Intravenous Ascorbic Acid Research Articles

Intravenous ascorbic acid administration following ROSC, with and without hypothermia, both improved myocardial dysfunction and survival in cardiac arrest of ventricular fibrillationStatus: PendingCategory: Drugs

Purpose: Our previous studies disclosed intravenous administration of ascorbic acid (AA) during cardiopulmonary resuscitation (CPR) facilitates resuscitation and improves outcomes in ventricular fibrillation (VF) cardiac arrest.1,2 However, the effect of AA administrated after return of spontaneous circulation (ROSC) and the interaction with hypothermia has not been clarified. We hypothesized that intravenous administration of AA after ROSC, with and without hypothermia, both can improve myocardial dysfunction and survival in VF cardiac arrest.

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 Ascorbic acid on EPO-hyporesponsive anemia in Hemodialysis patients

We performed the present study to evaluate the efficacy of intravenous and oral ascorbic acid in improving anemia and iron availability on EPO-hyporesponsive anemia in hemodialysis patients with hyperferritinemia. This study of three months duration was conducted in 49 patients with Hb <11 g/dL and ferritin levels greater than 300 ng/ml. Blood samples for measurement of Hb, Hct, serum iron, ferritin, TIBC, transferrin saturation, EPO dose were obtained after baseline and at the end of study after three months. Patients were randomly divided into three groups. 16 patients had received standard care(group 1), 17 patients had received standard care and daily oral ascorbic acid at a dose of 500 mg/day(group 2), and 16 patients had received standard care and 300mg of intravenous vitamin C with each dialysis session(group 3). Forty-seven patients completed the study. All of patients dialyzed 4 hours, 3 times a week with similar kt/V. Hb, serum iron, serum ferritin, transferrin saturation and EPO dose was similar in the three groups at baseline. After 3 month, Hemoglobin and hematocrit and transferrin saturation significantly increased in group 2,3. but not changed in group 1. EPO dose and ferritin level decreased in group 2,3. but not changed in group 1. There was no difference between group 2 and 3. In conclusion, intravenous or oral ascorbic acid therapy can improve hyperferritinemia and EPO hyporesponsive anemia in hemodialysis patients. And The effect of intravenous and oral ascorbic acid are similar.Table 1. Baseline and 3 month DataGroup1(n=16)Group2(n=17)Group3(n=14)baselineAfter3monthbaselineAfter3monthbaselineAfter3monthHb(g/dl8.9+1.48.8+1.38.8+1.39.5+1.29.0+1.29.6+1.2Fe(u/L)55.84+2358.6+1958.57+2563.7+2261.12+216729+19EPOdose(unit/week)147291453815584123691498611345Ferritin(ug/l)764+217781+192783+191646+189754+220634+231Transferrin saturation(%)18+6.418+5.820.6+5.526.4+4.419.8+4.924.5+3.2*is p<0.5 Table 1. Baseline and 3 month Data *is p<0.5

Intravenous ascorbic acid does not block the pressor or sympathetic nerve response to ischemic fatiguing rhythmic handgrip exercise

Reactive oxygen species stimulate group IV muscle afferents in rats but the effects of oxidative stress on the exercise pressor reflex in humans is unknown. The purpose of the current study was to determine the effect of intravenous ascorbic acid (Vitamin C) on the exercise pressor reflex in humans. Seven young healthy nonsmokers participated in the current study, which was part of a large protocol in our laboratory. On Day 1, they underwent systemic infusions of saline and then Vitamin C; on Day 2, they underwent a saline time/volume control. Muscle sympathetic nerve activity (MSNA), heart rate, and blood pressure were monitored throughout baseline, ischemic fatiguing rhythmic handgrip exercise, and post‐handgrip circulatory arrest. The change in mean arterial pressure from baseline to fatigue was not different between saline (Δ 35±6 mmHg) and Vitamin C (Δ 31±6 mmHg). Similarly, heart rate (Δ 22±4 bpm vs Δ 26±4 bpm) and MSNA burst rate (Δ 22±6 bpm vs Δ 22±5bpm) were also not different between treatments. Metaboreflex activation and time control experiments similarly showed no treatment effects. The current data suggest that oxidative stress does not contribute to the magnitude of blood pressure or MSNA response seen during fatiguing handgrip in young healthy subjects.This study supported by P01 HL096570 (LIS) and UL1 RR033184 (LIS)

The effect of intravenous ascorbic acid in hemodialysis patients with normoferritinemic anemia

BackgroundHemodialysis (HD) patients with functional iron deficiency often develop resistance to recombinant human erythropoietin (rhEPO). Recent studies have shown that intravenous ascorbic acid (IVAA) administration could override rhEPO resistance in HD patients. This study was undertaken to test the effects of IVAA in HD patients with normoferritinemic functional iron deficiency accompanied by EPO-hyporesponsive anemia.MethodsFifty-eight HD patients with normoferritinemic anemia (between 100 and 500 μg/L) were included and divided into the control (N=25) and IVAA (N=33) groups. IVAA patients received 500 mg of IVAA with each dialysis session for 3 months and an additional 4-month follow-up after the end of the therapy.ResultsTwenty patients had a response to IVAA with a significant increase in hemoglobin level (Hgb>1.0 g/dL) and reduction of weekly rhEPO dosage compared with the control group after 3 months of treatment (P<0.05). Compared with non-responders, transferrin saturation (TSAT) was significantly decreased in the responders group (26±11 vs. 35±14%, P<0.05) on baseline data. There was a significant increase in serum iron and TSAT (baseline vs. 3 months, serum iron 57±22 vs. 108±22 μg/dL, TSAT 26±11 vs. 52±7%, P<0.05) and a decrease in serum ferritin (377±146 vs. 233±145 ng/mL, P<0.05) in the responders group (N=20), but no significant changes in the control and non-responders groups (N=13) at 3-month treatment.ConclusionIVAA can be a potent and effective adjuvant therapy for HD patients with rhEPO-resistant normoferritinemic anemia. In addition, IVAA can reduce the dosage of rhEPO for anemia correction.

A phase I open-label, dose-escalation study of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer.

323 Background: IV ascorbic acid (vit c) is a prodrug for steady state formation of ascorbate radical (Asc·-) in the extracellular space resulting in sustained production of H2O2 leading to selective killing of tumor cells by a pro-oxidative mechanism. In preclinical models of panc cancer pharmacologic concentrations of Asc·- with gem resulted in a synergistic cytotoxic response. We conducted a Phase I dose escalation study of IV ascorbic acid with gem plus erlotinib chemo as first line therapy in panc cancer. Methods: Patients with adv panc cancer were enrolled using a standard 3+3+3 design to assess the safety and pharmacology of IV vit c in combo with gem and erlotinib. Cohort 1 received 50 g IV vit c and subsequent cohorts were escalated by 25 g to a final dose of 100 g. Pts were given 3 infusions of vit c per week on separate days for 8 w (1 cycle). IV gem was given on day 1 (1000 mg/m2) and weekly for 7 w followed by a rest week. Oral erlotinib (100 mg) was given daily for 8 w. Trt continued until disease progression or toxicity. Steady state ascorbate PK was assessed in cohorts 2 and 3. AEs were determined using NCI CTCAE v3.0. Tumor responses were assessed per RECIST. Results: Of 14 pts enrolled, 9 or 3 per cohort completed the study. Median age was 64 years. 5 pts did not complete trt (2 discontinued, 3 died). 9 pts completed at least 24 ascorbic acid trts and 1 cycle of gem/erlotinib therapy. There were 24 AEs. These included 15 non-serious AEs and 8 SAEs. The most frequent AEs were grade 1/2 thrombocytopenia. Other grade 1/2 events included anemia, hyperglycemia, abd discomfort, ascites and infection. SAEs: 2 grade 3 heme, 1 grade 3 GI, 1 grade 3 infectious and 2 grade 4 thrombosis. Plasma asc levels were 25.3 - 31.9 mm/L for pts receiving the 100g dose. 8 of the 9 pts had a reduction in the panc primary with 1 pt having no change at 8 w. For non-target lesions, 2 had PD and 7 had SD per RECIST. Conclusions: Overall safety data do not reveal AEs other than those expected in patients with metastatic panc cancer and/or treatment with gem and erlotinib. Addition of IV ascorbic acid did not increase toxicity. Preliminary efficacy results are encouraging. A phase II study is planned.

Effect of short-term intravenous ascorbic acid on reducing ferritin in hemodialysis patients

Resistance to recombinant erythropoietin (rEPO) in hemodialysis patients may be due to inadequate iron recruitment and defect in iron use. In this cross over randomized clinical trial, 30 hemodialysis patients with serum ferritin levels of ≥500 ng/ml, hemoglobin ≤11.0 g/dl, and transferrin saturation (TSAT) of 20% or less were administrated intravenous iron (50-100 mg/wk) and rEPO (120-360 U/kg/wk) for 6 months. Patients were excluded if there was a clear explanation for rEPO hyporesponsiveness. Patients were divided into two groups. Group1 received standard care and 500 mg of intravenous ascorbic acid (IVAA) with each dialysis session in the first week of each month for a total of 3 months. Group 2 received standard care only. After 2 month washout period, groups were crossed over. Each month hemoglobin (Hb) was assessed. Iron, TIBC (transferrin iron binding capacity), TSAT, iPTH (intact parathyroid hormone), liver enzymes, albumin and cholesterol levels were measured every 3 months. After 3 months of intervention, Hb significantly increased from 10.11 to 12.19 g/dl (P <0 0.001; 95% confidence interval [CI] 2.7-1.4) and TSAT increased from 18.9 to 28.1% (P = 0.008; 95% CI 0.09-3), while ferritin and serum iron declined significantly from 1391 to 938 ng/ml (P = 0.001; 95% CI 216-689), 97.2 to 64.6 (P = 0.001; 95% CI 14.8-50.4) in the study group. Change of Hb over time in IVAA group was significant (P < 0.0005). There were significant differences between two groups in change of Hb level over time (P < 0.0005) and treatment effect (P = 0.002). Baseline laboratory tests were similar in the two groups and there was no carry over effect at phase 2. We showed that low amount of IVAA could reduce ferritin level and enhance Hb and TSAT, suggesting improved iron utilization.

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.

Intravenous ascorbic acid (vitamin C) administration in myomectomy: a prospective, randomized, clinical trial

To assess the usefulness of using ascorbic acid (vitamin C) administration in abdominal myomectomy. A total of 102 patients were divided two groups in this prospective, clinical trial. Group A had received 2g of ascorbic acid during a myomectomy, and group B had a myomectomy without any interventions. The operative time, blood loss, days of hospitalization, post-operative complications and rate of blood transfusions were compared between the two groups. The blood loss (521.44±199.24 vs. 932.9±264.38ml; p value <0.001), duration of the operation time (42±13.9 vs. 68±21.7min; p value <0.001), days of hospitalization (2.7±0.69 vs. 3.1±0.59days; p value 0.002) in group A were significantly less than in group B (p value 0.001). The chance risk ratio of a blood transfusion in group A was 0.4 (7.7 vs. 18% 95% CI of 0.1-1; p value 0.07). There was a significant correlation between the volume of bleeding and post-operative complications in both groups (p value in group A=0.03; in group B=0.004). The administration of ascorbic acid (vitamin C) in abdominal myomectomy could reduce the blood loss during the procedure, operation time and days of hospitalization.

Intravenous ascorbic acid to prevent and treat cancer-associated sepsis?

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.

Ascorbic acid plus gemcitabine (gem) and erlotinib (erl) in patients with metastatic pancreatic cancer (mPanc): Preliminary safety results.

e14659 Background: Intravenous ascorbic acid in pharmacologic concentrations, via production of extracellular hydrogen peroxide and reactive oxygen species, has selective cytotoxicity to cancer cells but not normal cells and tissues in vitro and in vivo. In this study we have evaluated safety and tolerability of ascorbic acid combined with gem/erl in patients with mPanc, and we now report preliminary safety results. Methods: This is the phase I, open label portion of a phase I/II trial. The primary objective is to determine safety and tolerability of intravenous ascorbic acid at three dosage levels with gem/erl. The secondary objective is to evaluate tumor free progression. Eligible patients were >18 yrs of age, life expectancy > 3 months, histologically confirmed mPanc and ECOG PS 0/1. All patients received intravenous ascorbic acid at three times weekly combined with gem 1,000 mg/m2 weekly for 7 weeks and erl 100 mg oral daily. After a week of rest and reevaluation, subsequent cycles consisted of gem 1,000 mg/m2 weekly times 3 with 1 week of rest. The study used a 3+3+3 design with three different ascorbic acid doses: 50 gm, 75 gm, and 100 gm infused over 90-minute duration. Safety and tolerability is based on dose-limiting toxicities (DLTs), and grade 3/4 combination chemotherapy related adverse events (AEs) deemed clinically significant by the investigator. Plasma levels of ascorbic acid, gem, and erl will be determined. The primary endpoint was incidence of DLTs. Results: No DLT has been reported for the first 5 DLT evaluable subjects. Accrual to part 1 continues. Five patients have enrolled in part 1; 4 patients were female. Mean age was 69 years (60-82); ECOG 0/1 = 4/1. No grade 4 or 5 treatment related DLTs were seen. Serious possible AEs included diarrhea (grade 3) in one pt and jaundice (grade 3) in 1 pt. One pt had partial response, 2 pts had stable disease, and 2 pts had disease progression. Conclusions: Ascorbic acid combined with gem/erl has been well tolerated and may in the future offer potential in pts with mPanc. The MTD has not yet been reached. Treatment-related AEs Number of pts Grade of toxicity Nausea/vomiting 1 1 Infection 0 Diarrhea 2 1, 3 Erythema 1 1 Thrombocytopenia 2 1, 2 Rash 1 1 Jaundice 1 3 No significant financial relationships to disclose.

Intravenous Ascorbic Acid Infusion Improves Myocardial Perfusion Grade During Elective Percutaneous Coronary Intervention: Relationship With Oxidative Stress Markers

Our goal was to explore whether antioxidant vitamin C infusion is able to affect the microcirculation perfusion in patients undergoing elective percutaneous coronary intervention for stable angina. Periprocedural myocardial injury in the setting of elective percutaneous coronary intervention is associated with increased risk of death, recurrent infarction, and revascularization at follow-up. Despite excellent epicardial blood flow, impaired microcirculatory reperfusion may persist and increases the risk of vascular recurrences. Post-percutaneous coronary intervention induced-oxidative stress is one of the potential mechanisms accounting for impaired perfusion. Fifty-six patients were enrolled in a prospective, single-center, randomized study comparing 1 g vitamin C infusion (16.6 mg/min, over 1 h before percutaneous coronary intervention) versus placebo. At the baseline, Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade <2 was observed in 89% and in 86% of patients randomized to the placebo or vitamin C infusion group, respectively (p > 0.05). After percutaneous coronary intervention, these percentages decreased in the placebo group (32%) and in greater measure in the vitamin C group (4%, p < 0.01). Complete microcirculatory reperfusion (TIMI myocardial perfusion grade = 3) was achieved in 79% of the vitamin C-treated group compared with 39% of the placebo group (p < 0.01); 8-hydroxy-2-deoxyguanosine (p < 0.002) and 8-iso-prostaglandin F(2alpha) (p < 0.02) plasma levels significantly increased in the placebo group while they were significantly reduced in the vitamin C-treated group (p < 0.0001). TIMI myocardial perfusion grade changes from the baseline showed significant correlation with 8-hydroxy-2-deoxyguanosine (p < 0.006) or 8-iso-prostaglandin F(2alpha) (p < 0.01) plasma levels changes. In patients undergoing elective percutaneous coronary intervention, impaired microcirculatory reperfusion is improved by vitamin C infusion suggesting that oxidative stress is implicated in such a phenomenon.

Lowering the Erythropoietin Requirement for Dialysis Patients with Functional Iron Deficiency Using Ascorbic Acid (Vitamin C)

AbstractBACKGROUNDHemodialysis patients with functional iron deficiency often require excess recombinant human erythropoietin (EPO). In a few small studies, ascorbic acid (AA) has been shown to reduce EPO requirements. The goal of this study was to determine the lowest effective and safe dose of AA for these patients.METHODSThis was an open‐labeled, prospective, single‐center study involving hemodialysis patients with serum ferritin &gt;500 ng/mL and transferrin saturation &lt;20%. Patients with C‐reactive protein (CRP) &gt;2 mg/dL were excluded. The study comprised of 4 consecutive phases: intravenous AA 100 mg (phase I), 200 mg (phase II), 300 mg (phase III), and oral AA 250 mg (phase IV). Oxalate and AA levels were obtained before and after each treatment phase.RESULTSA total of 8 patients were enrolled and 6 patients completed the study. Positive impact of AA supplementation on lowering the EPO requirement was mainly seen with the 300 mg dosage and maintained on oral supplementation. Neither the oxalate nor AA levels increased significantly during the study. Overall the patients tolerated both forms of ascorbic acid well.CONCLUSIONThe role of AA in reducing the EPO requirement appears promising. Larger studies are needed to examine the safety and confirm the efficacy of AA in these patients.

Acute Severe Chromium Poisoning After Dermal Exposure to Hexavalent Chromium

Severe acute chromium poisoning related to dermal involvement has rarely been reported in the literature. We report a case of acute severe chromium poisoning through skin exposure as a result of a chemical burn of 15% of the body surface area and multiple organ failure after short-term exposure. Medical interventions, including mechanical ventilation, continuous venovenous hemofiltration, and plasmapheresis were performed. In addition, a chelating agent, dimercaptopropane sulfonic acid, was infused intravenously, combined with intravenous N-acetylcysteine and ascorbic acid as adjuvant therapy. The patient was discharged on day 33 without long-term sequelae. The consequence of transdermal exposure of hexavalent chromium should not be overlooked.

Ascorbic acid combined with ibuprofen in hypoxic ischemic encephalopathy: a randomized controlled trial

Free oxygen radicals and proinflammatory cytokines are important causes for brain injury in neonates with hypoxic ischemic encephalopathy (HIE). Our objectives were to test the hypothesis that a combination of antioxidants (ascorbic acid) and anti-inflammatory agents (ibuprofen) can ameliorate the brain injury in HIE and improve neurodevelopmental outcomes when given to term infants immediately after birth. In a prospective, randomized, double-blinded controlled trial, 60 asphyxiated term infants were assigned to one of two groups, intervention and control. The intervention group (n=30) received intravenous ascorbic acid and oral ibuprofen for 3 days; and the control group (n=30) received similar volumes of a placebo. We measured a panel of cytokines at enrollment and administered the treatment drugs within 2 h after birth. Neurological evaluations and developmental screenings were performed for all survivors at 6 months of age. The Intervention and Control groups did not differ in the severity of HIE at enrollment, the concentrations of IL-1 beta and IL-6, the incidence of mortality (37 vs 33%), the incidence of neurological abnormalities at hospital discharge (47 vs 55%) and the incidence of developmental delay at 6 months of age (32 vs 40%), respectively. None of the observed complications were related to intervention. Serum interleukin (IL)-1 beta and IL-6 concentrations correlated positively with the severity of HIE at birth (P<0.01), whereas only serum IL-6 correlated with neurodevelopmental outcome at 6 months (P<0.001). Early administration of ascorbic acid and ibuprofen did not affect outcomes in infants with perinatal asphyxia. This study does not explain whether our intervention was not effective in blocking free radicals and inflammatory cytokines, if the dosing and route of administration were inadequate, or if other mediators existed that could have a more powerful role in brain injury during hypoxia-ischemia.

Oxalic acid excretion after intravenous ascorbic acid administration

Ascorbic acid is frequently administered intravenously by alternative health practitioners and, occasionally, by mainstream physicians. Intravenous administration can greatly increase the amount of ascorbic acid that reaches the circulation, potentially increasing the risk of oxalate crystallization in the urinary space. To investigate this possibility, we developed gas chromatography mass spectrometry methodology and sampling and storage procedures for oxalic acid analysis without interference from ascorbic acid and measured urinary oxalic acid excretion in people administered intravenous ascorbic acid in doses ranging from 0.2 to 1.5 g/kg body weight. In vitro oxidation of ascorbic acid to oxalic acid did not occur when urine samples were brought immediately to pH less than 2 and stored at −30°C within 6 hours. Even very high ascorbic acid concentrations did not interfere with the analysis when oxalic acid extraction was carried out at pH 1. As measured during and over the 6 hours after ascorbic acid infusions, urinary oxalic acid excretion increased with increasing doses, reaching approximately 80 mg at a dose of approximately 100 g. We conclude that, when studied using correct procedures for sample handling, storage, and analysis, less than 0.5% of a very large intravenous dose of ascorbic acid is recovered as urinary oxalic acid in people with normal renal function.

Urogenital Disorders Associated With Gut Failure and Intestinal Transplantation

Intestinal transplantation has been increasingly performed in patients with short bowel syndrome and irreversible gut failure with successful outcomes. In parallel a common association was observed between gut failure and different urological disorders. To our knowledge this study is the first to address such an important clinical observation with special reference to the underlying disease. The medical records of 175 consecutive adult intestinal recipients were reviewed. Data were compiled and described according to the documented urogenital disorder, cause of intestinal failure and treatment modality, including transplantation. Of the patients 43 experienced a total of 53 urogenital disorders for an overall incidence of 25%, including 24 (56%) who had the disorder before referral and 19 (44%) in whom the morbidity developed as a result of transplantation. Interestingly hypercoagulability, pseudo-obstruction, Crohn's disease and Gardner's syndrome were the underlying urogenital and intestinal disorder pathologies in 6.3% of the study patients. Treatment for prior urogenital disorders, including malignancy, precipitated intestinal failure in 3.4% of the referred patients. Reciprocally surgical treatment for the primary intestinal disease and management of gut failure by total parenteral nutrition, followed by transplantation, resulted in different urogenital complications in 17.7% of the total population with an 8.6% incidence of chronic renal failure. Gut failure and intestinal transplantation are commonly associated with different urogenital disorders. Accordingly a designated urological service should be considered part of the multidisciplinary team required for treating this unique population.

Treatment of Non-APL Acute Myelogenous Leukemia with Intravenous Arsenic Trioxide Plus Ascorbic Acid.

Introduction: Arsenic trioxide (ATO) has demonstrated efficacy in acute promyelocytic leukemia (APL), inducing complete remissions (CR) in 85% of relapsed patients. On the other hand, ATO alone has no activity in non-APL AML. Although this difference could be explained by degradation of the APL specific PML/RAR fusion protein, ATO has shown to be active against APL cells by mechanisms that are independent of this gene rearrangement. ATO-induced apoptosis correlates inversely with intracellular concentrations of reduced glutathione (GSH) via generation of reactive oxygen species (ie, cells with high concentrations of GSH are more resistant to ATO). APL cells were found to have low levels of GSH compared to non-AML cells. Agents that reduce intracellular GSH, such as ascorbic acid (AA), increase ATO-induced apoptosis and can overcome resistance to ATO in non-APL AML cell lines; AA alone has no activity in these cells. Thus, the combination of ATO and AA was evaluated in patients with non-APL AML.Methods: ATO (0.25 mg/kg/d) was administrated intravenously over 1–4 hours with intravenous AA (1g/d, given 30 minutes after ATO) for five days/week (five days on/2 days off) for five weeks (25 doses=one cycle). These doses were based on a phase I/II trial of ATO + AA in patients with multiple myeloma (Behalis et al Clin Cancer Res 8:3658, 2002). Responding patients received an additional consolidation cycle of 25 doses followed by maintenance including ATO + AA two weeks of every month for 4 cycles. Patients who failed to respond after two cycles were considered treatment failures.Results: Eleven patients, aged 36–84 years (median: 66 years), were enrolled: 5 had relapsed after chemotherapy; and 6 elderly, aged 66–84, (including 5 with antecedent MDS), were previously untreated. One patient was discontinued prematurely because of QT prolongation. Major response was seen in 3 (27%) pts: CR or CRp in 2 patients and decrease in bone marrow blasts to <5% with reduced transfusion requirements in 1 patient. Three additional patients had a drop in peripheral blood blasts from 85% and 51% to <5%. All responding patients, except for 1, were previously untreated. Responses were observed after the first treatment cycle. Duration of responses were 6 months in the CR and CRp patients, and 1 week, 2 months and 4 months in the other responders. Four pts failed and had progressive disease; one patient died on study from progressive disease and infection. Grade 3/4 toxicity included infection (n=8), and QT (>500 msec), anorexia, fatigue, sensory neuropathy, elevated bilirubin (n=1 each). One responding patient developed shortness of breath with severe hypoxemia, reminiscent of the APL differentiation syndrome, which responded immediately to dexamethasone.Conclusion: ATO + AA can have anti-leukemic activity in poor risk non-APL AML with much less toxicity than chemotherapy, especially in previously untreated patients. Most relapsed patients did not respond to ATO +AA, suggesting that chemotherapy can induce resistance to this combination. Further studies are needed to explore the potential of ATO +AA as a front-line therapy instead of intensive chemotherapy in elderly patients with non-APL AML.

Effect of Intravenous Ascorbic Acid in Hemodialysis Patients With EPO-Hyporesponsive Anemia and Hyperferritinemia

Although erythropoietin (EPO)-hyporesponsive anemia in hemodialysis patients most commonly results from iron deficiency, the contributory role of chronic inflammation and oxidative stress in its pathogenesis is poorly understood. We conducted an open-label prospective study to assess the effect of vitamin C, an antioxidant, on EPO-hyporesponsive anemia in hemodialysis patients with unexplained hyperferritinemia. Forty-six of 262 patients in an inner-city hemodialysis center met the inclusion criteria (administration of intravenous iron and EPO for > or = 6 months at a dose > or = 450 U/kg/wk, average 3-month hemoglobin [Hb] level < or = 11.0 g/dL [< or = 110 g/L], ferritin level > or = 500 ng/mL (microg/L), and transferrin saturation [TSAT] < or = 50%). Patients were excluded if they had a clear explanation for the EPO hyporesponsiveness. Four patients refused to participate. The remaining patients were randomly assigned; 20 patients to receive standard care and 300 mg of intravenous vitamin C with each dialysis session (group 1) and 22 patients to receive standard care only (group 2). Study duration was 6 months. During the study, 1 patient from group 1 was removed (upper gastrointestinal bleeding) from final analysis. Monthly assessment included Hb level, mean corpuscular volume, iron level, iron-binding capacity, ferritin level, TSAT, and Hb content in reticulocytes. In addition, biointact parathyroid hormone, aluminum, C-reactive protein (CRP), and liver enzymes were measured every 3 months. Age, sex, race, and time on dialysis therapy were similar in both groups. At 6 months, Hb levels significantly increased from 9.3 to 10.5 g/dL (93.0 to 105.0 g/L) in group 1, but not group 2 (9.3 to 9.6 g/dL [93.0 to 96.0 g/L]; P = 0.0001). Similarly, TSAT increased from 28.9% to 37.3% in group 1, but not group 2 (28.7% to 29.3%; P = 0.0001). EPO dose (477 to 429 versus 474 to 447 U/kg/wk), iron-binding capacity (216 to 194 versus 218 to 257 microg/dL [38.7 to 34.7 versus 39 to 46 micromol/L]), and CRP level (2.8 to 0.9 versus 2.8 to 2.2 mg/dL) decreased significantly in group 1, but not in controls. Changes in Hb content in reticulocytes and ferritin level also were statistically significant in group 1. There was no change in biointact parathyroid hormone levels. Although serum iron levels and intravenous iron doses changed within each group, changes were equal between the 2 groups. In hemodialysis patients with refractory anemia and hyperferritinemia, vitamin C improved responsiveness to EPO, either by augmenting iron mobilization from its tissue stores or through antioxidant effects.