High-dose Intravenous Ascorbic Acid Research Articles

Phase II Study Assessing Safety and Preliminary Efficacy of High Dose Intravenous Ascorbic Acid in Patients with TET2 Mutant Clonal Cytopenias

Background: Clonal cytopenia(s) of undetermined significance ( CCUS) is defined as persistent cytopenias arising in the context of myeloid neoplasm ( MN)-associated somatic mutations ( MT) in hematopoietic stem cells. Patients ( PTs) with TET2MT CCUS have a high probability of progression to MN. To date, no FDA-approved therapies exist for CCUS, and PTs often have similar cytopenias/transfusion needs as those with myelodysplastic syndromes ( MDS). TET2 is an ascorbic acid (AA)-dependent dioxygenase that catalyzes the conversion of 5-methylcytosine ( 5mC) to 5-hydroxymethylcytosine ( 5hmC), providing rationale to study high-dose IV (HI)-AA in TET2MT CCUS. Here we report the final results of this pilot trial. Methods: This is an investigator-initiated, single-institutional, phase II trial assessing the safety and efficacy of HI-AA in PTs with TET2MT CCUS (NCT03418038). PTs≥ 18 years with ≥1 TET2MT with or without additional somatic MTs, without prior treatment, and with any of the following laboratory criteria: (1) hemoglobin ( Hb) ≤10g/dL, (2) absolute neutrophil count ( ANC) ≤1(10^9/L), (3) platelet count ( PLT)≤100 (10^9/L) were eligible. HI-AA (1g/kg, maximum 100g) was given 3 times weekly for 12 weeks. The primary endpoint was hematologic response rates determined by MDS IWG 2018 criteria at week 20. (Platzbecker Blood 2018) and reported as hematologic improvement ( HI)- erythropoietic ( HI-E), platelets ( HI-P), neutrophils ( HI-N). Secondary endpoints include safety and adverse events ( AEs), graded by NCI-CTCAE v4.03. Correlative studies include changes in TET2MT variant allele fraction ( VAF), in vitro colony formation and differentiation, global and sequence-specific DNA methylation/hydroxymethylation, and quantitative 5hmC estimated by IHC in bone marrow biopsy specimens. Results: Ten patients were enrolled, with a median age of 71.4 (range: 65, 79) years, 8 (80%) males. The median number of mutations was 3, with 9 (90%) having co-mutations. All PTs but one [-Y] had normal karyotype. Baseline Hb levels were normal in all but one who was red blood transfusion dependent. Five (50%) PTs were thrombocytopenic, and 5 (50%) PTs had ANC<1 (10^9/L). ( Table). HI-AA was well tolerated with the most common AEs being infusion-related polyuria (40%) and polydipsia (40%, 3 Grade 1, 1 Grade 2). One (10%) PT had constipation and headaches (both Grade 1), and 1 (10%) experienced dyspepsia. No treatment-related Grade 3 or 4 AEs' or deaths were reported. The median follow-up duration was 16.8 months (range: 9.4, 24.1). Overall, no PTs met the criteria for HI. There were no significant differences with regards to median Hb, PLT, and ANC values at baseline, week 20, and 1-year (median Hb: 13.3, 12.5, and 12.7 g/dL, p=0.93; PLT: 97 vs. 120 vs. 92.5X10^9/L, p>0.99, and ANC: 0.9 vs. 1.2 vs. 1.3X10^9/L, p=0.99). By CTCAE grading criteria for cytopenias, 3 (30%) PTs had an improvement in severity of cytopenias, while 2 had worsening. One (10%) PT had an improvement in PLT (baseline vs. week 20: 62 vs 192X10^9/L) but was morphologically deemed to meet criteria for CMML-1 at week 20. Four (40%) PTs met criteria for disease progression (PT_4, 7,8,10); CMML-1- 2 and MDS-2. The median time to progression was 5 months (95% CI: 4.9, unreached). Two PTs had mutational clonal evolution, with 1 (PT_8) acquiring a RUNX1 (VAF: 20%) and 1 (PT_9) acquiring 2 CBL mutations (both VAF:4%) at one-year follow-up. There were no significant differences regarding the clinical characteristics or the TET2 variants between PTs who had stable disease vs. progression. There were no significant differences in TET2 VAF at baseline, week 20, and 1-year (median: 39% vs. 43% vs. 42%, p=0.54). We profiled changes in 5-mC and 5-hmC (Ilumina EpicArray) in PTs pre- and post-IV AA treatment and did not observe global changes. However, we were able to highlight site-specific changes in differentially methylated regions, largely resulting in hypomethylation at enhancer sites and affecting actively transcribed states in PTs with an improvement in cytopenia(s) severity by CTACE criteria ( Figure). Conclusion: We report the final safety and efficacy analysis of HI-AA in PTs with TET2 MT CCUS. The trial data suggest that HI-AA is safe and well tolerated. Although there were no significant responses by IWG MDS criteria, alleviation in severity of cytopenias in a subset of PTs (n=3) along with correlative epigenetic changes in enhancer regions, needs further exploration.

Effect of high-dose intravenous ascorbic acid on microcirculation and endothelial glycocalyx during sepsis and septic shock: a double-blind, randomized, placebo-controlled study

Previous studies indicate supplemental vitamin C improves microcirculation and reduces glycocalyx shedding in septic animals. Our randomized, double-blind, placebo-controlled trial aimed to investigate whether a high dose of intravenous ascorbic acid (AA) might improve microcirculation and affect glycocalyx in septic patients. In our study, 23 septic patients were supplemented with a high dose (50 mg/kg every 6 h) of intravenous AA or placebo for 96 h. Sublingual microcirculation was examined using a handheld Cytocam-incident dark field (IDF) video microscope. A sidestream dark field video microscope (SDF), connected to the GlycoCheck software (GlycoCheck ICU®; Maastricht University Medical Center, Maastricht, the Netherlands), was employed to observe glycocalyx. We found a significantly higher proportion of perfused small vessels (PPV) 6 h after the beginning of the trial in the experimental group compared with placebo. As an indicator of glycocalyx thickness, the perfused boundary region was lower in capillaries of the 5–9 μm diameter in the AA group than placebo after the first dose of AA. Our data suggest that high-dose parenteral AA tends to improve microcirculation and glycocalyx in the early period of septic shock. The study was retrospectively registered in the clinicaltrials.gov database on 26/02/2021 (registration number NCT04773717).

Phase II Study Assessing Safety and Preliminary Efficacy of High Dose Intravenous Ascorbic Acid in Patients with TET2 Mutant Clonal Cytopenias of Undetermined Significance

Background: Clonal cytopenia(s) of undetermined significance (CCUS) is defined as persistent cytopenias arising in the context of myeloid neoplasm (MN)-associated somatic mutations (MT) in hematopoietic stem cells. Patients (PTs) with TET2 mutant (TET2MT) CCUS have a high probability of progression to MN. To date, no FDA-approved treatment for CCUS exist, with PTs often having similar cytopenias and transfusion needs as those with myelodysplastic syndromes (MDS). High dose intravenous ascorbic acid (HI-AA) demonstrates anti-cancer activity via two mechanisms: (1) hydrogen peroxide-induced oxidative stress and (2) DNA demethylation mediated by TET activation (cofactor for TET1/2/3). TET2 is an AA and oxoglutarate-dependent dioxygenase that catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC), providing the rationale to study HI-AA in TET2MT CCUS. Methods: This is an investigator-initiated, single-arm, single-institution, phase II trial assessing the safety and preliminary efficacy of HI-AA for PTs with TET2MT CCUS (NCT03418038). PTs³ 18 years with TET2MT CCUS (≥1 TET2MT with or without additional somatic MTs) and with any of the following laboratory criteria: (1) hemoglobin (Hb) ≤10g/dL, (2) absolute neutrophil count (ANC) ≤1(10^9/L), (3) platelet count (PLT)≤100 (10^9/L) are eligible. HI-AA (1g/kg, maximum 100g) is given 3 times weekly for 12 weeks through a PICC line, with response assessments before each cycle (4 weeks), at 20 weeks, and one year. The primary endpoint is the hematologic response rates determined by the proposed MDS IWG 2018 criteria at week 20. (Platzbecker Blood 2018) and reported as hematologic improvement (HI)- erythropoietic (HI-E), platelets (HI-P), neutrophils (HI-N). Secondary endpoints include safety and adverse events (AEs). AEs were graded using NCI-CTCAE v4.03. Correlative studies include changes in TET2MT variant allele fraction (VAF), TET2 activity, DNA methylation, hydroxymethylation, and 5hmC in bone marrow cells as determined by immunohistochemistry (IHC). Results: As of July 22, 2022, 8 (89%) of 9 enrolled PTs completed 12 weeks of therapy. The mean age was 74 (SD: 5.4) years, 7 (87.5%) males. One PT (PT_X) came off study after cycle one due to a PICC line-associated thrombosis. All PT were TET2MT (44% truncating), with 8 of 9 (89%) having co-mutations (4- 2 MTs, 3- 3 MTs, and 1- 4 MTs; 2 had ≥1 TET2MT). Comutations included SRSF2 (55%), ASXL1 (22%), ZRSR2 and KRAS (11% each). HI-AA was well tolerated with the most common AEs being infusion-related polyuria (56%) and polydipsia (44%, 3 Grade 1, 1 Grade 2). One (11%) PT had constipation and headaches (both Grade 1), and 1 (11%) experienced dyspepsia. No treatment-related Grade 3 or 4 AEs or deaths were observed. Six of 8 (75%) assessable PTs had post-treatment response assessments at week 20, with 3 PTs having completed 1-year assessments. All PTs' baseline Hb was within the normal range, except for 1 (17%) (PT_5- TET2MT/SRSF2MT) PT who continued to remain red blood transfusion dependent. Five (63%) PTs were thrombocytopenic PLT <100 (10^9/L), with 2 (25%) PTs (PT_1 and PT_7) having PLT £50 (10^9/L) and 5 (83%) PTs had ANC<1 (10^9/L) with 1 (17%) (PT_8) with ANC <0.5 (10^9/L). One (17%) PT met criteria for HI-P (PT_6 had an increment to 118 (10^9/L) at week 20- TET2MT/SRSF2MT/KRASMT) and 1 (17%) PT met criteria for HI-N (PT_2, ANC baseline:1.08 vs. week 20: 1.76(10^9/L)-TET2MT/SRSF2MT). PT_1, who had a baseline PLT of 25 (10^9/L) and ANC of 0.72 (10^9/L), had disease progression to MDS-EB-1 (TET2MT/SRSF2MT) at week 20. The 3 PTs with 1 year follow-up have stable disease. Panel 1 demonstrates changes in blood parameters with treatment. Panel 2 shows IHC determined changes in 5hmC changes with two control samples: normal control and TET2MT CMML. In 5 assessable PTs, there were no changes in TET2 VAF at 20 weeks (mean VAF : baseline 37.2% vs. week 20: 36.6%, p=0.3). Additional correlative studies are ongoing. Conclusion: We report safety and preliminary efficacy analysis for the first clinical trial dedicated to TET2MT CCUS. The early results of this pilot demonstrate that HI-AA is safe and has potential for biological and clinical effects. At last follow-up, 2 (33%) PTs met criteria for HI (HI-P-1 and HI-N-1), 3 PTs (50%) had stable disease, and 1 (17%) PT progressed to MDS. Future studies assessing potential synergy of adding HI-AA to standard of care therapies for TET2MT clonal processes are planned. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Intravenous Ascorbic Acid and Lung Function in Severely Ill COVID-19 Patients.

Current evidence suggests that ascorbic acid improves the host’s immune system and, therefore, may play a role in reducing the severity of infectious diseases. Coronavirus disease 2019 (COVID-19) is a potentially life-threatening viral infection that mainly infects the lungs. The objective of this review was to synthesize the existing findings from studies related to the effect of intravenous ascorbic acid on lung function in COVID-19 patients. For this review, PubMed, Cochrane, SCOPUS, EMBASE, Clinical Trial Registry, and Google Scholar databases were searched from December 2019 to May 2022. There was a total of six studies that investigated the large dose of ascorbic acid infusion intravenously on lung function in severely ill subjects with COVID-19. Out of six, three studies found that high-dose intravenous ascorbic acid improved lung function markers, and three studies found null results. Infusions of 12 g/d and 24 g/d of intravenous ascorbic acid had shown a significant improvement in lung function markers in two clinical trials. Studies that administered 8 g/d, 2 g/d, and 50 mg/kg/d of intravenous ascorbic acid found no influence on mechanical ventilation need and other lung function markers in critically ill subjects with COVID-19. Overall, the effect of intravenous ascorbic acid on the lung function of subjects with COVID yielded equivocal findings. More double-blinded, randomized, clinical studies with a larger sample size are required to confirm the effect of ascorbic acid in ameliorating the lung pathologies associated with COVID infection.

High Dose Intravenous Ascorbic Acid (Vitamin C) and Glutathione as Integrative Therapy in a Patient with Diffuse Large B-Cell Lymphoma: Case Report

Diffuse Large B-Cell Lymphoma is the most common Non-Hodgkin’s Lymphoma. Given its prevalence, there is an interest in studying the treatments available and how these can be improved. The standard treatment is a chemotherapeutic regimen known as R-CHOP. The goal of this paper is to inform of an integrative approach to R-CHOP, implementing high dose intravenous Vitamin C (AA) with glutathione (GSH). In the case presented herein, the patient attained complete remission with a minimal toxicity profile and an excellent performance status. These results present a possible viable approach for patients suffering of Diffuse Large B-Cell Lymphoma. In this paper, we also briefly review the literature available on the aforementioned treatment.

Phase II trial assessing safety and preliminary efficacy of high-dose intravenous ascorbic acid in patients with TET2-mutant clonal cytopenias of undetermined significance.

TPS7076 Background: Clonal cytopenias of undetermined significance (CCUS) is operationally defined as unexplained persistent cytopenias arising in the context of leukemia-associated somatic driver mutations in hematopoietic stem and progenitor cells, without morphologic evidence for an underlying hematological neoplasm. Patients with TET2 mutant ( TET2MT) CCUS have a high probability of progression to myeloid neoplasms, with approximated 10-year cumulative rates of progression being 90%. To date, no FDA-approved treatment for CCUS has been established, and we have shown that these patients can have transfusion burdens akin to patients with myelodysplastic syndrome (MDS) (Li M et al. Blood Adv 2020). Thus there is an urgent and unmet need for therapies for these patients. Intravenous (IV) ascorbic acid (AA) dosed at pharmacologic concentrations could have anti-cancer activity via two mechanisms: (1) hydrogen peroxide-induced oxidative stress and (2) DNA demethylation mediated by TET activation (cofactor for TET1/2/3). TET2, the primary enzyme for catalyzing oxidative reactions, converts 5-methylcytosine to 5-hydroxymethylcytosine, a crucial step leading to iterative DNA demethylation. Our study hypothesis is that IV AA in TET2MT CCUS will restore hematopoiesis and limit clonal progression by stimulating TET2 (the unmutated allele) and TET3 activities. Methods: LS1781 (NCT03418038) is an investigator-initiated, prospective, single-arm, single-institution, phase II trial assessing the safety and preliminary efficacy of high dose of IV AA for patients with TET2MT CCUS (harboring ≥1 TET2MT or TET2MT combined with concurrent spliceosome MTs). IV AA (1g/kg, maximum 100g) is given 3 times weekly for 12 weeks through a central line with assessments being carried out before each cycle (4 weeks), at 12 weeks, and one year. The primary endpoint is the hematologic response rates determined by MDS IWG 2018 criteria. Secondary endpoints include safety and side effects. Exploratory endpoints include the impact of AA on TET2MT variant allele fraction, plasma cytokine levels, DNA methylation, and hydroxymethylation (as measured by Infinium MethylationEPIC array), and TET activity. Patients 18 years or older with TET2MT CCUS, and with any of the following laboratory criteria: (1) hemoglobin ≤10g/dL, (2) absolute neutrophil count (ANC) ≤1000/mm3, (3) platelet count ≤100,000/mm3 are eligible. Fifteen patients will be enrolled at Mayo Clinic Rochester and the Mayo Clinic Health System. Dose modifications have been established and will be considered based on adverse events. Treatment will be discontinued for disease progression or in the event of ≥Grade 3 adverse events that don’t resolve promptly. Enrollment to the trial began in June 2021, with 7 patients enrolled at abstract submission. Clinical trial information: NCT03418038.

Role of ascorbic acid infusion in critically ill patients with transfusion-related acute lung injury.

In critically ill patients, transfusion-related acute lung injury (TRALI) remains the leading cause of transfusion-related fatalities in critical care settings and is associated with inflammation and oxidative stress state. Recent research raised the potential efficacy of high-dose intravenous ascorbic acid (VC) in critically ill patients. The aim of this trial was to investigate the effect of high-dose intravenous VC as a targeted therapy for TRALI in terms of serum proinflammatory (interleukin [IL]-8, IL-1β, C-reactive protein), anti-inflammatory (IL-10), oxidative stress (superoxide dismutase, malondialdehyde) markers, and plasma VC levels. Secondary outcomes were oxygenation (PaO2 /FiO2 ratio), vasopressor use, duration of mechanical ventilation, ICU length of stay, 7-day mortality and 28-day mortality. Eighty critically ill patients with TRALI (n = 80) were randomized to receive 2.5 g/6h intravenous vitamin C for 96 hours (ASTRALI group) or placebo. Patients were followed up to measure the outcomes initially (T0) and at the end of treatment (T96). When compared to the control group, the ASTRALI group at T96 showed significantly higher median of IL-10 (31.6± 25.8 vs 17.7± 12.0pg/mL, P <.0001) levels and superoxide dismutase (12 876 ± 4627 U/L vs 5895 ± 6632 U/L, P <.0001) activities, and lower median C-reactive protein (76 ± 50 vs 89 ± 56 mg/L, P =.033), IL-8 (11.8±7.3 vs 35.5± 19.8pg/mL, P <.0001) and malondialdehyde (0.197 ±0.034 vs 0.234 ±0.074 μM/L, P =.002) levels. High-dose ascorbic acid was associated with significantly reduced oxidative stress, reduced pro-inflammatory markers except IL-1β, elevated anti-inflammatory marker and elevated plasma VC levels.

Efficiency of long-term high-dose intravenous ascorbic acid therapy in locally advanced basal cell carcinoma - a pilot study.

IntroductionThe anti-cancer properties of high-dose intravenous ascorbic acid have been demonstrated in various malignancies. In our recent study, we tested topically applied ascorbic acid to treat basal cell carcinoma (BCC), and achieved a good clinical response.AimBased on these results, we decided to examine the efficacy and tolerability of high-dose intravenous ascorbic acid (IVA) for locally advanced BCC.Material and methodsIn this pilot study, patients diagnosed with locally advanced BCC who were not amenable to radiation, surgical or local therapy (no other treatment option was available at the time) received intravenous ascorbic acid (1–1.8 g/kg), in an outpatient setting, 1–3 times per week for a mean duration of 42 ±23.6 weeks. This therapy was generally well tolerated.ResultsAmong 4 patients who had a total of 165 (mean: 41 ±51, range: 1–114) skin lesions, 3 patients achieved stable disease and one had progressive disease. There was substantial variability in individual tumor response to therapy. With the aid of two-photon microscopy and second harmonic generation imaging techniques, alterations in collagen structure were observed between tumor nests during IVA therapy.ConclusionsOur results suggest that IVA is well tolerated in a small group of patients with extensive BCCs. However, in the era of smoothened (Smo) receptor inhibitors, it may only be considered as an adjuvant therapy in treatment-resistant cases.

The safety and pharmacokinetics of high dose intravenous ascorbic acid synergy with modulated electrohyperthermia in Chinese patients with stage III-IV non-small cell lung cancer

Ascorbic acid (AA) infusion and modulated electrohyperthermia (mEHT) are widely used by integrative cancer practitioners for many years. However, there are no safety and pharmacokinetics data in Chinese cancer patients. We carried out a clinical trial to evaluate the safety and pharmacokinetics of those methods in patients with stage III-IV non-small cell lung cancer (NSCLC). Blood ascorbic acid in the fasting state was obtained from 35 NSCLC patients; selecting from them 15 patients with stage III-IV entered the phase I study. They were randomized allocated into 3 groups, and received doses 1.0, 1.2, 1.5g/kg AA infusions. Participants in the first group received intravenous AA (IVAA) when mEHT was finished, in the second group IVAA was administered simultaneously with mEHT and in the third group IVAA was applied first, and followed with mEHT. Pharmacokinetic profiles were obtained when they received solely IVAA and when IVAA in combination with mEHT. The process was applied 3 times a week (every other day, weekend days off) for 4weeks. We found that fasting plasma AA levels were significantly correlated with stage of the disease. Peak concentration of AA was significantly higher in the simultaneous treatments than in other combinations with mEHT or in solely IVAA-managed groups. IVAA synergy with simultaneous mEHT is safe and the concomitant application significantly increases the plasma AA level for NSCLC patients.

A phase I-II clinical trial to evaluate the safety, pharmacokinetics, and efficacy of high-dose intravenous ascorbic acid synergy with mEHT in Chinese patients with stage III-IV non-small cell lung cancer.

e20078 Background: Ascorbic acid (AA) infusion and modulated electrohyperthermia (mEHT) are widely used by integrative cancer practitioners for many years. However, there are no safety and pharmacokinetics data in Chinese cancer patients. Methods: Blood ascorbic acid in the fasting state was obtained from 35 NSCLC patients; selecting from them 15 patients with stage III-IV entered the phase I-II study. They were randomized allocated into 3 groups. Pharmacokinetic profiles were obtained when they received solely IVAA at concentrations of 1g/kg, 1.2g/kg, and 1.5g/kg, and when IVAA in combination with mEHT. The process was applied 3 times a week for 4 weeks. Participants in the first group received IVAA when mEHT was finished, in the second group IVAA was administered simultaneously with mEHT and in the third group IVAA was applied first, and followed with mEHT. All patients started the trial doses of 1 g/kg for 8 treatments. When there was no DLT observed, the test dose for patients increased to 1.2 g/kg and 1.5 g/kg. DLT was defined as any reversible grade ≥3 adverse events, whether haematological or non-haematological. Results: Fasting plasma AA levels were significantly correlated with stage of the disease. Peak concentration of AA were significantly higher in the simultaneous treatments than in other combinations with mEHT or in solely IVAAmanaged groups. The average scores for the functioning scales continuously increased and the symptoms gradually decrease over the full cycle of the study.3/7 patients with squamous cell lung cancer were CR, 4/7 were PR. 1/8 patient with adenocarcinoma cell lung cancer was PR, 5/8 were SD, and 2/8 were died. Conclusions: IVAA synergies with simultaneous mEHT is safe and the concomitant application significantly increases the plasma AA level for NSCLC patients. QOL is improved when they receive the above treatments. Patients diagnosed with squamous cell lung cancer were sensitive to the above two treatments. Clinical trial information: NCT02655913.

43P - A phase I-II clinical trial to evaluate the safety, pharmacokinetics and efficacy of high dose intravenous ascorbic acid synergy with mEHT in Chinese patients with stage III-IV non-small cell lung cancer

43P - A phase I-II clinical trial to evaluate the safety, pharmacokinetics and efficacy of high dose intravenous ascorbic acid synergy with mEHT in Chinese patients with stage III-IV non-small cell lung cancer

Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer

PurposeThis phase I clinical trial evaluated the safety, tolerability, and pharmacokinetics of high-dose intravenous (i.v.) ascorbic acid as a monotherapy in patients with advanced solid tumors refractory to standard therapy.MethodsFive cohorts of three patients received i.v. ascorbic acid administered at 1 g/min for 4 consecutive days/week for 4 weeks, starting at 30 g/m2 in the first cohort. For subsequent cohorts, dose was increased by 20 g/m2 until a maximum tolerated dose was found.ResultsAscorbic acid was eliminated by simple first-order kinetics. Half-life and clearance values were similar for all patients of all cohorts (2.0 ± 0.6 h, 21 ± 5 dL/h m2, respectively). C max and AUC values increased proportionately with dose between 0 and 70 g/m2, but appeared to reach maximal values at 70 g/m2 (49 mM and 220 h mM, respectively). Doses of 70, 90, and 110 g/m2 maintained levels at or above 10–20 mM for 5–6 h. All doses were well tolerated. No patient demonstrated an objective antitumor response.ConclusionsAscorbic acid administered i.v. at 1 g/min for 4 consecutive days/week for 4 weeks produced up to 49 mM ascorbic acid in patient’s blood and was well tolerated. The recommended dose for future studies is 70–80 g/m2.

Effect of high-dose intravenous vitamin C on inflammation in cancer patients.

BackgroundAn inflammatory component is present in the microenvironment of most neoplastic tissues. Inflammation and elevated C-reactive protein (CRP) are associated with poor prognosis and decreased survival in many types of cancer.Vitamin C has been suggested as having both a preventative and therapeutic role in a number of pathologies when administered at much higher-than-recommended dietary allowance levels.Since in vitro studies demonstrated inhibition of pro-inflammatory pathways by millimolar concentrations of vitamin C, we decided to analyze the effects of high dose IVC therapy in suppression of inflammation in cancer patients.Methods45 patients with prostate cancer, breast cancer, bladder cancer, pancreatic cancer, lung cancer, thyroid cancer, skin cancer and B-cell lymphoma were treated at the Riordan Clinic by high doses of vitamin C (7.5 g -50 g) after standard treatments by conventional methods.CRP and tumor markers were measured in serum or heparin-plasma as a routine analysis. In addition, serum samples were collected before and after the IVCs for the cytokine kit tests.ResultsAccording to our data positive response to treatment, which was demonstrated by measurements of C- reactive protein, was found in 75% of patients and progression of the inflammation in 25% of patients. IVC treatments on all aggressive stage cancer patients showed the poor response of treatment.There was correlation between tumor markers (PSA, CEA, CA27.29 and CA15-3) and changes in the levels of C-reactive protein.Our test of the effect of IVC on pro-inflammatory cytokines demonstrated that inflammation cytokines IL-1α, IL-2, IL-8, TNF-α, chemokine eotaxin and CRP were reduced significantly after treatments.ConclusionsThe high dose intravenous ascorbic acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients. In our study, we found that modulation of inflammation by IVC correlated with decreases in tumor marker levels.In summary, our data support the hypothesis that high dose intravenous ascorbate treatments may reduce inflammation in cancer patients. Our results suggest that further investigations into the use of IVC to reduce inflammation in diseases where inflammation is relevant are warranted.

Effect of high dose intravenous ascorbic acid on the level of inflammation in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a major inflammatory joint disease that causes cartilage destruction, bone erosions, and joint destruction. Oxidative stress is elevated in RA patients implying reactive oxygen species (ROS) are possible mediators of tissue damage. ROS trigger a cascade of events through nuclear factors’ activation (NF-kappa B), which up-regulates gene expression of pro-inflammatory cytokines that mediate the immune responses causing inflammation. As ascorbic acid can reduce oxidative stress, decrease production of pro-inflammatory cytokines, and suppress the activation of NF-kappa B, we suggest that millimolar concentration of ascorbic acid may be useful in RA treatment. In our study we analyzed the effect of intravenous vitamin C (IVC) treatment on eleven subjects with RA. Our data suggest that IVC therapy with dosages of 7.5 g - 50 g can reduce inflammation. The level of inflammation as measured by C-reactive protein levels was decreased on average by 44%. Based on our pilot study, we hypothesize that IVC therapy can be a useful strategy in treating RA.

Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models

Two popular complementary, alternative, and integrative medicine therapies, high-dose intravenous ascorbic acid (AA) and intravenous glutathione (GSH), are often coadministered to cancer patients with unclear efficacy and drug–drug interaction. In this study we provide the first survey evidence for clinical use of iv GSH with iv AA. To address questions of efficacy and drug–drug interaction, we tested 10 cancer cell lines with AA, GSH, and their combination. The results showed that pharmacologic AA induced cytotoxicity in all tested cancer cells, with IC50 less than 4mM, a concentration easily achievable in humans. GSH reduced cytotoxicity by 10–95% by attenuating AA-induced H2O2 production. Treatment in mouse pancreatic cancer xenografts showed that intraperitoneal AA at 4g/kg daily reduced tumor volume by 42%. Addition of intraperitoneal GSH inhibited the AA-induced tumor volume reduction. 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-oxidative anti-cancer mechanism of pharmacologic AA and suggest that AA and GSH administered together provide no additional benefit compared with AA alone. There is an antagonism between ascorbate and glutathione in treating cancer, and therefore iv AA and iv GSH should not be coadministered to cancer patients on the same day.