Study of Vitamin C Pharmacology

The intravenous administration of high dose ascorbate (IVC) has increased in popularity among complementary and alternative medicine practitioners: thousands of patients received IVC, at an average dose of 0.5 g/kg, without significant side effects. While IVC may have a variety of possible applications, it has generated the most interest for its potential use in treating cancer. To continue our efforts to find properties of Vitamin C in enhancement of patient well-being, we studied its pharmacology in cancer patients.

Using our cancer patient database, we analyzed vitamin C absorption in cancer patients before and after IVC therapy.  Our results support the theory that cancer patients are deficient in vitamin C, and that tumors and other tissues act as vitamin C “sinks”, so that extra IVC treatments are needed in order to replenish depleted stores:

• For a given dose of IVC, cancer patients, on average, achieved lower plasma ascorbate increases compared to healthy adults.
• Among cancer patients, subjects with lower pre-treatment serum ascorbate levels tend to show less of a serum level increase post IVC.
• In cancer patients, subjects who had metastatic tumor burdens showed significantly lower plasma ascorbate levels post-IVC as compared to subjects who had primary tumors but no metastases.
• Cancer patients with elevated levels of the inflammation marker CRP tended to have lower serum ascorbate levels pre-treatment and post-IVC.
• Plasma ascorbate levels post-IVC in cancer patients were lower in patients with higher levels of tumor markers.

The results of the study were published in a peer-reviewed journals:

• Clinical experience with intravenous administration of ascorbic acid: achievable levels in blood for different states of inflammation and disease in cancer patients. Mikirova NA, Casciari JJ, Riordan NH and Hunninghake RE. Journal of Translational Medicine, 2013, 11:191 (Aug 2013).
• Intravenous ascorbic acid protocol for cancer patients: scientific rationale, pharmacology, and clinical experience. Mikirova NA, Casciari JJ Hunninghake RE, Riordan NH. Functional Foods in Health and Disease 2013; 3(8):344-366

1. High dose intravenous ascorbic acid on suppression of inflammation in patients with cancer and rheumatoid arthritis.

Inflammation represents a series of biological responses of immune cells and vascular tissues to harmful stimuli such infection or inflammation.  Acute inflammation refers to the early stage immune system response to an injury: vascular permeability increases to allow elevated blood flow and white blood cell migration to the site.  This in turn leads to acute reactions such as redness, swelling, and temperature increase.  White blood cells activation also leads to increased production of inflammatory cytokines such as interleukin one (IL-1), interleukin six  (IL-6) and tumor necrosis factor alpha (TNF-α).  If the injury persists, however, the inflammation response can become chronic.  This leads to a situation where white blood cells such as macrophages continue producing cytokines and, while continuing their attack on foreign microbes, release reactive oxygen species (ROS) and other chemicals that harm normal tissue.  Chronic inflammation is thought to be involved in the progression of several sustained illnesses, including rheumatoid arthritis, asthma, irritable bowel syndrome, atherosclerosis, diabetes, and cancer.

Inflammation plays a key role in tumor development, affecting tumor proliferation, angiogenesis, metastasis, and resistance to therapy. Key features of cancer-related inflammation (CRI) include leukocyte infiltration, cytokine build-up, tissue remodelling, and angiogenesis. Infiltrating leukocytes such as tumor associated macrophages (TAMs), neutrophils, dendritic cells, and lymphocytes establish an inflammatory microenvironment and are key components in tumors of epithelial origins. In clinical studies, TAMs are associated with poor prognosis, while the use of anti-inflammatory agents is associated with reduced instances of certain cancers. Several studies indicate that inflammation is a marker of high cancer risk and poor treatment outcome. In response to systemic inflammation, and in particular in response to elevated IL-6 levels, the liver produces (C-reactive protein) CRP, a protein that binds to dead or dying cells to activate the complement system.

This led to our interest in what clinical markers of chronic inflammation are available, how do these markers correlate with disease status, and how to therapies commonly used at the Riordan Clinic, intravenous vitamin C (IVC) therapy, for example, affect inflammation.

Our inflammation research began with a study of our patient history database to determine how inflammation markers such as CRP correlate with cancer markers and how they changed during IVC.

• IVC therapy was associated decreases in cancer markers as well as decreases in CRP and in pro-inflammatory cytokines (interleukins 1, 2, and 8, as well as interferon-gamma). Since inflammation is associated with poor cancer prognosis, this was an important finding.
• Our clinical data supported the hypothesis that high dose intravenous ascorbate treatments may reduce inflammation in cancer patients.
• We published our results in a peer-reviewed journal: Effect of high-dose intravenous vitamin C on inflammation in cancer patients  Mikirova NA, Casciari JJ, Taylor PR and Rogers AM  Journal of Translational Medicine, 2012, 10:189 (Sep 2012)
• Intravenous ascorbic acid to prevent and treat cancer-associated sepsis. Ichim TE, Minev B, Braciak T, Luna B, Hunninghake R, Mikirova NA, Jackson JA,  et al. Journal of Translational Medicine 2011, 9:25

Later we conducted a similar analysis based on patients who had rheumatoid arthritis and were treated with IVC.  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 subjects with RA. Our data suggested 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

Some of our key findings:

• CRP levels in arthritis patients correlate with weight and fat content: obesity was associated with inflammation in these subjects.
• CRP reductions with IVC therapy were more dramatic when the treatments were given more frequently.
• We published our results in a peer-reviewed journal: Effect of high dose intravenous ascorbic acid on the level of inflammation in patients with rheumatoid arthritis  Mikirova NA, Rogers AM, Casciari JJ, Taylor PR  Modern Research in Inflammation, 2012, 1(2):26-32 (Nov 2012)