Intravenous Ascorbic Acid Research Articles

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

Introduction: Arsenic trioxide (ATO) is an exceptionally active drug in acute promyelocytic leukemia (APL), inducing complete remissions (CR) in 85% of relapsed patients. ATO also has clinical activity in myelodysplastic syndromes (MDS). In non-APL AML cells lines, ATO induces apoptosis in vitro; however, in a small study of 11 non-APL AML patients, ATO showed no activity (Parmer et al Leuk Res 28:090, 2004). ATO-induced apoptosis has been shown to correlate inversely with the level of intracellular reduced glutathione (GSH) via generation of reactive oxygen species; cells with high concentrations of GSH are more resistant to ATO. Ascorbic acid (AA) increases apoptosis and overcomes resistance to ATO in multiple myeloma, non-APL AML and other cell lines by reducing intracellular GSH levels. AA alone has no activity in these cells. We therefore administered ATO plus AA to patients with non-APL AML.Methods: ATO 0.25 mg/kg was administrated intravenously over 1-4 hours with 1 gram of intravenous AA given 30 minutes after ATO daily for five days a 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 (Bahlis 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: Nine patients aged 36–84 years (median: 66 years) were treated: 5 pts. had refractory AML or relapsed after chemotherapy; 4 elderly pts,. aged 66–84, with antecedent MDS were previously untreated. Activity was seen in 5 (56%) patients, including all 4 of the previously untreated pts: CR in 1 pt. (patient with an early relapse), CRp in 1 pt., decrease in bone marrow blasts to <5% with reduced transfusion requirements in 1 pt, and drop in peripheral blood blasts from 84% and 51% to <5% in 2 patients. Responses were observed after the first treatment cycle. Duration of responses were 6 months in the CR and CRp pts., and 1 week, 2 months. and 4 months in the other responders. Four pts had progressive disease; one patient died on study from progressive disease and infection. Grade 3 /4 toxicity included: infection in 8 pts., and anorexia, sensory neuropathy, elevated bilirubin in 1 pt. each. One responding patient developed shortness of breath with severe hypoxemia, reminiscent of the APL differentiation syndrome, which responded immediately to dexamethasone.Conclusions: ATO + AA has anti-leukemic activity in non-APL AML patients. Despite the high doses of ATO, higher than used in APL and MDS, toxicity was tolerable. This combination could be a less toxic alternative front-line approach to intensive chemotherapy in elderly patients with non-APL AML. Further study of ATO + AA is warranted either alone or in combination with other agents in an attempt to further improve the results.

Efficacy and safety of oral versus intravenous ascorbic acid for anaemia in haemodialysis patients

Intravenous (i.v.) ascorbic acid (AA) improves anaemia in iron-overloaded, erythropoietin (rEPO) hyporesponsive haemodialysis patients. While oral AA is readily attainable, the efficacy and safety of oral versus i.v. AA has not been examined. We conducted an open-label randomised parallel study on the effects of 8 weeks of 250 mg oral AA (n=10) compared with 250 mg i.v. AA (n=11) 3x/week on haemoglobin (Hb), ferritin and rEPO dose in 21 iron-overloaded haemodialysis patients. We also examined the effect of 3 months of 500 mg oral AA 3x/week (n=70) compared with no treatment (n=83) on Hb, ferritin and rEPO dose in 153 haemodialysis patients. Patients had severe AA deficiency (mean 2.2+/-SE 0.4 mg/L; normal range, 4.0-14.0). Following treatment, the plasma AA level increased (P<0.001), but was not significantly different between the groups. There was no change in Hb, iron availability and rEPO dose with oral or i.v. AA. There was a significant increase in serum oxalate but no significant changes in left ventricular function or renal calculi formation. In the second study, oral AA had no effect on Hb, rEPO dose and ferritin in the whole group and a subgroup of 30 with anaemia. Haemoglobin and iron availability did not improve following oral or i.v. AA in this select small group of iron-overloaded haemodialysis patients or in a larger population of haemodialysis patients given oral AA at a higher dose and for a longer duration. AA supplementation may still be warranted in view of severe AA deficiency in haemodialysis patients.

Combination of intravenous iron sucrose and ascorbic acid in hemodialysis patients

Combination of intravenous iron sucrose and ascorbic acid in hemodialysis patients

Combination of intravenous iron sucrose and ascorbic acid in hemodialysis patients

Combination of intravenous iron sucrose and ascorbic acid in hemodialysis patients

PRETREATMENT WITH INTRAVENOUS ASCORBIC ACID PRESERVES ENDOTHELIAL FUNCTION DURING ACUTE HYPERGLYCAEMIA (R1)

1. Acute hyperglycaemia may impair endothelial function. Ascorbic acid (AA), administered intra-arterially, has been reported to improve endothelium-dependent vasodilatation during a forearm hyperglycaemic clamp. Using a randomized, double-blind, placebo-controlled, cross-over study, we investigated the potential for intravenous ascorbic acid to modify the endothelial response to acute systemic hyperglycaemia in humans. 2. Nine healthy male volunteers were recruited from the hospital staff. Endothelial function was determined by measuring the forearm blood flow responses to intrabrachial infusions of endothelium-dependent (ED) and endothelium-independent (EID) vasodilators. The endothelial function index (EFI) was derived from the ratio of ED and EID vasodilatation. Haemodynamic and endothelial function measurements were performed at baseline and then repeated 2 h after a systemic hyperglycaemic clamp (14 mmol/L). The subjects, studied on two separate occasions, were randomized to placebo or 2 g intravenous ascorbic acid prior to the initiation of hyperglycaemia. 3. After systemic hyperglycaemia with placebo pretreatment, the EFI fell from 1.08 +/- 0.21 to 0.74 +/- 0.13 (difference (95% confidence interval): 0.34 (0.20, 0.47); P < 0.001). When subjects were pretreated with ascorbic acid, the EFI was not affected by hyperglycaemia (1.11 +/- 0.21 to 1.12 +/- 0.17; P = 0.938). This difference between placebo and ascorbic acid was significant (P < 0.001). Plasma ascorbate concentrations decreased during hyperglycaemia and correlated directly with the reduction in the EFI (r = 0.798; P < 0.001). 4. Pretreatment with an intravenous bolus of ascorbic acid can prevent endothelial dysfunction during acute systemic hyperglycaemia. Therefore, ascorbic acid may have potential therapeutic use in clinical situations where acute hyperglycaemia may be a complication.

Antioxidants Reverse Reduction of the Human Hypoxic Ventilatory Response by Subanesthetic Isoflurane

In subanesthetic concentrations, volatile anesthetics reduce the acute hypoxic response (AHR), presumably by a direct action on the carotid bodies but by an unknown molecular mechanism. To examine a possible involvement of reactive oxygen species or changes in redox state in this inhibiting effect, the authors studied the effect of antioxidants on the isoflurane-induced reduction of the AHR in humans. In 10 volunteers, the authors studied the effect of antioxidants (intravenous ascorbic acid and oral alpha-tocopherol) on the reduction by isoflurane (0.12% end-tidal concentration) of the AHR on a 3-min isocapnic hypoxic stimulus (hemoglobin oxygen saturation 86 +/- 4%). All subjects participated in three separate sessions in which the effects of the antioxidants (session 1), placebo (session 2), and sham isoflurane plus antioxidants (session 3) were tested on the (sham) isoflurane-induced effect on the AHR. Isoflurane reduced the acute hypoxic response from 0.82 +/- 0.41 l . min . % to 0.49 +/- 0.23 l . min . % and from 0.89 +/- 0.43 l . min . % to 0.48 +/- 0.28 l . min . % in sessions 1 and 2, respectively (mean +/- SD; P < 0.05 vs. control). This reduction of the AHR was completely reversed by antioxidants (AHR = 0.76 +/- 0.39 l . min . %; not significantly different from control, session 1) but not by placebo in session 2 (AHR = 0.50 +/- 0.30 l . min . %; P < 005 vs. control). Sham isoflurane or antioxidants per se had no effect on the hypoxic response. The data indicate that isoflurane may depress the AHR by influencing the redox state of oxygen-sensing elements in the carotid bodies. This finding may have clinical implications for patients who are prone to recurrent hypoxic episodes, e.g., due to upper airway obstruction, in the postoperative period when low-dose isoflurane may persist in the body for some time.

Treatment of Acute Myelogenous Leukemia (non-APL) with Intravenous Trisenox® (Arsenic Trioxide) and Ascorbic Acid: Preliminary Results.

Introduction: Arsenic trioxide (ATO) is an exceptionally active drug in acute promyelocytic leukemia (APL), inducing complete remissions in 85% of relapsed patients. ATO also has clinical activity in myelodysplastic syndrome (MDS). In non-APL AML cells lines, ATO induces apoptosis in vitro; however, in a small study of 11 non-APL AML patients, ATO showed no activity (Parmer et al Leuk Res 28:090, 2004). In some types of cancer cells, ATO-induced apoptosis has been shown to correlate inversely with the level of intracellular reduced glutathione (GSH) via generation of reactive oxygen species; cells with high concentrations of GSH are more resistant to ATO. Ascorbic acid (AA) increases apoptosis and overcomes resistance to ATO in multiple myeloma, non-APL AML and other cell lines by reducing intracellular GSH levels. AA alone has no activity in these cells. We therefore conducted a clinical trial in patients with non-APL AML combining ATO and AA.Methods: ATO at a dose of 0.25 mg/kg is administrated intravenously over 1–3 hour with 1 gram of intravenous AA given within 30 minutes daily for five days a 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 receive an additional consolidation cycle of 25 doses followed by maintenance of two weeks of every month of ATO+ AA for 4 cycles. Patients who fail to respond after two cycles are considered treatment failures.Results: Seven patients have so far enrolled: three (aged 36,52,59) had relapsed after chemotherapy, and four aged 66–84 (median 70), never received chemotherapy. For these untreated patients ATO+AA was given as front line treatment. In three of the four previously untreated patients the number of bone marrow blasts dropped from > 40% to < 5% (2 pts. after 1 cycle; 1 pt. after 2 cycles) At the time of this report only one of the responding patients received more than one cycle and had improvement in the peripheral blood counts. The three patients, who failed chemotherapy, did not respond to ATO+AA (one patient received only one cycle). Despite the high doses of ATO, higher than used in APL and MDS, the combination was very well tolerated with grade 3 toxicity in one patient only (sensory neuropathy). One responding patient developed shortness of breath with severe hypoxemia, reminiscent of the APL differentiation syndrome, which responded immediately to dexamethasone.Conclusion: These preliminary results in patients with non-APL AML suggest that: (1) AA +ATO has anti-leukemia activity in untreated non-APL AML patients with minimal toxicity; (2) more than one cycle is probably needed to achieve a response in the peripheral blood counts; (3) in non-APL AML, ATO can cause the so called “differentiation syndrome” which should be anticipated and treated early. If confirmed in additional patients, ATO+AA might be a less toxic alternative upfront approach to intensive chemotherapy in elderly patients with non-APL AML.

Urinary Oxalate Excretion Increases in Home Parenteral Nutrition Patients on a Higher Intravenous Ascorbic Acid Dose

Vitamin C can be metabolized to oxalate. Case reports have suggested an association between IV vitamin C and urinary oxalate excretion. Recently, the US Food and Drug Administration required the dose of vitamin C in IV multivitamin preparations to be increased from 100 mg to 200 mg/d. We compared the urinary oxalate excretion level in stable home total parenteral nutrition (TPN) patients receiving both doses of vitamin C. Each participant provided a 24-hour urine sample for oxalate determination on the vitamin C dose (100 mg/d), and again after at least 1 month on the increased vitamin C dose (200 mg/d). A 2-day diet diary was completed covering the day before and the day of the urine collection and was analyzed for oxalate and vitamin C content. Comparisons were made using Student paired t test and Wilcoxon signed rank. Thirteen patients (7 males/6 females) aged 63.1 +/- 12.2 years who had no history of nephrolithiasis and had received TPN for 55.9 +/- 78.8 months were enrolled. The most common indication for TPN was short bowel syndrome (38.5%). Eight patients had an intact colon. Urinary oxalate excretion increased on the 200-mg vitamin C dose, from 0.34 +/- 0.13 to 0.44 +/- 0.17 mmol/d (mean increase = 0.10 mmol/d; p = .04; 95% confidence interval 0.004 to 0.19 mmol/d). Oral intake of vitamin C and oxalate did not differ between the 2 collection periods. In therapeutically used doses, IV vitamin C increases urinary oxalate excretion, potentially predisposing susceptible individuals to nephrolithiasis. This factor should be considered in patients receiving home TPN.

Protective effects of ascorbic acid on arterial hemodynamics during acute hyperglycemia

Mortality increases when acute coronary syndromes are complicated by stress-induced hyperglycemia. Early pulse wave reflection can augment central aortic systolic blood pressure and increase left ventricular strain. Altered pulse wave reflection may contribute to the increase in cardiac risk during acute hyperglycemia. Chronic ascorbic acid (AA) supplementation has recently been shown to reduce pulse wave reflection in diabetes. We investigated the in vivo effects of acute hyperglycemia, with and without AA pretreatment, on pulse wave reflection and arterial hemodynamics. Healthy male volunteers were studied. Peripheral blood pressure (BP) was measured at the brachial artery, and the SphygmoCor pulse wave analysis system was used to derive central BP, the aortic augmentation index (AIx; measure of systemic arterial stiffness), and the time to pulse wave refection (Tr; measure of aortic distensibility) from noninvasively obtained radial artery pulse pressure (PP) waveforms. Hemodynamics were recorded at baseline and then every 30 min during a 120-min systemic hyperglycemic clamp (14 mmol/l). The subjects, studied on two separate occasions, were randomized in a double-blind, crossover manner to placebo or 2 g intravenous AA before the initiation of hyperglycemia. During hyperglycemia, AIx increased and Tr decreased. Hyperglycemia did not change peripheral PP but did magnify central aortic PP and diminished the normal physiological amplification of PP from the aorta to the periphery. Pulse wave reflection, as assessed from peripheral pulse wave analysis, is enhanced during acute hyperglycemia. Pretreatment with AA prevented the hyperglycemia-induced hemodynamic changes. By protecting hemodynamics during acute hyperglycemia, AA may have therapeutic use.

A comparison of intravenous ascorbic acid versus intravenous iron for functional iron deficiency in hemodialysis patients

A comparison of intravenous ascorbic acid versus intravenous iron for functional iron deficiency in hemodialysis patients

Effect of ascorbic acid administration in hemodialysis patients on in vitro oxidative stress parameters: influence of serum ferritin levels

Background:Ascorbic acid supplementation has been recommended to circumvent resistance to erythropoietin, which sometimes occurs in iron-overloaded uremic patients. In considering the pro-oxidant effect of ascorbic acid, the authors hypothesize that adjuvant therapy with larger doses of ascorbic acid in hemodialysis patients with iron overload may raise the risk of increasing free radical generation. The oxidative stress of intravenous ascorbic acid supplementation in hemodialysis patients was evaluated in this study. Methods:Six healthy subjects and 29 hemodialysis patients were enrolled. Chemical scavenging activity of various compounds was measured by in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Free radical generation was determined in vitro by lucigenin-enhanced chemiluminescence (LucCL) assay on blood samples. Blood biochemistries were also measured simultaneously in hemodialysis patients 1 minute before and 5 minutes later in the presence or absence of intravenous injection of 300 mg ascorbic acid. Results:Ascorbic acid presented a strong antioxidant effect in DPPH chemical reaction. On the contrary, it exerted pro-oxidant effect when mixed with plasma or whole blood of healthy subjects and hemodialysis patients. The pro-oxidant effect of ascorbic acid detected by LucCL was attenuated by various iron chelators and superoxide dismutase. In hemodialysis patients, the changes of LucCL intensity were significantly higher in the ascorbic acid-treated group than those in the control group (1261.0 ± 401.9 v 77.4 ± 62.5 relative light unit [RLU]; P < 0.05). Adjuvant ascorbic acid therapy resulted in significantly higher LucCL intensity in hemodialysis patients with ferritin ≥600 ng/mL (1,348.2 pmol/L) than those with ferritin less than 600 ng/mL (2,296.0 ± 763.8 v 414.3 ± 88.0 RLU; P<0.05). The changes of LucCL intensity were positively correlated with serum ferritin level (R2=0.8673; P<0.05). However, there was no significant correlation between the responses of LucCL intensity to ascorbic acid administration and transferrin saturation (R2=0.195; P=0.0665). Conclusion:Persons with excess ascorbic acid supplement in the blood or plasma generate iron-chelator-suppressible chemiluminescents suggestive of free radical formation. Whether the findings occur in vivo or that the free radicals generated in vitro lead to toxicity in patients is not known from this study. These results suggest that either lower parenteral dose or lower infusion rate of ascorbic acid may be more appropriate for adjuvant therapy in iron-overloaded uremic patients.

Low Dose Intravenous Ascorbic Acid for Erythropoietin-Hyporesponsive Anemia in Diabetic Hemodialysis Patients with Iron Overload

Background. Recent report demonstrates that inadequate iron mobilization and defective iron utilization may cause recombinant erythropoieitin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. The effect of intravenous ascorbic acid (IVAA) in HD patients selected on the basis of iron overload and EPO resistance also has been proven. However, it is uncertain whether IVAA still works in diabetic ESRD patients with hyperferritinemia. Therefore, the aim of this study focusing on diabetic ESRD patients was to analyze the potential effect of low dose IVAA on improvement of anemia and erythropoiesis-related parameters when compared with control period. Patients and Method. This study consisted of 22 chronic hemodialysis patients with type II diabetes in a single dialysis unit. In studies of this type, all eligible patients are followed up, but the primary comparison is still between different sequentially treatment including control period and post-IVAA period in same patients. IVAA patients received ascorbic acid, 100 mg each administered intravenously three times per week for eight weeks of treatment and four months of post-treatment follow-up. Results. The demographic characteristics of 22 diabetic uremic patients show that mean age is 63.6 ± 10.2 years old. The ratio of sex (M/F) = 10/12. Mean duration of HD is 46.7 ± 33.2 months. As for the urea kinetic study between these two periods including KT/V, nPCR, and URR, there is no significantly different. As for anemia-related parameters, Hb and Hct increased significantly in post-IVAA period after 3 months compared with control period, while MCV did not increase significantly. Serum ferritin significantly decreased at study completion. The same situation is for iron. As for TS, it significantly increased at one month and further markedly increased at subsequent three months. Conclusion. This study has demonstrated that short-term low dose IVAA therapy can facilitate iron release from reticuloendothelial system but also increase iron utilization in diabetic hemodialysis patients with iron overload. Therefore, IVAA is a potential adjuvant therapy to treat erythropoeitin-hyporesponsive anemia in iron-overloaded patients.

Intravenous n‐acetylcysteine, ascorbic acid and selenium‐based anti‐oxidant therapy in severe acute pancreatitis

Background: To observe outcome in a cohort of patients with severe acute pancreatitis receiving multiple anti‐oxidant therapy. Methods: An observational study was carried out in 46 consecutive patients with acute pancreatitis fulfilling current Atlanta consensus criteria for severe disease. All patients received multiple anti‐oxidant therapy based on intravenous selenium, N‐acetylcysteine and ascorbic acid plus β‐carotene and α‐tocopherol delivered via nasogastric tube. Principal outcomes were the effect of anti‐oxidant supplementation on anti‐oxidant levels, morbidity and mortality in patients on anti‐oxidant therapy, case‐control analysis of observed survival compared to predicted survival derived from logistic organ dysfunction score (LODS), logistic regression analysis of factors influencing outcome and side effect profile of anti‐oxidant therapy. Results: Paired baseline and post‐supplementation data were available for 25 patients and revealed that anti‐oxidant supplementation restored vitamin C (P = 0.003) and selenium (P = 0.028) toward normal. In univariate survival analysis, patient survival to discharge was best predicted by admission APACHE‐II score with relative risk of death increasing 12.6% for each unit increase (95% CI 6.0% to 19.6%). The mean LODS calculated on admission to hospital was 3.7 (standard error of the mean 4.1) giving a predicted mortality for the cohort of 21%. The observed in‐hospital mortality was 43%. Conclusions: Case‐control analyses do not appear to demonstrate any benefit from the multiple anti‐oxidant combination of selenium, N‐acetylcysteine and ascorbic acid in severe acute pancreatitis.

INCREASED TUMOR NECROSIS FACTOR ALPHA (TNF-α) AND NATURAL KILLER CELL (NK) FUNCTION USING AN INTEGRATIVE APPROACH IN LATE STAGE CANCERS

Natural products may increase cytotoxic activity of Natural Killer Cells (NK) Tumor Necrosis Factor alpha (TNF-α) while decreasing DNA damage in patients with late-stage cancer. Pilot studies have suggested that a combination of Nutraceuticals can raise NK cell function and TNF-α alpha activity and result in improved clinical outcomes in patients with late stage cancer. The objective of the study is to determine if Nutraceuticals can significantly raise NK function and TNF levels in patients with late stage cancer. After informed consent was obtained, 20 patients with stage IV, end-stage cancer were evaluated (one bladder, five breast, two prostate, one neuroblastoma, two non-small cell lung, three colon, 1 mesothelioma, two lymphoma, one ovarian, one gastric, one osteosarcoma). Transfer Factor Plus (TFP®, 3 tablets 3 times per day), IMUPlus® (non denatured milk whey protein, 40 gm/day); Intravenous (50 to 100 gm/day) and oral (1–2 gm/day) ascorbic acid; Agaricus Blazeii Murill teas (10 gm/day); Immune Modulator Mix (a combination of vitamin, minerals, antioxidants and immune-enhancing natural products); nitrogenated soy extract (high levels of genistein and dadzein) and Andrographis Paniculata (500 mg twice daily) were used. Baseline NK function by standard 4 h 51Cr release assay and TNF alpha and receptor levels were measured by ELISA from resting and phytohemagglutinin (PHA) stimulated adherent and non-adherent Peripheral Blood Mononuclear Cell (PBMC). Total mercaptans and glutathione in plasma were taken and compared to levels measured 6 months later. Complete blood counts and chemistry panels were routinely monitored. As of a mean of 6 months, 16/20 patients were still alive. The 16 survivors had significantly higher NK function than baseline (p<.01 for each) and TNF-α levels in all four cell populations studied (p<.01 for each). Total mercaptans (p<.01) and TNF-α receptor levels were significantly reduced (p<.01). It was also observed that hemoglobin, hematocrit and glutathione levels were significantly elevated. The only toxicity noted was occasional diarrhea and nausea. The quality of life improved for all survivors by SF-36 form evaluation. An aggressive combination of immunoactive Nutraceuticals was effective in significantly increasing NK function, other immune parameters and hemoglobin from PBMC or plasma in patients with late stage cancers. Nutraceutical combinations may be effective in late stage cancers. Clinical outcomes evaluations are ongoing.

Iron loading and large doses of intravenous ascorbic acid promote lipid peroxidation in whole serum in guinea pigs.

Large doses of ascorbic acid may mobilise Fe from Fe-binding proteins in vivo which in turn could catalyse lipid peroxidation, a process associated with degenerative diseases. This hypothesis was tested in vitro in the serum of Fe-loaded animals. Eighteen male guinea pigs weighing about 500 g on arrival were allocated to two groups of nine. Fe loading was induced in one group by two intraperitoneal injections of 200 mg iron dextran given on days 1 and 5. Blood (6 ml) was drawn from all animals on day 12 by cardiac puncture. Serum and LDL were separated. Serum was tested for loosely-bound Fe (bleomycin assay) and lipid peroxidation (thiobarbituric acid reactive substances (TBARS) assay) and LDL for susceptibility to in vitro oxidation (TBARS and conjugated diene assays). On day 12, another intraperitoneal injection of 200 mg iron dextran was given to the animals in the Fe-loaded group. On day 19, all animals were given 75 mg ascorbic acid by intraperitoneal injection. Blood (6 ml) was drawn 4 h later by cardiac puncture. Serum and LDL assays were repeated. Ascorbic acid increased loosely-bound Fe and in vitro oxidation in the serum from animals of the Fe-loaded group but not in the serum from animals of the control group. Susceptibility of LDL to in vitro oxidation increased after the ascorbic acid injection in the control group but there was no further increase in the Fe-loaded group. These data suggest that large doses of ascorbic acid promote Fe mobilisation and in vitro oxidation in the serum of Fe-loaded animals.

Effect of Ascorbic Acid on Endothelial Dysfunction of Epicardial Coronary Arteries in Chronic Smokers Assessed by Cold Pressor Testing

Background: In chronic smokers there is evidence for increased formation of oxygen-derived free radicals within the vessel wall impairing endothelial function. It has been suggested that the inactivation of endothelium-derived nitric oxide by oxygen free radicals contributes to endothelial dysfunction. Hence, we tested the hypothesis that in chronic smokers the antioxidant ascorbic acid could improve abnormal endothelial function of epicardial coronary arteries. Methods and Results: Thirty-one patients (mean age 57 ± 9 years) referred for routine diagnostic catheterization for evaluation of chest pain and without angiographically significant coronary artery stenoses were randomly assigned to one of the study groups to assess vasomotor response of epicardial coronary arteries due to cold pressor testing (CPT) before and after intravenous infusion of 3 g of ascorbic acid or 100 ml × 0.9% saline infusion. In 6 controls (mean age 55 ± 3 years) CPT led to a similar increase in luminal area before and after ascorbic acid administration (26.5 ± 15.0 vs. 28.4 ± 17.7%, p = NS). In 15 chronic smokers (mean age 55 ± 9 years), CPT induced a decrease in the luminal area of –18.5 ± 6.3%. This flow-dependent vasoconstriction was significantly reversed to 7.7 ± 6.2% (p ≤ 0.03) vasodilation after intravenous ascorbic acid administration. In 10 chronic smokers (mean age 57 ± 11 years) saline infusion (placebo) did not have a significant effect on CPT-induced vasoconstriction (–12.7 ± 5.1 vs. –13.1 ± 5.1%, p = NS). The CPT-induced increase in luminal area in chronic smokers after ascorbic acid infusion was significant compared to controls and placebo (each p ≤ 0.05). Our assessment of endothelium-independent responses to nitroglycerin revealed no significant differences between the single study groups (p = NS). Conclusion: In chronic smokers acute intravenous administration of ascorbic acid significantly improves CPT-induced coronary endothelium-dependent dysfunction. According to the current understanding, this effect is due to improved cellular redox imbalance and prevention of nitric oxide inactivation in the endothelium and subendothelial space.

A Study for Improvement of Erythropoietin Responsiveness in Hemodialysis Patients

Background: Anemia in chronic renal failure plays an important role in increasing morbidity of dialysis patients. The causes of the anemia are multifactorial. With using of erythropoietin(EPO) most of uremia-induced anemia can be overcome. However, about 10% of renal failure patients shows EPO-resistant anemia. Hyporesponsiveness to EPO has been related to many factors: iron deficiency, aluminum intoxication, inflammations, malignancies and secondary hyperparathyroidism. So I evaluated the improvement of EPO responsiveness after correction of above several factors. Materials and Methods: Seventy-two patients on hemodialysis over 6 months were treated with intravenous ascorbic acid(IVAA, 300 mg t.i.w. for 12 weeks), After administration of IVAA for 12 weeks, patients were classified into several groups according to iron status, serum aluminum levels and i-PTH levels. Indivisualized treatments were performed: increased iron supplement for absolute iron deficiency, active vitamin D3 for secondary hyperparathyroidism and desferrioxamine(DFO, 5 mg/kg t.i.w.) for aluminum intoxication or hyperferritinemia. Results: 1) Result of IVAA therapy for 12 weeks on all patients(n=72). Hemoglobin levels at 2, 4, 6 week were significantly elevated compared to baseline, but those of hemoglobin at 8, 10, 12 week were not significantly different. 2) Result of IVAA therapy for 20 weeks on patients with 100 ferritin and transferrin saturation(Tsat) below 30%(n=30). After treatment of IV AA for 12 weeks, patients were evaluated the response of therapy according to iron status. Patients with 100 ferritin and Tsat below 30% showed the most effective response. These patients were treated further for 8 weeks. Hemoglobin levels at 2, 4 week were significantly increased compared to baseline with significantly reduced doses of EPO at 2, 4, 6, 10, 12, 16, 20 week. Concomitantly significantly improvement of Tsat at 2, 6, 16, 20 week compared to baseline were identified. 3) Result of IVAA therapy for 12 weeks followed by DFO therapy for 8 weeks on patients with serum aluminum above 4 (n=12) Hemoglobin levels were not significantly increased during IVAA therapy for 12 weeks but dosages of EPO were significantly decreased at 2, 4, 6, 8 week during DFO therapy compared to pre-treatment status. Conclusion: IVAA can be helpful for the treatment of the anemia caused by functional iron deficiency and can reduce the dosage of EPO for anemia correction. And administration of low dose DFO, in cases of increased serum aluminum level, can reduce the requirement of EPO.

Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia

Inadequate iron mobilization and defective iron utilization may cause recombinant erythropoietin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. We have demonstrated that intravenous ascorbic acid (IVAA), but not intravenous iron medication, can effectively circumvent the functional iron-deficient erythropoiesis associated with iron overload in HD patients. However, it is uncertain whether all HD patients with hyperferritinemia will consistently respond to IVAA and which index may indicate functional iron deficiency in the special entity. Therefore, a prospective study was conducted to establish the guidelines for IVAA adjuvant therapy. Sixty-five HD patients with serum ferritin levels of more than 500 microgram/liter were recruited and divided into the control (N = 19) and IVAA (N = 46) groups. IVAA patients with a hematocrit (Hct) of less than 30% received 300 mg of ascorbic acid three times per week for eight weeks. Controls had a Hct of more than 30% and did not receive the adjuvant therapy. Red blood cell and reticulocyte counts, iron metabolism indices, erythrocyte zinc protoporphyrin (E-ZPP), and the concentrations of plasma ascorbate and oxalate were examined before and following the therapy. Thirteen patients (four controls and nine IVAA patients) withdrew by the end of the study. Eighteen patients had a dramatic response to IVAA with a significant increase in their hemoglobin and reticulocyte index and a concomitant 24% reduction in rEPO dose after eight weeks. This paralleled a significant rise in serum iron and transferrin saturation (TS) and a fall in E-ZPP and serum ferritin (baselines vs. 8 weeks, serum iron 68 +/- 37 vs. 124 +/- 64 microgram/dl, TS 27 +/- 10 vs. 48 +/- 19%, E-ZPP 123 +/- 44 vs. 70 +/- 13 micromol/mol heme, and serum ferritin 816 +/- 435 vs. 587 +/- 323 microgram/liter, P < 0. 05). Compared with responders, mean values of hemoglobin, rEPO dose, iron metabolism parameters, and E-ZPP showed no significant changes in controls (N = 15) and in non-responders (N = 19). Thirty-seven patients (18 responders and 19 non-responders) were further analyzed by receiver operating characteristic curves to seek the criteria for prediction of a response to IVAA treatment. The results showed that E-ZPP at a cut-off level of more than 105 micromol/mol heme and TS at a level of less than 25% were more specific to confirm the status of functional iron deficiency in iron-overloaded patients. The two criterion values had the highest accuracy to predict a response to treatment. Functional iron-deficient erythropoiesis plays a role in rEPO-hyporesponsive anemia in HD patients with hyperferritinemia. IVAA may be an adjuvant therapy for rEPO in these patients, and E-ZPP of more than 105 micromol/mol heme and TS of less than 25% should be used to guide the IVAA treatment.

Erythropoietin hyporesponsiveness: From iron deficiency to iron overload

Iron deficiency is the most frequently encountered cause of suboptimal response to recombinant human erythropoietin (rHuEPO). Carefully assessing iron status is of paramount importance in chronic renal failure patients prior to or during rHuEPO therapy. Because there is great need for iron in the EPO-stimulated erythroid progenitors, it is essential that serum ferritin and transferrin saturation levels should be maintained over 300 microg/liter and 30%, respectively. Investigators have shown that oral iron is unlikely to keep pace with the iron demand for an optimal rHuEPO response in uremics. Therefore, patients with iron deficiency will always require intravenous iron therapy. The early and prompt iron supplementation can lead to reductions in rHuEPO dose and hence cost. After the iron deficiency has been corrected or excluded, we must remember all of the possible causes of hyporesponsiveness in every rHuEPO-treated patient. As dose requirements vary, it is not clear which dose of rHuEPO causes this hyporesponsiveness. However, if the patient with iron repletion does not respond well after the induction period, the major causes blunting the response to rHuEPO should be investigated. Most factors are reversible and remediable, except resistant anemia associated with hemoglobinopathy or bone marrow fibrosis, which requires a further increase in the rHuEPO dose. By means of early detection and correction of the possible causes, the goal of increasing therapeutic efficacy can be achieved. Iron overload may lead to an enhanced risk for infection, cardiovascular complication, and cancer. Over-treatment with iron should be avoided in dialysis patients, despite the fact that the safe upper limit of serum ferritin to avoid iron overload is not clearly defined. On the other hand, functional iron deficiency may develop even when serum ferritin levels are increased. Controversy remains as to whether intravenous iron therapy can overcome this form of hyporesponsiveness in iron-overloaded patients. Moreover, a treatment option of iron supplementation is not warranted in these patients, as the potential hazards of iron overload will be worsened. We demonstrated that the mean hematocrit significantly increased from 25.1+/-0.9% to 31+/-1.2% after eight weeks of intravenous ascorbate therapy (300 mg three times a week) in 12 hemodialysis patients with serum ferritin levels of more than 500 microg/liter. The enhanced erythropoiesis paralleled with a rise in transferrin saturation (27.8+/-2.5% vs. 44.8+/-9.5%, P < 0.05) and reductions in erythrocyte zinc protoporphyrin (130+/-32 vs. 72+/-19 micromol/mol heme, P < 0.05) and monthly rHuEPO dose (24.2+/-4.5 vs. 16.8+/-3.4 x 10(3) units, P < 0.05) at the end of study. It is speculated that ascorbate supplementation not only facilitates the iron release from storage sites and its delivery to hematopoietic tissues, but also increases iron utilization in erythroid cells. Our study provides a more complete understanding of the pathogenesis of iron overload-related anemia and the development of an adjuvant therapy, intravenous ascorbic acid, to the existing treatments.

Methemoglobinemia in a Patient Receiving Flutamide

Methemoglobinemia in a Patient Receiving Flutamide