High-dose ascorbate sensitizes NSCLC and GBM cells to radio-chemotherapy

Posted by Dr Dan Carter, 6 May 2017
An April 2017 article in Cancer Cell adds further support for the use of IV Ascorbate to improve responses to conventional oncology treatments. Key points include:

  • O2⋅− and H2O2 increase labile iron causing cancer cell-selective ascorbate toxicity
  • Therapeutic levels of ascorbate are achievable and well tolerated in GBM and NSCLC
  • Cancer cell oxidative metabolism can be targeted with ascorbate for cancer therapy

From the Summary

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 pro-oxidant 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.

Significance of Findings

Despite advances in treatment strategies, 5-year overall survival in NSCLC and GBM has not significantly increased over the last 20 years. Here, we demonstrate that pharmacological ascorbate represents an easily implementable and non-toxic agent that may increase treatment efficacy when combined with standard-of-care radio-chemotherapy in NSCLC and GBM. Furthermore, the mechanism by which ascorbate is selectively toxic to cancer cells versus normal cells is shown to involve alterations in redox-active iron metabolism mediated by mitochondrial O2⋅− and H2O2. As fundamental defects in oxidative metabolism leading to increased steady-state levels of O2⋅− and H2O2 emerge as targetable hallmarks of cancer cells, the current findings support a generalized mechanism for the application of pharmacological ascorbate in cancer therapy.

Schoenfeld JD, et al. O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell. 2017 Apr 10;31(4):487-500.e8. doi: 10.1016/j.ccell.2017.02.018. Epub 2017 Mar 30. PMID: 28366679

Problems with Cochrane reviews of diet and chronic disease

Posted by Dr Dan Carter, July 8, 2016
AS Truswell has clearly explained why Cochrane reviews can lead to misleading conclusions when dealing with the effects of diet, especially when chronic diseases are involved.

The sum of evidence-based nutrition has to be more than a Cochrane-type meta-analysis of randomised controlled trials (RCTs). Most of the evidence base in nutrition is observational, especially cohort studies. RCTs of diet change through to disease outcome are uncommon and the change has usually been addition or removal of only a single food component. Trials with whole diets through to disease outcome are rare and dietary changes made by individuals are unlikely to be an exact copy of the prescription. It is hard to even imagine a trial in which half (randomised) of a large group of middle-aged people agree to avoid vegetables for 5 y and be followed up to see who will develop cancer. Most of the USA’s health claims, permitted by the Food and Drug Administration, are not supported by RCTs. But where controlled trials of nutritional change and disease outcome have been achieved, they must be reviewed very carefully. Two Cochrane reviews on diet and cardiovascular disease (CVD), published in the widely read British Medical Journal (BMJ), were criticised after their publication and the conclusions have not been subsequently adopted by expert committees. The first of these reviews was ‘Dietary fat and prevention of CVD: a systematic review’. The second was ‘Systematic review of long term effects of advice to reduce dietary salt in adults’. A critique of these two Cochrane reviews is presented here as a contribution to our discussion of the potential of Cochrane methodology to the reliability of knowledge about diet and disease.

European Journal of Clinical Nutrition (2005) 59, Suppl 1, S150–S154. doi:10.1038/sj.ejcn.1602189 PMID: 16052203

Poor and/or biased study interpretation does not negate the positive uses of IV magnesium post myocardial infarct (MI)

Posted by Dr Dan Carter, June 29, 2016
I was looking over a Facebook post today about the efficacy of IV Mg for MI, and it piqued my interest in looking at more recent research, since the post referred to studies from 1986 and 1992.

In double-blind, placebo-controlled study, they looked at 273 patients who were admitted to the hospital for a heart attack. The study revealed that after 4 weeks, the people who received magnesium, only 7% died versus 19% who did not get magnesium; magnesium cut the death rate by 63%.
What was interesting is the fact that the study indicated that patients were generally given less than the 2 cc of magnesium which is the recommended dose.
Furthermore, the injection of magnesium decreased arrhythmias by 55%. Arrhythmia is a major concern following MI. [Abstract: In a double-blind, placebo-controlled study, 273 patients with suspected acute myocardial infarction (AMI) were randomised to receive either magnesium intravenously or placebo immediately on admission to hospital. Of 130 patients with proven AMI 56 received magnesium and 74 received placebo. During the first 4 weeks after treatment mortality was 7% in the magnesium group and 19% in the placebo group. In the magnesium group 21% of patients had arrhythmias that needed treatment, compared with 47% in the placebo group. No adverse effects of intravenous magnesium were observed. [PMID: 2868254]

Another study in the same medical journal showed that magnesium produced a 24% reduction in the number of deaths in one month after the heart attack.
Besides the proven benefits for victims of a heart attack, another study showed patients who were given IV magnesium had a 76% reduction in death from a fatal blood clot. This study also showed that aspirin was of no benefit. [PMID: 1351547]

A PubMed search for the terms IV Magnesium and Myocardial Infarct came up two papers I’ll discuss briefly.

A 2015 rat study where MI was induced by isoprenaline used MgSO4 270 mg/kg intraperitoneally or an equivalent volume of physiological saline. The study authors concluded that although Mg(2+) had no detrimental effects on electrical or hemodynamic activity in ISO-induced MI, the lack of infarct prevention may detract from its utility in MI therapy. [PMID: 26212925] This is hardly surprising since the principle application of Mg for MI is prevention of arrhythmia, and one of the physiological actions of Mg is to potentiate the coagulant activities of clotting factor IV. [PMID: 8621478] It would appear that the authors looked at the wrong outcomes.

A 1995 article in the journal circulation, however, found that early treatment with MgSO4 resulted in both a significant reduction in lethal arrhythmias and infarct size when subjects (swine in this case) were treated soon after infarct initiation. To wit:
“ Lethal arrhythmias were significantly reduced in the Mg-early group. Infarct size was determined by vital staining. Infarct size was 0.16±0.05 g/kg body wt (Mg-early), 0.35±0.08 g/kg (Mg-late), and 0.42±0.04 g/kg for the control group” [PMID: 7586365]

Since Cochrane reviews have become popular, it is evident in some cases that meta-analysis can also lead to questionable conclusions. In their usual serious style, they state that mortality and morbidity from acute myocardial infarction (AMI) remain high, and that intravenous magnesium started early after the onset of AMI is thought to be a promising adjuvant treatment. But conflicting results from earlier trials and meta-analyses warrant a systematic review of available evidence. [PMID: 17443517] They go on to conclude that:
(1) it is unlikely that magnesium is beneficial in reducing mortality both in patients treated early and in patients treated late, and in patients already receiving thrombolytic therapy.
(2) it is unlikely that magnesium will reduce mortality when used at high dose (>=75 mmol)
(3) magnesium treatment may reduce the incidence of ventricular fibrillation, ventricular tachycardia, severe arrhythmia needing treatment or Lown 2-5, but it may increase the incidence of profound hypotension, bradycardia and flushing
(4) the areas of uncertainty regarding the effect of magnesium on mortality remain the effect of low dose treatment (< 75 mmol) and in patients not treated with thrombolysis.   Conclusions 1 and 2 can be refuted by the Woods study in Lancet [PMID: 1351547] as it was a large randomised, double blind, placebo controlled study utilizing 2316 subjects. Woods concluded that 28-day mortality did not indicate any effect modification by thrombolysis or aspirin, or by previous treatment with beta blockers and calcium antagonists. Conclusion 3 would infer that serious MI after-effects such as arrhythmia are minimized in the review, while side effects well understood and avoidable by those familiar with IV nutrient therapy are maximized. Conclusion 4 (and 2) utilized Mg doses of >=75 mmol, which if my calculations are correct [http://www.mgwater.com/convert.shtml] comes out at 36.946 mL of 50% MgSO4. That is a dose at which blood electrolyte concentration monitoring is absolutely necessary. Safe dose and infusion rate can be found at https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=8f775557-e414-4119-89a8-c19334f5f116&type=display Lower doses of Mg, such as those used in IV nutrient therapy, have been shown to be effective in controlling arrhythmia, especially in combination with taurine.

After looking at readily available literature, I would posit that Mg use after myocardial infarct is indeed useful, especially when administered as soon as possible after the MI. The Cochrane review seems to show bias in favor of pharmaceutical agents rather than a relatively inexpensive mineral such as magnesium, a common finding in a medical journal system dominated by drug advertising and pharmaceutical company funding of CME events (this is a simple fact, not a judgment of the journal and medical education system lacking merit).

Arginine and glutamine improve wound healing

Posted by Dr Dan Carter, September 17, 2015
We cover all of the clinically significant amino acids in our advanced IV seminars. New information is constantly being generated and indexed on PubMed; this information is incorporated into our seminars so it is worthwhile to update your IV nutrient knowledge periodically – we recommend updates at least every five years.

Adv Wound Care (New Rochelle). 2014 Nov 1;3(11):691-707.
Micronutrients, Arginine, and Glutamine: Does Supplementation Provide an Efficient Tool for Prevention and Treatment of Different Kinds of Wounds?
Ellinger S.

Abstract
Significance: Wound-healing complications are a clinical problem with a considerable socioeconomic burden. Since several nutrients play a physiological role in wound healing, supplementation of these nutrients may improve wound healing. Recent Advances: Oral nutritional supplements and enteral formulas providing arginine, glutamine, and micronutrients such as ascorbic acid and zinc should improve the healing of pressure ulcers (PU) and the healing of surgical, traumatic, and burned wounds. Is their efficacy proved from clinical intervention trials? Critical Issues: Formulas that are rich in energy, protein, arginine, vitamin C, and zinc can improve PU healing, whereas their efficacy for PU prevention is less clear. High-dose supplementation of vitamin C, zinc, and pantothenic acid may improve the healing of surgical wounds in healthy subjects. Arginine lowers the risk of fistulas in patients undergoing elective surgery due to gastrointestinal cancer. However, formulations also enriched with n-3-fatty acids and ribonucleic acids lower the risk of several wound complications, thus being more effective than isolated arginine. Glutamine and antioxidant micronutrients (vitamin C and E, zinc, selenium, and copper) can improve the healing of surgical, traumatic, and burned wounds. Future Directions: Considerable evidence suggests that formulations, indicated especially for critically ill patients, support the healing of PU and the healing of surgical and burned wounds. However, their optimal composition with regard to the dose of individual components has to be determined in future studies. Further well-designed trials should investigate the impact of certain nutrients for the prevention of PU and for the healing of surgical wounds in healthy subjects.

PMID: 25371852

Wallcur Practi bags – not quite finished

Posted by Dr Dan Carter
FDA MedWatch came out with this safety alert yesterday. Thanks to Dr Tim Murbach for sending this to me.

Simulated IV Solutions from Wallcur: CDER Statement- FDA’s Investigation into Patients being Injected

[Posted 1/14/2015]

AUDIENCE: Risk Manager, Health Professionals, Pharmacy

ISSUE: FDA and the Centers for Disease Control and Prevention (CDC) are continuing to investigate multiple instances of Wallcur’s simulated intravenous (IV) saline products being administered to patients. These products are not sterile and should not be injected in humans or animals. So far, more than 40 patients have received infusions of the simulated saline products, and there have been many adverse events associated with these incidents including fever, chills, tremors and headache. Some patients were hospitalized, and there is one death associated with the use of these products; it is not known if this death is directly related to the use of the product.

BACKGROUND: Wallcur’s simulated IV saline solution, Practi-0.9% sodium chloride solution, was shipped to medical clinics, surgical centers, and urgent care facilities in numerous states. While Sodium Chloride 0.9% Injection (IV normal saline) has been in tight supply, FDA has been working with manufacturers to increase supply. In addition, FDA is not objecting to the temporary distribution of additional IV normal saline from alternate sources Fresenius Kabi USA, Baxter Healthcare Corp., and B. Braun Medical Inc. Currently, there is supply available from several manufacturers as posted on FDA’s website.
…Continue Reading

Wallcur Practi bag update – final?

Posted by Dr Dan Carter

I relayed this information a couple of days ago via our IV chat line, and am including it in our blog to have a more permanent “information location” until this matter is concluded. See our two previous blog posts to get the full story.

There are no warnings on the bags stating “Not for human or animal injection. For simulation practice only.” This bolded quote is taken from Wallcur’s order page for the “Practi-50 mL I.V. Solution Bag (for simulation). The bags themselves do not have this warning.

In another email to me on January 5, our very helpful Florida physician further elucidated what is known:
[Quote]
The FDA, CDC and State Health Departments (I think in all 50 states) are involved in notifying Health Care Facilities and Hospitals. I think they have been in the process of doing so since at least 12/30/2014. However, another problem is that they do not seem to have a complete list of providers or facilities that may have received this fluid.
…Continue Reading

Update to Wallcur Practi IV Solution Bags – Urgent

Posted by Dr Dan Carter

The FDA needs to take immediate and emergency action in the case of Wallcur Practi IV Solution Bags that are supposed to be used only for IV start practice. I (Dr Carter) received an email from a physician in Florida who has personal experience with the Practi Bags in question. I have anonymized his email…

[Quote]
Dr Carter,

I am an Internal Medicine Physician in [City], Florida and I read your blog in reference to the Wallcur IV solutions being administered to patients.

The problem with this particular “practice” solution is that it has found its way in to the normal supply chains for hospitals and clinics and reading the label three times over as you suggest, is not going to change the fact that all it says is Normal Saline, however when administered to a patient it causes severe illness, shock and inflammation and in some cases death. As a provider who ordered this fluid I can ensure you that this is a matter of erroneous and false labeling for an extremely dangerous product floating around in the IV supply chain. Nowhere on this bag does it say “Do not use in humans or animals,” “For practice use only,” or any such thing, in short, it needs to be removed quickly from the shelves of clinics and hospitals and then there needs to be some serious new regulations in regards to the labeling of “practice” IV solutions.

[Name] MD
[City], FL
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Importance of correct label reading hits the news

Posted by Dr Dan Carter

Physicians who administer or supervise the administration of intravenous drugs and solutions know how critical it is to read the labels of these products before giving them to patients. IV set-up protocols normally require redundant reading of labels at least three times prior to administration, in order to insure that the correct drug/solution is given. A recent posting from the FDA illustrates this important point once again:

[Quote] IV Solutions from Wallcur of San Diego: CDER Statement – FDA Warns Health Care Professionals Not to Inject Patients
AUDIENCE: Risk Manager, Health Professionals, Pharmacy

ISSUE: The U.S. Food and Drug Administration is alerting health care professionals not to use Wallcur, LLC, simulated intravenous (IV) products in human or animal patients. These products are for training purposes only. There have been reports of serious adverse events associated with the use of certain of these products – i.e., Practi IV Solution Bags.
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The TACT Trial – Presentation by PI* Dr Gervasio Lamas & the movie Unleaded

Posted by Dr Dan Carter

I was fortunate to be present at a talk given by Dr Gervasio Lamas, the principle investigator *(PI) for the TACT (Trial to Assess Chelation Therapy) trial; he gave a good overview of the trial design and results at the ACAM spring meeting, held May 31-June 2, 2013. Dr. Lamas is the Chairman of Medicine at Mount Sinai Medical Center and Chief of the Columbia University Division of Cardiology at Mount Sinai Medical Center. This LINK http://www.miami-cardiology.com/dr-gervasio-lamas.php  gives you access to his complete bio. I got the sense that he was very courageous to serve as study chair for the TACT trail, as he has received his fair share of grief from mainstream medicine due to what has been termed the “inconvenient evidence” that chelation therapy is both safe and effective. Ref: [http://www.forbes.com/sites/harlankrumholz/2013/03/27/chelation-therapy-what-to-do-with-inconvenient-evidence/]

Dr Lamas is not the only person being denigrated for his willingness to be associated with the trial, the editors of  JAMA, the Journal of the American Medical Association have received a lot of criticism for publishing the trial results in the journal.  …Continue Reading

The TACT Trial

Posted by Dr Dan Carter

The Trial to Assess Chelation Therapy (TACT) was published in the Journal of the American Medical Association (JAMA) on March 27, 2013. The objective was to determine if an EDTA-based chelation treatment reduces cardiovascular events. The trail was a double-blind, placebo-controlled, 2 × 2 factorial randomized design, enrolling 1708 patients aged 50 years or older who had experienced a myocardial infarction (MI) at least 6 weeks prior and had serum creatinine levels of 2.0 mg/dL or less. Participants were recruited in the US and Canada. Enrollment commenced in September 2003 and follow-up continued until October 2011 (median, 55 months). Two hundred eighty nine patients (17% of total; 115 in the EDTA group and 174 in the placebo group) withdrew consent during the trial.

A synopsis of the JAMA abstract: http://jama.jamanetwork.com/article.aspx?articleid=1672238

Patients were randomized to receive 40 infusions of 500 mL chelation solution (3 g disodium EDTA, 7 g ascorbate, B vitamins, electrolytes, procaine, and heparin) (n=839) vs. placebo (n=869) and an oral vitamin-mineral regimen vs. an oral placebo. Weekly infusions were administered for 30 weeks, followed by 10 infusions 2-8 weeks apart. Sixteen percent discontinued infusions (n=38 [16%] in the chelation group and n=41 [15%] in the placebo group) due to adverse events.

The pre-defined primary end point was a composite of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. This report describes the treatment comparison of EDTA chelation vs. placebo. The significance threshold required for final analysis was P = .036.

Qualifying previous MIs occurred a median of 4.6 years prior to enrollment. Median age was 65 years, 18% female, 9% nonwhite, and 31% diabetic. The primary end point occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.99]; P = .035). There was no effect on total mortality (chelation: 87 deaths [10%]; placebo, 93 deaths [11%]; HR, 0.93 [95% CI, 0.70-1.25]; P = .64). The effect of EDTA chelation on the components of the primary end point other than death was of similar magnitude as its overall effect (MI: chelation, 6%; placebo, 8%; HR, 0.77 [95% CI, 0.54-1.11]; stroke: chelation, 1.2%; placebo, 1.5%; HR, 0.77 [95% CI, 0.34-1.76]; coronary revascularization: chelation, 15%; placebo, 18%; HR, 0.81 [95% CI, 0.64-1.02]; hospitalization for angina: chelation, 1.6%; placebo, 2.1%; HR, 0.72 [95% CI, 0.35-1.47]). Sensitivity analyses examining the effect of patient dropout and treatment adherence did not alter the results.

Among stable patients with a history of MI, use of an intravenous chelation regimen with disodium EDTA, compared with placebo, modestly reduced the risk of adverse cardiovascular outcomes, many of which were revascularization procedures. These results provide evidence to guide further research but are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI.

End synopsis

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