necropsy. L-10 cells formed tumors that metastasized to the lymph nodes, with tumor burdens reaching nearly 50 grams in untreated animals. Subcutaneous injections of ascorbate (500 mg/kg/day) inhibited tumor growth by as much as sixty-five percent, with oral supplementation reducing it by roughly fifty percent. Tumor growth correlated inversely with intra-tumor ascorbate concentration, the latter exceeding 2 mM in some cases. Ascorbate concentrations sufficient to kill tumor cells can be safely achieved in solid tumors in vivo, suggesting a possible role for high doseintravenous ascorbate in treating cancer.
PMID: 16116933 [PubMed – indexed for MEDLINE]
Integr Cancer Ther. 2005 Mar;4(1):32-44.
Orthomolecular oncology review: ascorbic acid and cancer 25 years later.
González MJ, Miranda-Massari JR, Mora EM, Guzmán A, Riordan NH, Riordan HD, Casciari JJ, Jackson JA, Román-Franco A.
Source
University of Puerto Rico, Medical Sciences Campus, Graduate School of Public Health, Department Human Development, Nutrition Program, PO Box 365067, San Juan, PR. mgonzalez@rcm.upr.edu
Abstract
The effect of ascorbic acid on cancer has been a subject of great controversy. This is a follow-up review of the 1979 article by Cameron, Pauling, and Leibovitz published in Cancer Research. In this updated version, the authors address general aspects of ascorbic acid and cancer that have been presented before, while reviewing, analyzing, and updating new existing literature on the subject. In addition, they present and discuss their own mechanistic hypothesis on the effect of ascorbic acid on the cancer cell. The objective of this review is to provide an updated scientific basis for the use of ascorbic acid, especially intravenously as adjuvant treatment in pharmacological nutritional oncology.
PMID: 15695476 [PubMed – indexed for MEDLINE]
P R Health Sci J. 2004 Jun;23(2):115-8.
Intravenous vitamin C as a chemotherapy agent: a report on clinical cases.
Riordan HD, Riordan NH, Jackson JA, Casciari JJ, Hunninghake R, González MJ, Mora EM, Miranda-Massari JR, Rosario N, Rivera A.
Source
Center for the Improvement of Human Functioning, RENAC Project, Wichita, KS, USA.
Abstract
A series of seven cases are presented in which intravenous vitamin C has been used as antineoplastic agent in the treatment of different types of cancers. The cancers cases reviewed are the following: Renal cell carcinoma (2), Colorectal cancer (1), Pancreatic cancer (1), Non-Hodgkin’s lymphoma (2) and breast cancer (1). Toxic reactions were not observed at these high doses of intravenous Vitamin C. All patients were prescreened for Glucose 6–phosphate dehydrogenase deficiency before administering intravenous Vitamin C in order to prevent hemolysis.
PMID: 15377059 [PubMed – indexed for MEDLINE]
J Cell Biochem. 2004 Oct 1;93(2):257-70.
L-ascorbic acid represses constitutive activation of NF-kappaB and COX-2 expression in human acute myeloidleukemia, HL-60.
Han SS, Kim K, Hahm ER, Lee SJ, Surh YJ, Park HK, Kim WS, Jung CW, Lee MH, Park K, Yang JH, Yoon SS, Riordan NH, Riordan HD, Kimler BF, Park CH,Lee JH, Park S.
Source
Samsung Medical Center, and Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
Abstract
There is increasing evidence that L-ascorbic acid (LAA) is selectively toxic to some types of cancer cells at pharmacological concentrations, functioning as a pro-oxidant rather than as an anti-oxidant. However, the molecular mechanisms by which LAA initiates cellular signaling leading to cell death are still unclear. In an effort to gain insight into these mechanisms, the effects of LAA on eukaryotic transcription nuclear factor NF-kappaBand cyclooxygenase-2 (COX-2) expression were investigated. In the present study, LAA suppressed DNA binding activity of NF-kappaB, composed of a p65/p50 heterodimer, through inhibition of degradation of inhibitory kappaB-alpha (IkappaB-alpha) and prevention of nuclear translocation of p65. The inhibitory effect of LAA on NF-kappaB activity was dependent upon glutathione levels in HL-60 cells, as well as generation of H2O2 but not superoxide anion. LAA also downregulated the expression of COX-2, which has a NF-kappaB binding site on its promoter, through repressing NF-kappaB DNA binding activity. Moreover, cotreatment of 1 microM arsenic trioxide (As2O3) with various concentrations of LAA enhanced an LAA-induced repression of NF-kappaB activity and COX-2 expression. In conclusion, our data suggest that LAA exerts its anti-tumor activity through downregulation of NF-kappaB activity and COX-2 expression, and these inhibitory effects can be enhanced by co-treatment with As2O3.
Copyright 2004 Wiley-Liss, Inc.
PMID: 15368354 [PubMed – indexed for MEDLINE]
P R Health Sci J. 2003 Sep;22(3):287-90.
Intravenous ascorbic acid: protocol for its application and use.
Riordan HD, Hunninghake RB, Riordan NH, Jackson JJ, Meng X, Taylor P, Casciari JJ, González MJ, Miranda-Massari JR, Mora EM, Rosario N, Rivera A.
Source
Center for the Improvement of Human Functioning, Biocommunications Research Institute, Wichita, KS, USA.
Abstract
High dose intravenous(i.v.) ascorbic acid (AA) has been used as therapy for infectious disease from bacterial and viral origin and adjuvant therapy for cancer. In this publication we describe a clinical protocol that has been developed over the past twenty years utilizing high dose i.v. AA as therapy for cancer. This includes principles of treatment, rationale, baseline workup, infusion protocol, precautions and side effects.
PMID: 14619456 [PubMed – indexed for MEDLINE]
P R Health Sci J. 2002 Mar;21(1):39-41.
Orthomolecular oncology: a mechanistic view of intravenous ascorbate’s chemotherapeutic activity.
González MJ, Miranda-Massari JR, Mora EM, Jiménez IZ, Matos MI, Riordan HD, Casciari JJ, Riordan NH, Rodríguez M, Guzmán A.
Source
University of Puerto Rico, Medical Sciences Campus, School of Public Health, Dept. Human Development, Nutrition Program, RECNAC II Project, GPO Box 365067, San Juan, PR, USA.
Abstract
The effect of vitamin C in cancer has been a subject of great controversy; mainly because of the inconsistent results obtained by oral intakes of ascorbate when used as an anticancer agent. We believe the intravenous application of ascorbate will provide more consistent results in cancer patients since Vitamin C blood levels attained are substantially higher in a range proven cytotoxic to malignant cells. In this article we will present and discuss our proposed mechanism on the chemotherapeutic activity exhibited by ascorbate.
PMID: 12013679 [PubMed – indexed for MEDLINE]
P R Health Sci J. 2002 Mar;21(1):21-3.
Inhibition of human breast carcinoma cell proliferation by ascorbate and copper.
González MJ, Mora EM, Miranda-Massari JR, Matta J, Riordan HD, Riordan NH.
Source
University of Puerto Rico, Medical Sciences Campus, School of Public Health, Dept. Human Development, Nutrition Program, RECNAC II Project, G.P.O. Box 365067, San Juan, PR, USA.
Abstract
We tested the effect of different concentrations of ascorbic acid (AA), 50, 100, 250 mg/500 mg/dL) with copper sulfate (CS), 10 mg/dL) on humanbreast carcinoma (MDA-MB231) cell proliferation in vitro. Cell proliferation was measured using a colori-metric assay (Cell proliferation kit II (XTT), Boehringer, NJ). The results of the mean absorbance of the tissue culture at different AA concentrations and a constant CS concentration were as follow: 0.82 +/- 0.03 (control, mean +/- SE), 0.64 +/- 0.02 (CS above); 0.48 +/- 0.03 (50 mg/dL) AA), 0.21 +/- 0.02 (100 mg/dL), 0.08 +/- 0.01 (250 mg/dL) AA, 0.60 +/- 0.05 (500 mg/dL). These results show that a combination of AA and CS inhibits human breast carcinoma cell proliferation in vitro. This cell proliferation inhibitory effect is directly proportional to the AA concentration with the exception of the 500 mg/dL AA dose. This chemotherapeutic effect was optimally enhanced when AA was added at a concentration of 250 mg/dL. The AA concentrations of 500 mg/dL had a biphasic effect on tumor cell proliferation probably due to back and forth redox reactions between AA and dehydroascorbic acid in a closed system. This study provides preliminary evidence that AA and SC can be used as biological response modifiers (BRM) for tumor growth inhibition.
PMID: 12013676 [PubMed – indexed for MEDLINE]
Br J Cancer. 2001 Jun 1;84(11):1544-50.
Cytotoxicity of ascorbate, lipoic acid, and other antioxidants in hollow fibre in vitro tumours.
Casciari JJ, Riordan NH, Schmidt TL, Meng XL, Jackson JA, Riordan HD.
Source
Bio-Communications Research Institute, Center for the Improvement of Human Functioning International, 3100 North Hillside Avenue, Wichita, KS 67219, USA.
Abstract
Vitamin C (ascorbate) is toxic to tumour cells, and has been suggested as an adjuvant cancer treatment. Our goal was to determine if ascorbate, in combination with other antioxidants, could kill cells in the SW620 hollow fibre in vitro solid tumour model at clinically achievable concentrations.Ascorbate anti-cancer efficacy, alone or in combination with lipoic acid, vitamin K3, phenyl ascorbate, or doxorubicin, was assessed using annexin V staining and standard survival assays. 2-day treatments with 10 mM ascorbate increased the percentage of apoptotic cells in SW620 hollow fibretumours. Lipoic acid synergistically enhanced ascorbate cytotoxicity, reducing the 2-day LC(50)in hollow fibre tumours from 34 mM to 4 mM. Lipoicacid, unlike ascorbate, was equally effective against proliferating and non-proliferating cells. Ascorbate levels in human blood plasma were measured during and after intravenous ascorbate infusions. Infusions of 60 g produced peak plasma concentrations exceeding 20 mM with an area under the curve (24 h) of 76 mM h. Thus, tumoricidal concentrations may be achievable in vivo. Ascorbate efficacy was enhanced in an additive fashion by phenyl ascorbate or vitamin K3. The effect of ascorbate on doxorubicin efficacy was concentration dependent; low doses were protective while high doses increased cell killing.
Copyright 2001 Cancer Research Campaign.
PMID: 11384106 [PubMed – indexed for MEDLINE] PMCID: PMC2363673 Free PMC Article
Med Hypotheses. 1995 Mar;44(3):207-13.
Intravenous ascorbate as a tumor cytotoxic chemotherapeutic agent.
Riordan NH, Riordan HD, Meng X, Li Y, Jackson JA.
Source
Project RECNAC, Bio-Communications Research Institute, Wichita, Kansas 67219, USA.
Abstract
Ascorbic acid and its salts (AA) are preferentially toxic to tumor cells in vitro and in vivo. Given in high enough doses to maintain plasma concentrations above levels that have been shown to be toxic to tumor cells in vitro, AA has the potential to selectively kill tumor cells in a manner similar to other tumor cytotoxic chemotherapeutic agents. Most studies of AA and cancer to date have not utilized high enough doses of AA to maintain tumor cytotoxic plasma concentrations of AA. Data are presented which demonstrate the ability to sustain plasma levels of AA in humans above levels which are toxic to tumor cells in vitro and suggests the feasibility of using AA as a cytotoxic chemotherapeutic agent.
PMID: 7609676 [PubMed – indexed for MEDLINE]
