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EDTA chelation therapy in the treatment of toxic metals exposure

BACKGROUND: Metal induced toxicity with wide range of physiological, biochemical and behavioral dysfunctions was reported in many studies. The chelation has been used for treatment to toxic metals’ exposure for many years. In our current clinical study, we compared different chelation protocols and two forms of EDTA (sodium calcium edetate and sodium edetate) in treatments of toxic metal exposure.
METHODS: A 24 h urine samples were collected from each subject before and after treatment by Ca-EDTA or Na-EDTA. The levels of toxic and essential metals were measured by Atomic Absorption Spectrometer (AAS) with graphite furnace and by Inductively Coupled Plasma Atomic Emission Spectrometer (ICP-AES). The cellular levels of ATP were determined by ATP-bioluminescence assay. Mitochondrial potential was measured by fluorometer and flow-cytometer after cells’ staining by mitochondrial dye.
RESULTS: Data from over 600 patients with a variety of complaints, but not acute toxic mineral exposure, given chelation therapy with sodium EDTA or calcium EDTA, were analyzed. Ca-EDTA and Na-EDTA at intravenous infusions of 3 g per treatment were equally effective in removing lead from the body, while Ca-EDTA was more effective in aluminum removal. The removal of lead was dose dependent but non-linear. Chelation by different doses of Na-EDTA (3 g and 1 g) resulted in mean difference in lead urine less than 50%. In addition, deficiencies in essential minerals correlated with greater pre-treatment lead and aluminum levels. The intrinsic toxicity of EDTA on cells was investigated. EDTA concentrations above 600 uM reduced cellular energy metabolism.
CONCLUSION: Based on our data, we proposed that low dosages of chelating agents might be preferential for patients with no–occupational exposure, as the benefit of chelation is not linear with dosage, the risk of exposure to antidotes is increasing with increased dosages, and excretion of essential metals significantly increases with increased antidote dosage.

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Intravenous Ascorbate as a Chemotherapeutic and Biologic Response Modifying Agent

For over 15 years we have studied high dose intravenous ascorbic acid (IAA) as an adjunctive therapy for cancer patients. Initially, doses of 15g per infusion were used, once or twice per week. These doses improved patients’ sense of well being, reduced pain, and in many cases prolonged life beyond prognostications of oncologists.

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Efficacy and Safety of L-Carnitine Treatment for Chronic Heart Failure: A Meta-Analysis of Randomized Controlled Trials

Background. Whether additional benefit can be achieved with the use of L-carnitine (L-C) in patients with chronic heart failure (CHF) remains controversial. We therefore performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of L-C treatment in CHF patients. Methods. Pubmed, Ovid Embase, Web of Science, and Cochrane Library databases, Chinese National Knowledge Infrastructure (CNKI) database, Wanfang database, Chinese Biomedical (CBM) database, and Chinese Science and Technology Periodicals database (VIP) until September 30, 2016, were identified. Studies that met the inclusion criteria were systematically evaluated by two reviewers independently. Results. 17 RCTs with 1625 CHF patients were included in this analysis. L-C treatment in CHF was associated with considerable improvement in overall efficacy (OR = 3.47, P < 0.01), left ventricular ejection fraction (LVEF) (WMD: 4.14%, P = 0.01), strike volume (SV) (WMD: 8.21 ml, P = 0.01), cardiac output (CO) (WMD: 0.88 L/min, P < 0.01), and E/A (WMD: 0.23, P < 0.01). Moreover, treatment with L-C also resulted in significant decrease in serum levels of BNP (WMD: −124.60 pg/ml, P = 0.01), serum levels of NT-proBNP (WMD: −510.36 pg/ml, P < 0.01), LVESD (WMD: −4.06 mm, P < 0.01), LVEDD (WMD: −4.79 mm, P < 0.01), and LVESV (WMD: −20.16 ml, 95% CI: −35.65 to −4.67, P < 0.01). However, there were no significant differences in all-cause mortality, 6-minute walk, and adverse events between L-C and control groups. Conclusions. L-C treatment is effective for CHF patients in improving clinical symptoms and cardiac functions, decreasing serum levels of BNP and NT-proBNP. And it has a good tolerance.

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The Plasma Pharmacokinetics of R-(+)-Lipoic Acid Administered as Sodium R-(+)-Lipoate to Healthy Human Subjects

BACKGROUND: The racemic mixture, RS-(+/-)-alpha-lipoic acid (rac-LA) has been utilized clinically and in a variety of disease models. Rac-LA and the natural form, R-lipoic acid (RLA), are widely available as nutritional supplements, marketed as antioxidants. Rac-LA sodium salt (NaLA) or rac-LA potassium salt (KLA) has been used to improve the aqueous solubility of LA. STUDY RATIONALE: Several in vitro and animal models of aging and age-related diseases have demonstrated efficacy for the oral solutions of LA salts in normalizing age-related changes to those of young animals. Other models and studies have demonstrated the superiority of RLA, the naturally occurring isomer over rac-LA. Despite this, RLA pharmacokinetics (PK) is not fully characterized in humans, and it is unknown whether the concentrations utilized in animal models can be achieved in vivo. Due to its tendency to polymerize, RLA is relatively unstable and suffers poor aqueous solubility, leading to poor absorption and low bioavailability. A preliminary study demonstrated the stability and bioavailability were improved by converting RLA to its sodium salt (NaRLA) and pre-dissolving it in water. The current study extends earlier findings from this laboratory and presents PK data for the 600-mg oral dosing of 12 healthy adult subjects given NaRLA. In addition, the effect of three consecutive doses was tested on a single subject relative to a one-time dosing in the same subject to determine whether plasma maximum concentration (Cmax) and the area under the plasma concentration versus time curve (AUC) values were comparable to those in animal studies and those achievable via intravenous infusions in humans.

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Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock

BACKGROUND: The global burden of sepsis is estimated as 15 to 19 million cases annually, with a mortality rate approaching 60% in low-income countries.

METHODS: In this retrospective before-after clinical study, we compared the outcome and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone, and thiamine during a 7-month period (treatment group) with a control group treated in our ICU during the preceding 7 months. The primary outcome was hospital survival. A propensity score was generated to adjust the primary outcome.

CONCLUSIONS: Our results suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine, are effective in preventing progressive organ dysfunction, including acute kidney injury, and in reducing the mortality of patients with severe sepsis and septic shock. Additional studies are required to confirm these preliminary findings.

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Impact of high dose vitamin C on platelet function

AIM: To examine the effect of high doses of vitamin C (VitC) on ex vivo human platelets (PLTs).

METHODS: Platelet concentrates collected for therapeutic or pro­phylactic transfusions were exposed to: (1) normal saline (control); (2) 0.3 mmol/L VitC (Lo VitC); or (3) 3 mmol/L VitC (Hi VitC, final concentrations) and stored appropriately. The VitC additive was preservative-free
buffered ascorbic acid in water, pH 5.5 to 7.0, adjusted with sodium bicarbonate and sodium hydroxide. The doses of VitC used here correspond to plasma VitC levels reported in recently completed clinical trials. Prior to supplementation, a baseline sample was collected for analysis. PLTs were sampled again on days 2, 5 and 8 and assayed for changes in PLT function by: Thromboelastography (TEG), for changes in viscoelastic properties; aggregometry, for PLT aggregation and adenosine triphosphate (ATP) secretion in response to collagen or adenosine diphosphate (ADP); and
flow cytometry, for changes in expression of CD-31, CD41a, CD62p and CD63. In addition, PLT intracellular VitC content was measured using a fluorimetric assay for ascorbic acid and PLT poor plasma was used for plasma coagulation tests [prothrombin time (PT), partial thrombplastin time (PTT), functional fibrinogen] and Lipidomics analysis (UPLC ESI-MS/MS).

CONCLUSION: Alterations in PLT function by exposure to 3 mmol/L VitC for 8 d suggest that caution should be exerted with prolonged use of intravenous high dose VitC.

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O2 and H2O2 - Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2 and H2O2 are capable of disrupting intracellular iron metabolism thereby selectively sensitizing non-small cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through prooxidant chemistry involving redox active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

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Vitamin C supplementation in the critically ill: A systematic review and meta-analysis

Background: Low plasma levels of vitamin C are associated with adverse outcomes, including increased mortality, in critically ill patients. Several trials have suggested that the administration of intravenous vitamin C in this setting may have beneficial effects, such as reducing the incidence of organ failure and improving survival. However, these studies have generally involved combination therapies consisting of vitamin C along with other antioxidants, confounding the effects of vitamin C
alone. The primary objective of this meta-analysis is to investigate the effects of isolated intravenous supplementation of vitamin C in adults with critical illness.

Methods: A database search was conducted for studies on the use of intravenous vitamin C in adult patients with critical illness. The primary outcome assessed was mortality at the longest follow-up time available. Secondary outcomes were the duration of mechanical ventilation, duration of vasopressor support, fluid requirements, and urine output in the first 24 h of intensive care unit admission.

Results: Five studies (four randomized controlled trials and one retrospective review) enrolling a total of 142 patients were included in this meta-analysis. Compared with controls, the administration of intravenous vitamin C was associated with a decreased need for vasopressor support (standardized mean difference −0.71; 95% confidence interval (−1.16 to −0.26); p = 0.002) and decreased duration of mechanical ventilation (standardized mean difference −0.5; 95% confidence interval (−0.93 to −0.06); p = 0.03), but no difference was found in mortality (odds ratio 0.76; 95% confidence interval (0.27 to 2.16); p = 0.6). Trends were also noted toward decreased fluid requirements and increased urine output. No adverse effects were reported.

Conclusion: The administration of intravenous vitamin C may lead to vasopressor sparing effects and a reduced need for mechanical ventilation in the critically ill, without affecting overall mortality. However, these results should be interpreted in light of the limitations of the primary literature and should serve as a preview of upcoming trials in this area.

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