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I v vit c: Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome

Содержание

Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome

PharmaNutrition. 2020 Jun; 12: 100190.

Prince Mohammad Bin Fahd University, P.O. Box 1664, Al Khobar, 31952, Saudi Arabia

Corresponding author.

Received 2020 Mar 31; Revised 2020 Apr 5; Accepted 2020 Apr 6.

Copyright © 2020 Elsevier B.V. All rights reserved.

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Abstract

The recent outbreak of Covid19 has required urgent treatments for numerous patients. No suitable vaccines or antivirals are available for Covid19. The efficiency against Covid19 of WHO therapies of choice, that are two antivirals developed for other pathologies, is controversial. Therefore, alternative approaches are required. Intravenous (IV) Vitamin C (Vit-C) has emerged as one of the other alternatives for this purpose. Here we review the effects of IV Vit-C on the immune system response, the antiviral properties of IV Vit-C, and finally the antioxidant properties of IV Vit-C to specifically address the cytokines’ storm characteristic of the Acute Respiratory Distress Syndrome (ARDS) that occur in the later cycle of the Covid19 infectious disease.

Keywords: Vitamin C, Severe acute respiratory syndrome coronavirus, Antiviral agents, Covid19, Cytokines

1.

 Introduction

The recent outbreak of Covid19 has required urgent treatments for numerous patients. The Covid19 originated in Wuhan, China has spread to other continents and has caused significant harm to the public.
represents a transmission electron microscope image of Covid19 along with a 3D structure of coronavirus. No suitable vaccines or antiviral drugs exist against Covid19. At the time of writing (15 March 2020), Coronavirus cases were already 173,085 (+19 % over the last 24 h, +5% the day before), with 6664 deaths (+23 % over the last 24 h, +6% the day before) vs. 77,784 recovered (+6% over the last 24 h), with some improvements in China. However, the condition is deteriorating in Western Europe, especially Italy. No cure for Covid19 is known at this time. In addition to administering oxygen, current treatments recommended by the World Health Organization (WHO) for the serious, critical cases of Covid19 include Remdesivir, Kaletra, and Kaletra plus Interferon (France24, “Conquering the coronavirus: the most pressing goal for these researchers in Paris”, youtu. be/L0wRSKnIErk). Remdesivir is an antiviral nucleotide developed as a treatment for the Ebola virus and Marburg virus infections. Kaletra is a combination of Lopinavir and Ritonavir (LPV/r). This is also used as antiviral nucleotide analogs developed for the treatment of HIV/AIDS. The third option is a combination of Kaletra with Interferon. Interferons are signaling proteins (cytokines) that infected cells produce and release in response to viruses. Interferons activate other cells of the immune system so that a stronger immune system response can be achieved. Interferon alphas are specifically recommended for viral infections and some cancers. The efficacy of these processes for Covid19 is controversial. Therefore, alternative approaches are urgently needed.

In China, the death rate was peaked at 3% a few weeks ago but is now declined to 0.7 %. Good results are obtained using Interferon Alpha 2B (IFNrec) without any combination with Kaletra. The use of Intravenous (IV) Vitamin C (Vit-C) has shown promise in this area in China. The IV Vit-C (or Ascorbic acid) protocols are mentioned in clinicaltrials.gov, for Covid19 and other pathologies. Shanghai now utilizes IV Vit-C in the treatment for Covid-19. Many physicians in China have identified promising results using IV Vit-C against Covid19. Thus, there is a need to urgently review the uses of IV Vit-C, pre- and post-infection, and during different stages of the infection. IV Vit-C is helping to develop a stronger immune system response, reducing the cytokines storm, or increasing antiviral activities through other unknown mechanisms.

Perhaps, the reduction of the cytokines storm in the late stages of the Covid19 infection is the most significant application of IV Vit-C. Covid19 pneumonia is a complex medical disorder with high morbidity and mortality rate. This causes severe lung injury that results in Acute Respiratory Distress Syndrome (ARDS), a life-threatening lung disorder. This process prevents the necessary oxygen to enter into the lungs and ultimately causes death. Coronaviruses increase oxidative stress that promotes cellular malfunction and ultimately results in organ failure. It is believed that pulmonary failure (ARDS) is the principal cause of Covid19′s action on humans. This helps to increase oxidative stress considerably because of the generation of free radicals and cytokines. This process finally leads to serious cellular injury, organ failure and death. The administration of anti-oxidizing agents along with proven conventional supportive therapies is believed to have an important role in controlling these medical situations. Appropriate vaccines and antiviral drugs for the Covid19 epidemic are not available. IV Vitamin C and other antioxidants are extremely good agents for ARDS. These can be applied clinically. Importantly, high dose IV Vit-C is safe and effective. In this paper, we review the use of high-dose Vit-C as an efficient method of treatment for patients with cancers and infections.

The antiviral properties of Vit-C help to reduce symptoms and mortality in children and adults [[1], [2], [3], [4]]. The antiviral activities of ascorbic acid was known and it was published almost 80 years ago [[5], [6], [7], [8], [9]] when scientists were involved in work on poliomyelitis. Moreover, the use of ascorbic acid as a medicinally crucial agent against various diseases was also well established [[10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]]. Applications of Vit-C are found in poliomyelitis [[22], [23], [24], [25], [26]]. Many other uses of Vit-C include hepatitis, herpes, chickenpox and measles, infectious mononucleosis, trichinosis, urethritis, Antabuse, arthritis, and cancer. Vit-C is also helpful for the treatment of elevated cholesterol and arteriosclerosis, [[27], [28], [29], [30], [31], [32]], corneal ulcers, glaucoma, burns, heatstroke, sunburn, slipped disc, toxins, and heavy metal poisonings [[33], [34], [35]]. The appropriate clinically effective vaccines and specific antivirals may serve effectively if they are available. Considering the current situation, the use of Vit-C as an antiviral agent should also be considered. Notably, Vit-C can be used alone or in combination with other available medicines to exert positive synergistic effects. Here we review the principal mechanism of actions of IV Vit-C that helps to make the immune system stronger, reduces the cytokines storm and inhibits oxidative processes. Under the first criteria, literature knowledge on cancer treatment will be reviewed first. Then, the antiviral properties will be reviewed, with focusing on the reduction of the oxidative pathways typical of the Covid19 ARDS.

2. Cancer treatment

A review of laboratory, animal and human studies and current clinical trials is provided regarding cancer treatments [36]. Vit-C is a crucial nutrient with redox properties, a cofactor of numerous enzymes, and it plays an important role in the synthesis of collagen [37]. A deficiency of Vit-C may result in scurvy [38]. Scurvy can cause collagen structure narrow and thin. It has been found that normal healthy situation can be maintained with the administration of Vit-C. In the mid-20th century, a study hypothesized that cancer can originate due to the alterations of the structures in connective tissues caused by Vit-C deficiency [39]. A review suggested that a high-dose of ascorbic acid can enhance host resistance. This study also identified the use of ascorbic acid in cancer therapy [40]. In general, Vit-C is synthesized from isomeric sugars d-glucose or d-galactose by numerous plants and animals. Interestingly, humans lack the enzyme l-gulonolactone oxidase which is required for ascorbic acid synthesis. On this basis, humans need Vit-C through food or other supplements [37].

Vit-C is an essential nutrient with redox properties in normal physiological situations [36]. Some cancer patients were treated successfully with high-dose of oral and/or IV Vit-C. However, two early randomized placebo-controlled studies of high-dose oral Vit-C (10 g/d) indicated no significant effects against cancers. These studies indicated marginal medical benefits between ascorbate- and placebo-treated groups. Laboratory experiments reported that high-dose of Vit-C can decrease cell proliferation in prostate, pancreatic, colon, mesothelioma, and neuroblastoma cancer cell lines. Studies of Vit-C combined with other medicines in animal models demonstrated inconclusive results. Importantly, IV Vit-C was well-tolerated in clinical trials. An IV administration of Vit-C (500 mg) was found to be more effective than oral administration since a higher blood concentration of ascorbate was found through the IV route. A study with Vit-C as ascorbate versus ascorbate formulations along with standard cancer therapies was performed in clinical trials. Two studies of high-dose Vit-C confirmed a better quality of life and fewer cancer-related toxicities. These results from preclinical and clinical trials of high-dose Vit-C with and without standard cancer therapies are note-worthy. However, it may be challenged that these investigations have a few shortcomings.

The use of high-dose Vit-C (IV and oral) for the management of cancer was started five decades ago [41]. The application of Vit-C therapy in the treatment of various cancers was promoted [42,43]. For example, two clinical trials of Vit-C were conducted many years ago [44,45]. Pharmacokinetic experiments identified considerable differences in the maximum achieved blood concentrations of Vit-C. It was found that the nature of the route of delivery was relevant. For example, if Vit-C was taken orally, plasma concentrations are controlled with a peak achievable concentration of less than 300 μM. However, this control was bypassed with IV administration of the vitamin, resulting in a very high level of Vit-C plasma concentration (up to 20 mM) [46,47]. Additional research suggested that pharmacological concentrations of ascorbate as achieved with IV administration may result in cell death in numerous cancer cell lines [48]. Health care practitioners who had participated in complementary and alternative medicine conferences in 2006 and 2008 were debated on the benefits/risks of high-dose IV Vit-C in patients. A total of 199 participants were chosen and out of which 172 were taken Vit-C. Specifically, IV Vit-C was recommended to fight against infection, cancer, and fatigue [49].

In the early 1970s, a case study was conducted with 50 cancer patients who were taken a high dose of ascorbic acid [41]. Conventional therapies were applied to these patients, but these were not successful. On this basis, these patients were recommended to take ascorbic acid. Different doses and schedules were used. For example, some patients were given IV ascorbic acid (10 g/day for 10 successive days), a few were given higher dose amounts, and some were chosen to give oral ascorbic acid (10 g/day) or a combination of both. A wide variety of responses were found. Dome of them had no or minimal response and some of them had tumor regression and tumor hemorrhage. Despite this important observation, a lack of control study prevented making any conclusion on the health benefits of ascorbic acid treatment. From a limited study published in 1975, it is apparent that one of the patients experienced tumor regression [60]. The patient who had reticulum cell sarcoma exhibited improvement due to the treatment with ascorbic acid. A reduction of the daily dose of ascorbic acid was not helpful since symptoms of the disease appeared. Notably, remission was successfully achieved again after the same patient was given a higher initial dose of ascorbic acid.

A larger study of terminal cancer patients treated with ascorbate was conducted in 1976. In this investigation, 100 terminal cancer patients [41] were given ascorbate through an acceptable and scientific way (10 g/day for 10 days IV, then repeated orally). The health conditions of these patients were evaluated concerning 1000 matched control patients from the same clinic. Interestingly, the average survival time for ascorbate-treated patients was considerably much higher (300 days) than that of the matched control group [42,43].

Two randomized investigations using placebo-controlled trials were performed. In these studies, cancer patients were taken either 10 g of oral Vit-C or placebo daily until signs of cancer go away. At the end of these investigations, no significant differences in clinical results were found between the two ascorbate- and placebo-treated groups [44,45].

A study disclosed three case reports on cancer patients who received IV Vit-C as their main medicines. During Vit-C uptake, the patients were also given other materials including vitamins, minerals, and botanicals. It was claimed that the cases are analyzed following the National Cancer Institute (NCI) Best Case Series procedures. Histopathologic tests found weak prognoses for these patients. But the survival period of these patients went up after being treated with IV Vit-C [61]. Vit-C was given from 15 g to 65 g, once or twice a week, for several months to these patients. Two studies demonstrated that IV Vit-C treatment helps to improve the quality of life and decreases the side effects associated with cancer [62,63].

Systematic studies identified that the doses of Vit-C to volunteers or cancer patients can be up to 1. 5 g/kg. No toxicity risks were seen (for example, glucose-6-phosphate dehydrogenase deficiency, renal diseases or urolithiasis). These studies identified that plasma concentrations of Vit-C can be much higher with IV administration than that of oral administration. The concentration was maintained for approximately 4 h [46,47].

A phase I study investigated the safety and efficiency of dual drug therapy by combining IV ascorbate with gemcitabine and erlotinib in stage IV pancreatic cancer patients. Fourteen subjects were evaluated in this study. The patients received IV gemcitabine (1000 mg for 30 min, once a week for 7 weeks), oral erlotinib (100 mg daily for 8 weeks), and IV ascorbate (50 g/infusion, 75 g/infusion, or 100 g/infusion 3 times per week for 8 weeks). No adverse effects were observed for ascorbic acid treatment. Five subjects received fewer than 18 of the proposed 24 ascorbate infusions. In three patients the disease was continued. Imaging tests were performed on nine patients to assess tumor size. This showed that the health situation was stable in each of them [64].

A 2013 phase I clinical investigation studied the effects of combining ascorbate with gemcitabine in the treatment of stage IV pancreatic cancer. During each 4-week cycle, patients were given gemcitabine weekly for 3 weeks and ascorbate for 4 weeks with a specific dose. This study found a progression-free and overall survival period. The combination of drug treatment was acceptable well [54].

In 2014, a phase I/IIA clinical trial measured the toxicities of two systems. The first one was combined IV ascorbate with carboplatin and the second one was ascorbate paclitaxel in stage III/IV ovarian cancer. More than 24 patients were chosen to receive either chemotherapy alone or chemotherapy and IV Vit-C. The chemotherapy was given for 6 months and IV Vit-C was continued for 12 months. Interestingly, IV Vit-C reduced chemotherapy-related toxicities [65].

A phase I/II clinical trial of high-dose IV Vit-C with numerous chemotherapeutic agents was conducted in 2015. This study was performed to evaluate multiple factors. Some important targets were to evaluate associated adverse effects, to determine the pharmacokinetic activities of Vit-C, to understand the clinical potential, to evaluate changes in mood and behavior and to assess the lifestyle [66].

A high-dose of IV Vit-C was analyzed in 14 patients. The procedures performed were tolerated well and were safe. A few temporary side effects were seen: increased urinary flow, thirst, nausea, vomiting, and chilling. It was important to note that an administration of chemotherapeutic agents did not alter the plasma concentration of Vit-C. A few patients were benefitted from this treatment because they experience temporary stable disease, demonstrate more activity with additional energy. However, since the group was small, no general conclusions from this study were drawn [66].

Recently, [67], a phase I study was evaluated to evaluate the safety, bioavailability, and efficiency of high-dose IV Vit-C in combination with chemotherapy regimens mFOLFOX6 or FOLFIRI. These were a combination of well-known agents: oxaliplatin, leucovorin, and 5-fluorouracil or leucovorin, 5-fluorouracil and irinotecan hydrochloride. This study was conducted on 36 patients with metastatic colorectal or gastric cancer. The principal aims were to evaluate the maximum-tolerated dose. Another goal was to determine the phase II dose of ascorbic acid with co-administration with mFOLFOX6 or FOLFIRI. Initially, all patients were given an identical chemotherapy treatment for 14 days with Vit-C infusions. Later, the concentration of ascorbic acid was altered for the dose-escalation investigation. This study demonstrated no dose-limiting toxicity. Therefore, a maximum-tolerated dose was not identified from this investigation. However, a dose of 1.5 g/kg for ascorbic acid was recommended for this phase II study. No adverse side effects were observed and the treatments were acceptable to the patients. Based on the success, a randomized phase III investigation is under progress. The goal of this study is to determine the clinical power of ascorbic acid against metastatic colorectal cancer in combination with mFOLFOX6 with or without bevacizumab [67].

Several studies were performed small doses of IV ascorbic acid treatment (1000 mg) with arsenic trioxide regimens, and mixed results were obtained [[68], [69], [70]].

Clinical investigations of ascorbate in combination with arsenic trioxide were reported [36]. Patients with non-small cell lung carcinoma (NSCLC) and glioblastoma multiforme (GBM) were treated in two clinical trials [71,72]. The patients in both of these trials were undergone conventional therapy along with IV Vit-C. IV Vit-C was administered under radiation therapy and in the presence of temozolomide. The toxicity and overall survival rate of the patients were favorable. The NSCLC clinical trial was a phase II procedure that has 14 patients with advanced cancer. These patients were also given both chemotherapy and IV Vit-C. The results of this investigation were also favorable.

Many trials with IV Vit-C in a combination with other medicines are under active investigation. Accordingly, 5 trials are being conducted by scientists at Iowa University, 4 phase II studies and 1 phase IB/II trial. The 4 phase II clinical trials are focused to identify the efficiency of high-dose ascorbic acid combined with common anticancer molecules. These studies with ascorbate are also progressing with many cancer cell lines. These include studies on non-small cell lung cancer therapy under radiation therapy and in the presence of carboplatin and paclitaxel; metastatic pancreatic adenocarcinoma in the presence of gemcitabine and nab-paclitaxel; pancreatic adenocarcinoma in the presence of gemcitabine and radiation therapy, and glioblastoma in the presence of temozolomide and radiation therapy. Another phase IB/II trial is investigating the safety and clinical performance of high-dose ascorbate with radiation therapy against soft tissue sarcoma.

Numerous studies used IV ascorbic acid at a fixed dose of 1000 mg with various amounts of arsenic trioxide as anticancer therapy. It was expected that the pro-oxidant character of IV ascorbic acid can improve the effects of arsenic trioxide by a sensitization process of the malignant cells to arsenic’s cytotoxic nature [72]. The combination therapies worked well. Some benefits against multiple myeloma were observed. However, the role of Vit-C in this was not determined [[73], [74], [75]]. In contrast, similar combination regimens were not effective and resulted in side effects, including the progression of the disease with particular cancer. Moreover, no anticancer effects against metastatic colorectal cancer [76] and metastatic melanoma were determined [77]. Since these trials were not placebo-controlled, the role of ascorbic acid to the results is unclear.

Intravenous (IV) high-dose ascorbic acid was well-tolerated in clinical trials [46], [78], [74], [71], [73], [64]. It was speculated that ascorbic acid may accelerate renal failure in patients with preexisting renal disorders [49]. Glucose-6-phosphate dehydrogenase (G-6-PD) deficient patients were not good candidates to have high doses of Vit-C due to hemolysis [[50], [51], [52]]. Vit-C was able to improve the bioavailability of iron. A large dose of Vit-C was not recommended for patients with hemochromatosis [53].

Vit-C in high doses reacted with a few anticancer compounds. These interactions were detected in preclinical studies. A phase I clinical investigation examined the feasibility of using high-dose IV ascorbate and gemcitabine in stage IV pancreatic cancer patients. It was important to know that the combination formula was well tolerated by patients. No adverse effects were observed [54].

In vitro and in vivo animal studies indicated ascorbate can alter the mechanism of the drug. For example, ascorbate with bortezomib altered the action of the medicine as a proteasome inhibiting agent and blocked bortezomib-mediated cell death [[55], [56], [57]]. This interaction was observed with a low concentration of Vit-C (40 mg/kg/day) to animals. The cell culture study on blood plasma with Vit-C (1 g/day) also demonstrated a large decrease in bortezomib’s growth inhibitory effect against multiple myeloma cells. The plasma of healthy volunteers was analyzed. Bortezomib growth inhibition on multiple myeloma cells was observed when a person takes 1 g of oral Vit-C per day. This amount had blocked the drug’s inhibitory properties against the 20S proteasome [57]. On the other hand, a study that utilized mice harboring human prostate cancer cell xenografts did not find any good effect of oral Vit-C (40 mg/kg/day or 500 mg/kg/day) on the tumor growth inhibitory action of this medicine [58]. Studies showed that dehydroascorbic acid, an oxidized form of Vit-C alters the cytotoxic properties of some chemotherapy drugs [59]. But, the concentration of dehydroascorbic acid is found to be low in dietary supplements and foods.

Despite some controversial results over the years, Vit-C had proven to have anticancer effects when given intravenously at high concentrations [79]. Some reports on the anticancer activities of Vit-C were dependent on the use of immune-deficient mice. These studies were conducted to examine the direct effects of ascorbate on tumors. It was found that the effects of Vitamin C are much stronger in the presence of an intact immune system [79]. These observations suggested a combination treatment which requires evaluation in patients.

3. Treatment of viral infections

The antiviral properties of Vit-C were recently reviewed [80]. Vit-C was used for the treatment of hypovitaminosis C in malnourished patients. A combination of hydrocortisone, ascorbic acid, and thiamine (HAT therapy) worked well in the treatment of patients with sepsis and septic shock [81]. There were 29 ongoing or completed clinical trials with Vit-C administration in sepsis. The effectiveness of Vit-C in preventing common cold [82] and other health disorders was questioned [83,84]. The ascorbic acid therapy for acute inflammatory disorders was based upon numerous biological studies following many decades of research. The current interest in Vit-C focuses on bacterial sepsis and septic shock in patients. More than 300 scientific and clinical studies supported mechanistic data to use Vit-C against this disease [85,86]. Some other additional role of Vit-C in the treatment of viral diseases is also possible. The biological concepts and evidence for the use of Vit-C in viral infections are described here.

Numerous studies identified that Vit-C in high dosages is virucidal [83]. This conclusion was based on in-vitro experiments. In the presence of copper and/or iron, high doses of Vit-C showed virucidal activity. This was explained through the formation of hydrogen peroxide and other radical initiators [87,88]. Moreover, the low pH value of the system was responsible for the in-vitro antiviral effects of Vit-C. Despite these studies, the in vivo virucidal activity of Vit-C was not confirmed. It was well established that Vit-C is a powerful antioxidant and it can exert pro-oxidant effects at high concentrations. The generation of reactive oxygen species through the reduction of transition metal is possible [89]. It was found that a very high-dose of one sodium salt of ascorbic acid (90 mM) kills Candida albicans in-vitro through an iron-catalyzed Fenton reaction [90]. An iron chelator 2,2′-bipyridyl inhibited this effect. An experiment demonstrated that Vit-C can decrease the viral load of the Ebstein-Barr virus (EBV) [91]. This observation suggested multiple mechanisms are involved in Vit-C-controlled anti-vital therapy. The activity of antigens and load was reduced through pre-treatment of human foreskin fibroblast and endothelial cells with ascorbate before cytomegalovirus (CMV) infection [92]. This observation was failed to reproduce when ascorbate is added after the infection. The immunomodulatory activities of Vit-C were responsible for this effect. In general, Ascorbic acid is concentrated in leucocytes, lymphocytes, and macrophages [93,94]. Chemotaxis was improved by Vit-C [[95], [96], [97]]. The neutrophil phagocytic activity and oxidative death were also enhanced [[95], [96], [97]]. Lymphocyte proliferation was also accelerated [[95], [96], [97]].

The rate-determining last step of ascorbic acid biosynthesis in animals is l-Gulono-γ-lactone oxidase or the isomeric Gulo form. Mutations in the gene of this enzyme prevented anthropoid primates and guinea pigs to synthesize this molecule. The effects of Vit-C in viral infections were studied via a Gulo (-/-) knockout mice system. It was shown that nasal inoculation of the h4N2 influenza virus is fatal in Gulo (-/-) mice in comparison to wild type mice [97]. Anti-viral cytokine interferon (IFN)-α/β became lower. However, the viral titers in the lung of ascorbic acid-insufficient Gulo (-/-) mice became more abundant [97]. The pro-inflammatory cytokines, tumor necrosis factor (TNF), interleukin-1 (IL-1)-α/β, and infiltration of inflammatory cells was increased in the lung. These results were corrected in Gulo (-/-) mice repleted with ascorbic acid before viral exposure occurs. Most probably, an impaired phosphorylation process of signal transducers and activators of transcription (STATs) was responsible for the decreased generation of IFN in Gulo (-/-) mice [98]. It was found that Gulo (-/-) mice as compared to wild type mice have an impaired immune response with higher lung pathological dysfunction when exposed to influenza h2N1 virus [98]. It was shown that restraint-stressed mice with h2N1-induced pneumonia have a dose-dependent reduction of mortality in the presence of ascorbate. Histopathological lung sections also demonstrated reduced problems in the treated mice [99]. An administration of Vit-C was helpful to recover mitochondrial membrane potential and gene expression of pro-inflammatory cytokines. Ascorbic acid was reported to have clinical activity against numerous other viruses including poliovirus, Venezuelan equine encephalitis, human lymphotropic virus type 1 (HTLV-1), human immunodeficiency virus (HIV) and rabies virus in addition to demonstrating activity against influenza and herpes virus [[100], [101], [102], [103], [104], [105], [106], [107]].

It is known that most of the infections activate phagocytes with the generation of reactive oxygen species (ROS). The ROS has a key role in deactivating viruses. Some of the ROS harm the host cells that cause viral-induced host injury. Respiratory syncytial virus (RSV) infects the upper and lower respiratory tract in infants and children. RSV infection of airway epithelial cells accelerates ROS production and this inhibits the concentration of the lung antioxidant enzymes. The oxidant-antioxidant amount and proportion in cells are critical to RSV pulmonary toxicity [108]. Lung pulmonary inflammation and injury are considerably reduced by the administration of antioxidants [109]. Ascorbic acid is a powerful antioxidant and therefore, it scavenges oxygen free radicals and restores other cellular antioxidants. These include tetrahydrobiopterin and α-tocopherol [94]. The hypothesis that Vit-C may become beneficial in the treatment of viral infections is based on two concepts. Patients with infectious diseases do not have a sufficient level of Vit-C due to metabolic consumption [110]. Vit-C has immunomodulating properties in patients with viral infections. This is possible by increasing the production of α/β interferons and downregulating the synthesis of pro-inflammatory cytokines. Despite that Vit-C have beneficial effects in viral infections no solid clinical data exists on this topic. Pauling suggested that Vit-C can be used for the treatment of the common cold. On this basis, most of the randomized controlled trials (RCTs’) targeted the role of Vit-C in the prevention and treatment of the cold symptoms. In an analysis of 29 RCTs, Vit-C failed to reduce cold disease [82]. No consistent effects of Vit-C were observed also on the duration of colds in patients. Several studies, however, complicated the interpretation of these data.

Ascorbic acid may have clinical effects in patients with infections caused by herpes viruses. Herpes zoster (HZV) infection takes place due to the reactivation of the latent Varicella-Zoster virus (VZV). This is particularly predominant because of the loss of cell-induced immunity with age. The concentration of ascorbic acid in plasma is decreased in post-herpetic neuralgia patients compared to healthy persons [111]. An RCT study was conducted with 41 patients who were subjected to IV Vit-C (50 mg/kg on days 1, 3 and 5) or placebo [111]. It was found that those patients who were taken IV Vit-C have experienced less pain. In a non-blinded RCT, the role of ascorbic acid on acute herpetic pain and postherpetic neuralgia were evaluated [112]. Eighty-seven patients were given 5 g of IV ascorbic acid on the first, third and fifth days or placebo. Interestingly, a few differences between the groups were observed. The treated group with Vit-C demonstrated a lower incidence of postherpetic neuralgia and a lower pain score. Vit-C is mostly concentrated in the aqueous humor of the anterior chamber of the eye. A retrospective cohort investigation indicated that oral Vit-C reduced the risk of herpes simplex keratitis in combination with an oral antiviral drug [111].

It was concluded only a few months before the start of the CoV19 epidemic that there is an urgent need for novel research about the application of IV Vit-C, targeting the management of infectious diseases [80]. Influenza A virus causes epidemics and pandemics that kill thousands of people every year. Experimental studies demonstrate a beneficial effect of ascorbic acid against influenza. Patients with respiratory disorders due to infection by influenza were treated with histone acetyltransferase (HAT) without corticosteroids. Remarkably, these patients showed rapid improvement after the initiation of HAT. Corticosteroids, on the other hand, have a complex role in the treatment of infection. As a result, corticosteroids may not be a standard choice in patients with influenza A infection [113,114]. Effective clinical trials are necessary to investigate the use of Vit-C against infections due to influenza, RSV, herpes, and other viral illnesses.

A large dose of IV ascorbic acid can be one treatment of choices for Covid19 pneumonia [115]. A report on this disease indicates the severity. For example, a 26 % ICU admission and a 4.3 % mortality rate are observed among 138 cases [116]. It is believed that ARDS is the main mechanism for Covid19′s action. This is followed by increased oxidative stress because of the release of free radicals and cytokines. Considering this mechanism of the process, a large dose of Vit-C should play a key role in the management of Covid19. A study indicates out of 99 Covid19 patients, 17 of them developed ARDS [117]. Eleven patients passed away due to multiple organ failure [117]. This death was explained due to increased oxidative stress and cytokine generation that lead to ARDS. Like influenza, coronaviruses are pandemic viruses that injure lung drastically [118]. This viral infection generates a “storm” of cytokines that reacts with the endothelial cells of the lung. This interaction causes neutrophil infiltration and enhances oxidative stress and damages the function of the lung barrier [118]. ARDS is characterized by strong hypoxemia. This is propagated because of multiple reasons. Uncontrolled inflammation, oxidative injury, and damage to the alveolar-capillary barrier are the main reasons [119]. The severe increased oxidative stress causes pulmonary injuries: lung injury (ALI) and ARDS. ALI and ARDS are key factors responsible for substantially high morbidity and mortality [120,121]. An increase of C-reactive protein (hsCRP), an indicator of inflammation and oxidative stress is seen among Covid19 patients [122]. The transcription factor nuclear factor-erythroid-2–related factor 2 (Nrf2) is a major regulator of antioxidant response element (ARE) driven cytoprotective protein expression. It is believed that the activation of Nrf2 signaling pathways plays a crucial role in preventing cells and tissues to undergo oxidative stress.

Ascorbic acid is a key compound of the antioxidant system in cells and tissues [123]. The biological and medicinal properties of Vit-C in critical care management are documented [124]. It is now accepted that both viral and bacterial infections result in the production of excess cytokine [118]. Antioxidants should be given to control pandemics (Covid19) because of the non-availability of pathogen-specific vaccines and drugs. This is further strengthened by the fact that a large dose of IV Vit-C has shown successful clinical results in viral ARDS and influenza [125].

A report is known that a 26-year-old woman developed viral ARDS (rhinovirus and enterovirus-D68) [118]. She was admitted to ICU and was not responsive to routine treatment. She was then placed on ECMO on day 3, a high dose of IV (200 mg/kg body/24 h, 4 doses, one every 6 h) was initiated on ECMO. Amazingly, the lungs of the patients showed excellent improvement on day 2 of high dose IV Vit-C infusion. This improvement was characterized by X-ray imaging. She was then continued to improve and was discharged from the hospital, without the requirement of additional oxygen. After a month, X-ray of her lungs indicated a complete cure. A severe medical problem of influenza was treated with high dose IV Vit-C successfully [125]. A young patient was recommended to take a high dose of IV Vit-C (50,000 mg of Vit-C in 1000 ml Ringer’s solution, infused over 90 min) and the condition of the patient improved notably by the next day. He was continued to take oral VC (2000 mg twice daily) [125].

The protective action of ascorbic acid is shown in [126]. A high dose IV Vit-C was used in 2009 to treat a New Zealand farmer (Primal Panacea) [127]. Vit-C was able to cut down ICU stay through an analysis of 18 clinical studies on 2004 ICU patients [128]. It was found that 17,000 mg/day IV Vit-C had shortened the ICU stay by 44 %. The use of IV Vit-C in 47 sepsis ICU cases was reported and a major reduction in death was possible [129]. Dietary antioxidants (Vit-C and sulforaphane) were helpful to manage oxidative-stress-induced acute inflammatory lung injury that requires mechanical ventilation [130]. Another antioxidant, natural curcumin has also been effective against inflammation that caused during pneumonia [131]. National Institutes of Health (NIH) states that high dose IV Vit-C (1.5 g/kd body weight) is safe for good health and without side effects [116].

4. Discussion and conclusions

Over the past century, the opinion that Vit-C can be used to treat cancer and viral infection has shown promises and controversies. There are cases where high dose Vit-C has shown benefits. In some cases, there have been no benefits. However, new knowledge regarding the pharmacokinetic properties of Vit-C, and recent preclinical studies, have revived interest in the utilization of high-dose Vit-C for cancer treatment [[132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145]]. Similar is the case of using IV Vit-C as antiviral, especially for the recent Covid19 [[146], [147], [148], [149], [150]]. It is believed that IV Vit-C has been particularly effective by inhibiting the production of cytokines storm due to Corvid19.

Covid19 pneumonia is an extremely rapidly developing disease with a high mortality rate. The main pathogenesis is the acute lung injury that causes ARDS and death. Antioxidants should have a role in the management of these conditions. Appropriate clinical studies and reports demonstrate that a timely administration of high dose IV Vit-C improves the outcome of Covid19 infection.

Additional studies detailing the use of IV Vit-C for the treatment of severe Covid19 infected pneumonia are definitively warranted. Covid19 may continue to happen in the future. Since the development of clinically active vaccines or antiviral drugs targeting specific diseases may take a long time to develop, the use of IV Vit-C as a universal agent for ARDS may have benefits behind Covid19. Additional clinical studies of the IV Vit-C and oral VC (such as liposomal-encapsulated VC) targeting other situations through different mechanisms are required to develop as soon as possible.

Author contributions

A.B. wrote the first draft of the manuscript. B.K.B. first revised the manuscript. Both authors further improved the manuscript.

Declaration of Competing Interest

The authors received no funding and have no conflict of interest to declare.

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Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome

PharmaNutrition. 2020 Jun; 12: 100190.

Prince Mohammad Bin Fahd University, P.O. Box 1664, Al Khobar, 31952, Saudi Arabia

Corresponding author.

Received 2020 Mar 31; Revised 2020 Apr 5; Accepted 2020 Apr 6.

Copyright © 2020 Elsevier B.V. All rights reserved.

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Abstract

The recent outbreak of Covid19 has required urgent treatments for numerous patients. No suitable vaccines or antivirals are available for Covid19. The efficiency against Covid19 of WHO therapies of choice, that are two antivirals developed for other pathologies, is controversial. Therefore, alternative approaches are required. Intravenous (IV) Vitamin C (Vit-C) has emerged as one of the other alternatives for this purpose. Here we review the effects of IV Vit-C on the immune system response, the antiviral properties of IV Vit-C, and finally the antioxidant properties of IV Vit-C to specifically address the cytokines’ storm characteristic of the Acute Respiratory Distress Syndrome (ARDS) that occur in the later cycle of the Covid19 infectious disease.

Keywords: Vitamin C, Severe acute respiratory syndrome coronavirus, Antiviral agents, Covid19, Cytokines

1. Introduction

The recent outbreak of Covid19 has required urgent treatments for numerous patients. The Covid19 originated in Wuhan, China has spread to other continents and has caused significant harm to the public.
represents a transmission electron microscope image of Covid19 along with a 3D structure of coronavirus. No suitable vaccines or antiviral drugs exist against Covid19. At the time of writing (15 March 2020), Coronavirus cases were already 173,085 (+19 % over the last 24 h, +5% the day before), with 6664 deaths (+23 % over the last 24 h, +6% the day before) vs. 77,784 recovered (+6% over the last 24 h), with some improvements in China. However, the condition is deteriorating in Western Europe, especially Italy. No cure for Covid19 is known at this time. In addition to administering oxygen, current treatments recommended by the World Health Organization (WHO) for the serious, critical cases of Covid19 include Remdesivir, Kaletra, and Kaletra plus Interferon (France24, “Conquering the coronavirus: the most pressing goal for these researchers in Paris”, youtu.be/L0wRSKnIErk). Remdesivir is an antiviral nucleotide developed as a treatment for the Ebola virus and Marburg virus infections. Kaletra is a combination of Lopinavir and Ritonavir (LPV/r). This is also used as antiviral nucleotide analogs developed for the treatment of HIV/AIDS. The third option is a combination of Kaletra with Interferon. Interferons are signaling proteins (cytokines) that infected cells produce and release in response to viruses. Interferons activate other cells of the immune system so that a stronger immune system response can be achieved. Interferon alphas are specifically recommended for viral infections and some cancers. The efficacy of these processes for Covid19 is controversial. Therefore, alternative approaches are urgently needed.

In China, the death rate was peaked at 3% a few weeks ago but is now declined to 0.7 %. Good results are obtained using Interferon Alpha 2B (IFNrec) without any combination with Kaletra. The use of Intravenous (IV) Vitamin C (Vit-C) has shown promise in this area in China. The IV Vit-C (or Ascorbic acid) protocols are mentioned in clinicaltrials.gov, for Covid19 and other pathologies. Shanghai now utilizes IV Vit-C in the treatment for Covid-19. Many physicians in China have identified promising results using IV Vit-C against Covid19. Thus, there is a need to urgently review the uses of IV Vit-C, pre- and post-infection, and during different stages of the infection. IV Vit-C is helping to develop a stronger immune system response, reducing the cytokines storm, or increasing antiviral activities through other unknown mechanisms.

Perhaps, the reduction of the cytokines storm in the late stages of the Covid19 infection is the most significant application of IV Vit-C. Covid19 pneumonia is a complex medical disorder with high morbidity and mortality rate. This causes severe lung injury that results in Acute Respiratory Distress Syndrome (ARDS), a life-threatening lung disorder. This process prevents the necessary oxygen to enter into the lungs and ultimately causes death. Coronaviruses increase oxidative stress that promotes cellular malfunction and ultimately results in organ failure. It is believed that pulmonary failure (ARDS) is the principal cause of Covid19′s action on humans. This helps to increase oxidative stress considerably because of the generation of free radicals and cytokines. This process finally leads to serious cellular injury, organ failure and death. The administration of anti-oxidizing agents along with proven conventional supportive therapies is believed to have an important role in controlling these medical situations. Appropriate vaccines and antiviral drugs for the Covid19 epidemic are not available. IV Vitamin C and other antioxidants are extremely good agents for ARDS. These can be applied clinically. Importantly, high dose IV Vit-C is safe and effective. In this paper, we review the use of high-dose Vit-C as an efficient method of treatment for patients with cancers and infections.

The antiviral properties of Vit-C help to reduce symptoms and mortality in children and adults [[1], [2], [3], [4]]. The antiviral activities of ascorbic acid was known and it was published almost 80 years ago [[5], [6], [7], [8], [9]] when scientists were involved in work on poliomyelitis. Moreover, the use of ascorbic acid as a medicinally crucial agent against various diseases was also well established [[10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]]. Applications of Vit-C are found in poliomyelitis [[22], [23], [24], [25], [26]]. Many other uses of Vit-C include hepatitis, herpes, chickenpox and measles, infectious mononucleosis, trichinosis, urethritis, Antabuse, arthritis, and cancer. Vit-C is also helpful for the treatment of elevated cholesterol and arteriosclerosis, [[27], [28], [29], [30], [31], [32]], corneal ulcers, glaucoma, burns, heatstroke, sunburn, slipped disc, toxins, and heavy metal poisonings [[33], [34], [35]]. The appropriate clinically effective vaccines and specific antivirals may serve effectively if they are available. Considering the current situation, the use of Vit-C as an antiviral agent should also be considered. Notably, Vit-C can be used alone or in combination with other available medicines to exert positive synergistic effects. Here we review the principal mechanism of actions of IV Vit-C that helps to make the immune system stronger, reduces the cytokines storm and inhibits oxidative processes. Under the first criteria, literature knowledge on cancer treatment will be reviewed first. Then, the antiviral properties will be reviewed, with focusing on the reduction of the oxidative pathways typical of the Covid19 ARDS.

2. Cancer treatment

A review of laboratory, animal and human studies and current clinical trials is provided regarding cancer treatments [36]. Vit-C is a crucial nutrient with redox properties, a cofactor of numerous enzymes, and it plays an important role in the synthesis of collagen [37]. A deficiency of Vit-C may result in scurvy [38]. Scurvy can cause collagen structure narrow and thin. It has been found that normal healthy situation can be maintained with the administration of Vit-C. In the mid-20th century, a study hypothesized that cancer can originate due to the alterations of the structures in connective tissues caused by Vit-C deficiency [39]. A review suggested that a high-dose of ascorbic acid can enhance host resistance. This study also identified the use of ascorbic acid in cancer therapy [40]. In general, Vit-C is synthesized from isomeric sugars d-glucose or d-galactose by numerous plants and animals. Interestingly, humans lack the enzyme l-gulonolactone oxidase which is required for ascorbic acid synthesis. On this basis, humans need Vit-C through food or other supplements [37].

Vit-C is an essential nutrient with redox properties in normal physiological situations [36]. Some cancer patients were treated successfully with high-dose of oral and/or IV Vit-C. However, two early randomized placebo-controlled studies of high-dose oral Vit-C (10 g/d) indicated no significant effects against cancers. These studies indicated marginal medical benefits between ascorbate- and placebo-treated groups. Laboratory experiments reported that high-dose of Vit-C can decrease cell proliferation in prostate, pancreatic, colon, mesothelioma, and neuroblastoma cancer cell lines. Studies of Vit-C combined with other medicines in animal models demonstrated inconclusive results. Importantly, IV Vit-C was well-tolerated in clinical trials. An IV administration of Vit-C (500 mg) was found to be more effective than oral administration since a higher blood concentration of ascorbate was found through the IV route. A study with Vit-C as ascorbate versus ascorbate formulations along with standard cancer therapies was performed in clinical trials. Two studies of high-dose Vit-C confirmed a better quality of life and fewer cancer-related toxicities. These results from preclinical and clinical trials of high-dose Vit-C with and without standard cancer therapies are note-worthy. However, it may be challenged that these investigations have a few shortcomings.

The use of high-dose Vit-C (IV and oral) for the management of cancer was started five decades ago [41]. The application of Vit-C therapy in the treatment of various cancers was promoted [42,43]. For example, two clinical trials of Vit-C were conducted many years ago [44,45]. Pharmacokinetic experiments identified considerable differences in the maximum achieved blood concentrations of Vit-C. It was found that the nature of the route of delivery was relevant. For example, if Vit-C was taken orally, plasma concentrations are controlled with a peak achievable concentration of less than 300 μM. However, this control was bypassed with IV administration of the vitamin, resulting in a very high level of Vit-C plasma concentration (up to 20 mM) [46,47]. Additional research suggested that pharmacological concentrations of ascorbate as achieved with IV administration may result in cell death in numerous cancer cell lines [48]. Health care practitioners who had participated in complementary and alternative medicine conferences in 2006 and 2008 were debated on the benefits/risks of high-dose IV Vit-C in patients. A total of 199 participants were chosen and out of which 172 were taken Vit-C. Specifically, IV Vit-C was recommended to fight against infection, cancer, and fatigue [49].

In the early 1970s, a case study was conducted with 50 cancer patients who were taken a high dose of ascorbic acid [41]. Conventional therapies were applied to these patients, but these were not successful. On this basis, these patients were recommended to take ascorbic acid. Different doses and schedules were used. For example, some patients were given IV ascorbic acid (10 g/day for 10 successive days), a few were given higher dose amounts, and some were chosen to give oral ascorbic acid (10 g/day) or a combination of both. A wide variety of responses were found. Dome of them had no or minimal response and some of them had tumor regression and tumor hemorrhage. Despite this important observation, a lack of control study prevented making any conclusion on the health benefits of ascorbic acid treatment. From a limited study published in 1975, it is apparent that one of the patients experienced tumor regression [60]. The patient who had reticulum cell sarcoma exhibited improvement due to the treatment with ascorbic acid. A reduction of the daily dose of ascorbic acid was not helpful since symptoms of the disease appeared. Notably, remission was successfully achieved again after the same patient was given a higher initial dose of ascorbic acid.

A larger study of terminal cancer patients treated with ascorbate was conducted in 1976. In this investigation, 100 terminal cancer patients [41] were given ascorbate through an acceptable and scientific way (10 g/day for 10 days IV, then repeated orally). The health conditions of these patients were evaluated concerning 1000 matched control patients from the same clinic. Interestingly, the average survival time for ascorbate-treated patients was considerably much higher (300 days) than that of the matched control group [42,43].

Two randomized investigations using placebo-controlled trials were performed. In these studies, cancer patients were taken either 10 g of oral Vit-C or placebo daily until signs of cancer go away. At the end of these investigations, no significant differences in clinical results were found between the two ascorbate- and placebo-treated groups [44,45].

A study disclosed three case reports on cancer patients who received IV Vit-C as their main medicines. During Vit-C uptake, the patients were also given other materials including vitamins, minerals, and botanicals. It was claimed that the cases are analyzed following the National Cancer Institute (NCI) Best Case Series procedures. Histopathologic tests found weak prognoses for these patients. But the survival period of these patients went up after being treated with IV Vit-C [61]. Vit-C was given from 15 g to 65 g, once or twice a week, for several months to these patients. Two studies demonstrated that IV Vit-C treatment helps to improve the quality of life and decreases the side effects associated with cancer [62,63].

Systematic studies identified that the doses of Vit-C to volunteers or cancer patients can be up to 1.5 g/kg. No toxicity risks were seen (for example, glucose-6-phosphate dehydrogenase deficiency, renal diseases or urolithiasis). These studies identified that plasma concentrations of Vit-C can be much higher with IV administration than that of oral administration. The concentration was maintained for approximately 4 h [46,47].

A phase I study investigated the safety and efficiency of dual drug therapy by combining IV ascorbate with gemcitabine and erlotinib in stage IV pancreatic cancer patients. Fourteen subjects were evaluated in this study. The patients received IV gemcitabine (1000 mg for 30 min, once a week for 7 weeks), oral erlotinib (100 mg daily for 8 weeks), and IV ascorbate (50 g/infusion, 75 g/infusion, or 100 g/infusion 3 times per week for 8 weeks). No adverse effects were observed for ascorbic acid treatment. Five subjects received fewer than 18 of the proposed 24 ascorbate infusions. In three patients the disease was continued. Imaging tests were performed on nine patients to assess tumor size. This showed that the health situation was stable in each of them [64].

A 2013 phase I clinical investigation studied the effects of combining ascorbate with gemcitabine in the treatment of stage IV pancreatic cancer. During each 4-week cycle, patients were given gemcitabine weekly for 3 weeks and ascorbate for 4 weeks with a specific dose. This study found a progression-free and overall survival period. The combination of drug treatment was acceptable well [54].

In 2014, a phase I/IIA clinical trial measured the toxicities of two systems. The first one was combined IV ascorbate with carboplatin and the second one was ascorbate paclitaxel in stage III/IV ovarian cancer. More than 24 patients were chosen to receive either chemotherapy alone or chemotherapy and IV Vit-C. The chemotherapy was given for 6 months and IV Vit-C was continued for 12 months. Interestingly, IV Vit-C reduced chemotherapy-related toxicities [65].

A phase I/II clinical trial of high-dose IV Vit-C with numerous chemotherapeutic agents was conducted in 2015. This study was performed to evaluate multiple factors. Some important targets were to evaluate associated adverse effects, to determine the pharmacokinetic activities of Vit-C, to understand the clinical potential, to evaluate changes in mood and behavior and to assess the lifestyle [66].

A high-dose of IV Vit-C was analyzed in 14 patients. The procedures performed were tolerated well and were safe. A few temporary side effects were seen: increased urinary flow, thirst, nausea, vomiting, and chilling. It was important to note that an administration of chemotherapeutic agents did not alter the plasma concentration of Vit-C. A few patients were benefitted from this treatment because they experience temporary stable disease, demonstrate more activity with additional energy. However, since the group was small, no general conclusions from this study were drawn [66].

Recently, [67], a phase I study was evaluated to evaluate the safety, bioavailability, and efficiency of high-dose IV Vit-C in combination with chemotherapy regimens mFOLFOX6 or FOLFIRI. These were a combination of well-known agents: oxaliplatin, leucovorin, and 5-fluorouracil or leucovorin, 5-fluorouracil and irinotecan hydrochloride. This study was conducted on 36 patients with metastatic colorectal or gastric cancer. The principal aims were to evaluate the maximum-tolerated dose. Another goal was to determine the phase II dose of ascorbic acid with co-administration with mFOLFOX6 or FOLFIRI. Initially, all patients were given an identical chemotherapy treatment for 14 days with Vit-C infusions. Later, the concentration of ascorbic acid was altered for the dose-escalation investigation. This study demonstrated no dose-limiting toxicity. Therefore, a maximum-tolerated dose was not identified from this investigation. However, a dose of 1.5 g/kg for ascorbic acid was recommended for this phase II study. No adverse side effects were observed and the treatments were acceptable to the patients. Based on the success, a randomized phase III investigation is under progress. The goal of this study is to determine the clinical power of ascorbic acid against metastatic colorectal cancer in combination with mFOLFOX6 with or without bevacizumab [67].

Several studies were performed small doses of IV ascorbic acid treatment (1000 mg) with arsenic trioxide regimens, and mixed results were obtained [[68], [69], [70]].

Clinical investigations of ascorbate in combination with arsenic trioxide were reported [36]. Patients with non-small cell lung carcinoma (NSCLC) and glioblastoma multiforme (GBM) were treated in two clinical trials [71,72]. The patients in both of these trials were undergone conventional therapy along with IV Vit-C. IV Vit-C was administered under radiation therapy and in the presence of temozolomide. The toxicity and overall survival rate of the patients were favorable. The NSCLC clinical trial was a phase II procedure that has 14 patients with advanced cancer. These patients were also given both chemotherapy and IV Vit-C. The results of this investigation were also favorable.

Many trials with IV Vit-C in a combination with other medicines are under active investigation. Accordingly, 5 trials are being conducted by scientists at Iowa University, 4 phase II studies and 1 phase IB/II trial. The 4 phase II clinical trials are focused to identify the efficiency of high-dose ascorbic acid combined with common anticancer molecules. These studies with ascorbate are also progressing with many cancer cell lines. These include studies on non-small cell lung cancer therapy under radiation therapy and in the presence of carboplatin and paclitaxel; metastatic pancreatic adenocarcinoma in the presence of gemcitabine and nab-paclitaxel; pancreatic adenocarcinoma in the presence of gemcitabine and radiation therapy, and glioblastoma in the presence of temozolomide and radiation therapy. Another phase IB/II trial is investigating the safety and clinical performance of high-dose ascorbate with radiation therapy against soft tissue sarcoma.

Numerous studies used IV ascorbic acid at a fixed dose of 1000 mg with various amounts of arsenic trioxide as anticancer therapy. It was expected that the pro-oxidant character of IV ascorbic acid can improve the effects of arsenic trioxide by a sensitization process of the malignant cells to arsenic’s cytotoxic nature [72]. The combination therapies worked well. Some benefits against multiple myeloma were observed. However, the role of Vit-C in this was not determined [[73], [74], [75]]. In contrast, similar combination regimens were not effective and resulted in side effects, including the progression of the disease with particular cancer. Moreover, no anticancer effects against metastatic colorectal cancer [76] and metastatic melanoma were determined [77]. Since these trials were not placebo-controlled, the role of ascorbic acid to the results is unclear.

Intravenous (IV) high-dose ascorbic acid was well-tolerated in clinical trials [46], [78], [74], [71], [73], [64]. It was speculated that ascorbic acid may accelerate renal failure in patients with preexisting renal disorders [49]. Glucose-6-phosphate dehydrogenase (G-6-PD) deficient patients were not good candidates to have high doses of Vit-C due to hemolysis [[50], [51], [52]]. Vit-C was able to improve the bioavailability of iron. A large dose of Vit-C was not recommended for patients with hemochromatosis [53].

Vit-C in high doses reacted with a few anticancer compounds. These interactions were detected in preclinical studies. A phase I clinical investigation examined the feasibility of using high-dose IV ascorbate and gemcitabine in stage IV pancreatic cancer patients. It was important to know that the combination formula was well tolerated by patients. No adverse effects were observed [54].

In vitro and in vivo animal studies indicated ascorbate can alter the mechanism of the drug. For example, ascorbate with bortezomib altered the action of the medicine as a proteasome inhibiting agent and blocked bortezomib-mediated cell death [[55], [56], [57]]. This interaction was observed with a low concentration of Vit-C (40 mg/kg/day) to animals. The cell culture study on blood plasma with Vit-C (1 g/day) also demonstrated a large decrease in bortezomib’s growth inhibitory effect against multiple myeloma cells. The plasma of healthy volunteers was analyzed. Bortezomib growth inhibition on multiple myeloma cells was observed when a person takes 1 g of oral Vit-C per day. This amount had blocked the drug’s inhibitory properties against the 20S proteasome [57]. On the other hand, a study that utilized mice harboring human prostate cancer cell xenografts did not find any good effect of oral Vit-C (40 mg/kg/day or 500 mg/kg/day) on the tumor growth inhibitory action of this medicine [58]. Studies showed that dehydroascorbic acid, an oxidized form of Vit-C alters the cytotoxic properties of some chemotherapy drugs [59]. But, the concentration of dehydroascorbic acid is found to be low in dietary supplements and foods.

Despite some controversial results over the years, Vit-C had proven to have anticancer effects when given intravenously at high concentrations [79]. Some reports on the anticancer activities of Vit-C were dependent on the use of immune-deficient mice. These studies were conducted to examine the direct effects of ascorbate on tumors. It was found that the effects of Vitamin C are much stronger in the presence of an intact immune system [79]. These observations suggested a combination treatment which requires evaluation in patients.

3. Treatment of viral infections

The antiviral properties of Vit-C were recently reviewed [80]. Vit-C was used for the treatment of hypovitaminosis C in malnourished patients. A combination of hydrocortisone, ascorbic acid, and thiamine (HAT therapy) worked well in the treatment of patients with sepsis and septic shock [81]. There were 29 ongoing or completed clinical trials with Vit-C administration in sepsis. The effectiveness of Vit-C in preventing common cold [82] and other health disorders was questioned [83,84]. The ascorbic acid therapy for acute inflammatory disorders was based upon numerous biological studies following many decades of research. The current interest in Vit-C focuses on bacterial sepsis and septic shock in patients. More than 300 scientific and clinical studies supported mechanistic data to use Vit-C against this disease [85,86]. Some other additional role of Vit-C in the treatment of viral diseases is also possible. The biological concepts and evidence for the use of Vit-C in viral infections are described here.

Numerous studies identified that Vit-C in high dosages is virucidal [83]. This conclusion was based on in-vitro experiments. In the presence of copper and/or iron, high doses of Vit-C showed virucidal activity. This was explained through the formation of hydrogen peroxide and other radical initiators [87,88]. Moreover, the low pH value of the system was responsible for the in-vitro antiviral effects of Vit-C. Despite these studies, the in vivo virucidal activity of Vit-C was not confirmed. It was well established that Vit-C is a powerful antioxidant and it can exert pro-oxidant effects at high concentrations. The generation of reactive oxygen species through the reduction of transition metal is possible [89]. It was found that a very high-dose of one sodium salt of ascorbic acid (90 mM) kills Candida albicans in-vitro through an iron-catalyzed Fenton reaction [90]. An iron chelator 2,2′-bipyridyl inhibited this effect. An experiment demonstrated that Vit-C can decrease the viral load of the Ebstein-Barr virus (EBV) [91]. This observation suggested multiple mechanisms are involved in Vit-C-controlled anti-vital therapy. The activity of antigens and load was reduced through pre-treatment of human foreskin fibroblast and endothelial cells with ascorbate before cytomegalovirus (CMV) infection [92]. This observation was failed to reproduce when ascorbate is added after the infection. The immunomodulatory activities of Vit-C were responsible for this effect. In general, Ascorbic acid is concentrated in leucocytes, lymphocytes, and macrophages [93,94]. Chemotaxis was improved by Vit-C [[95], [96], [97]]. The neutrophil phagocytic activity and oxidative death were also enhanced [[95], [96], [97]]. Lymphocyte proliferation was also accelerated [[95], [96], [97]].

The rate-determining last step of ascorbic acid biosynthesis in animals is l-Gulono-γ-lactone oxidase or the isomeric Gulo form. Mutations in the gene of this enzyme prevented anthropoid primates and guinea pigs to synthesize this molecule. The effects of Vit-C in viral infections were studied via a Gulo (-/-) knockout mice system. It was shown that nasal inoculation of the h4N2 influenza virus is fatal in Gulo (-/-) mice in comparison to wild type mice [97]. Anti-viral cytokine interferon (IFN)-α/β became lower. However, the viral titers in the lung of ascorbic acid-insufficient Gulo (-/-) mice became more abundant [97]. The pro-inflammatory cytokines, tumor necrosis factor (TNF), interleukin-1 (IL-1)-α/β, and infiltration of inflammatory cells was increased in the lung. These results were corrected in Gulo (-/-) mice repleted with ascorbic acid before viral exposure occurs. Most probably, an impaired phosphorylation process of signal transducers and activators of transcription (STATs) was responsible for the decreased generation of IFN in Gulo (-/-) mice [98]. It was found that Gulo (-/-) mice as compared to wild type mice have an impaired immune response with higher lung pathological dysfunction when exposed to influenza h2N1 virus [98]. It was shown that restraint-stressed mice with h2N1-induced pneumonia have a dose-dependent reduction of mortality in the presence of ascorbate. Histopathological lung sections also demonstrated reduced problems in the treated mice [99]. An administration of Vit-C was helpful to recover mitochondrial membrane potential and gene expression of pro-inflammatory cytokines. Ascorbic acid was reported to have clinical activity against numerous other viruses including poliovirus, Venezuelan equine encephalitis, human lymphotropic virus type 1 (HTLV-1), human immunodeficiency virus (HIV) and rabies virus in addition to demonstrating activity against influenza and herpes virus [[100], [101], [102], [103], [104], [105], [106], [107]].

It is known that most of the infections activate phagocytes with the generation of reactive oxygen species (ROS). The ROS has a key role in deactivating viruses. Some of the ROS harm the host cells that cause viral-induced host injury. Respiratory syncytial virus (RSV) infects the upper and lower respiratory tract in infants and children. RSV infection of airway epithelial cells accelerates ROS production and this inhibits the concentration of the lung antioxidant enzymes. The oxidant-antioxidant amount and proportion in cells are critical to RSV pulmonary toxicity [108]. Lung pulmonary inflammation and injury are considerably reduced by the administration of antioxidants [109]. Ascorbic acid is a powerful antioxidant and therefore, it scavenges oxygen free radicals and restores other cellular antioxidants. These include tetrahydrobiopterin and α-tocopherol [94]. The hypothesis that Vit-C may become beneficial in the treatment of viral infections is based on two concepts. Patients with infectious diseases do not have a sufficient level of Vit-C due to metabolic consumption [110]. Vit-C has immunomodulating properties in patients with viral infections. This is possible by increasing the production of α/β interferons and downregulating the synthesis of pro-inflammatory cytokines. Despite that Vit-C have beneficial effects in viral infections no solid clinical data exists on this topic. Pauling suggested that Vit-C can be used for the treatment of the common cold. On this basis, most of the randomized controlled trials (RCTs’) targeted the role of Vit-C in the prevention and treatment of the cold symptoms. In an analysis of 29 RCTs, Vit-C failed to reduce cold disease [82]. No consistent effects of Vit-C were observed also on the duration of colds in patients. Several studies, however, complicated the interpretation of these data.

Ascorbic acid may have clinical effects in patients with infections caused by herpes viruses. Herpes zoster (HZV) infection takes place due to the reactivation of the latent Varicella-Zoster virus (VZV). This is particularly predominant because of the loss of cell-induced immunity with age. The concentration of ascorbic acid in plasma is decreased in post-herpetic neuralgia patients compared to healthy persons [111]. An RCT study was conducted with 41 patients who were subjected to IV Vit-C (50 mg/kg on days 1, 3 and 5) or placebo [111]. It was found that those patients who were taken IV Vit-C have experienced less pain. In a non-blinded RCT, the role of ascorbic acid on acute herpetic pain and postherpetic neuralgia were evaluated [112]. Eighty-seven patients were given 5 g of IV ascorbic acid on the first, third and fifth days or placebo. Interestingly, a few differences between the groups were observed. The treated group with Vit-C demonstrated a lower incidence of postherpetic neuralgia and a lower pain score. Vit-C is mostly concentrated in the aqueous humor of the anterior chamber of the eye. A retrospective cohort investigation indicated that oral Vit-C reduced the risk of herpes simplex keratitis in combination with an oral antiviral drug [111].

It was concluded only a few months before the start of the CoV19 epidemic that there is an urgent need for novel research about the application of IV Vit-C, targeting the management of infectious diseases [80]. Influenza A virus causes epidemics and pandemics that kill thousands of people every year. Experimental studies demonstrate a beneficial effect of ascorbic acid against influenza. Patients with respiratory disorders due to infection by influenza were treated with histone acetyltransferase (HAT) without corticosteroids. Remarkably, these patients showed rapid improvement after the initiation of HAT. Corticosteroids, on the other hand, have a complex role in the treatment of infection. As a result, corticosteroids may not be a standard choice in patients with influenza A infection [113,114]. Effective clinical trials are necessary to investigate the use of Vit-C against infections due to influenza, RSV, herpes, and other viral illnesses.

A large dose of IV ascorbic acid can be one treatment of choices for Covid19 pneumonia [115]. A report on this disease indicates the severity. For example, a 26 % ICU admission and a 4.3 % mortality rate are observed among 138 cases [116]. It is believed that ARDS is the main mechanism for Covid19′s action. This is followed by increased oxidative stress because of the release of free radicals and cytokines. Considering this mechanism of the process, a large dose of Vit-C should play a key role in the management of Covid19. A study indicates out of 99 Covid19 patients, 17 of them developed ARDS [117]. Eleven patients passed away due to multiple organ failure [117]. This death was explained due to increased oxidative stress and cytokine generation that lead to ARDS. Like influenza, coronaviruses are pandemic viruses that injure lung drastically [118]. This viral infection generates a “storm” of cytokines that reacts with the endothelial cells of the lung. This interaction causes neutrophil infiltration and enhances oxidative stress and damages the function of the lung barrier [118]. ARDS is characterized by strong hypoxemia. This is propagated because of multiple reasons. Uncontrolled inflammation, oxidative injury, and damage to the alveolar-capillary barrier are the main reasons [119]. The severe increased oxidative stress causes pulmonary injuries: lung injury (ALI) and ARDS. ALI and ARDS are key factors responsible for substantially high morbidity and mortality [120,121]. An increase of C-reactive protein (hsCRP), an indicator of inflammation and oxidative stress is seen among Covid19 patients [122]. The transcription factor nuclear factor-erythroid-2–related factor 2 (Nrf2) is a major regulator of antioxidant response element (ARE) driven cytoprotective protein expression. It is believed that the activation of Nrf2 signaling pathways plays a crucial role in preventing cells and tissues to undergo oxidative stress.

Ascorbic acid is a key compound of the antioxidant system in cells and tissues [123]. The biological and medicinal properties of Vit-C in critical care management are documented [124]. It is now accepted that both viral and bacterial infections result in the production of excess cytokine [118]. Antioxidants should be given to control pandemics (Covid19) because of the non-availability of pathogen-specific vaccines and drugs. This is further strengthened by the fact that a large dose of IV Vit-C has shown successful clinical results in viral ARDS and influenza [125].

A report is known that a 26-year-old woman developed viral ARDS (rhinovirus and enterovirus-D68) [118]. She was admitted to ICU and was not responsive to routine treatment. She was then placed on ECMO on day 3, a high dose of IV (200 mg/kg body/24 h, 4 doses, one every 6 h) was initiated on ECMO. Amazingly, the lungs of the patients showed excellent improvement on day 2 of high dose IV Vit-C infusion. This improvement was characterized by X-ray imaging. She was then continued to improve and was discharged from the hospital, without the requirement of additional oxygen. After a month, X-ray of her lungs indicated a complete cure. A severe medical problem of influenza was treated with high dose IV Vit-C successfully [125]. A young patient was recommended to take a high dose of IV Vit-C (50,000 mg of Vit-C in 1000 ml Ringer’s solution, infused over 90 min) and the condition of the patient improved notably by the next day. He was continued to take oral VC (2000 mg twice daily) [125].

The protective action of ascorbic acid is shown in [126]. A high dose IV Vit-C was used in 2009 to treat a New Zealand farmer (Primal Panacea) [127]. Vit-C was able to cut down ICU stay through an analysis of 18 clinical studies on 2004 ICU patients [128]. It was found that 17,000 mg/day IV Vit-C had shortened the ICU stay by 44 %. The use of IV Vit-C in 47 sepsis ICU cases was reported and a major reduction in death was possible [129]. Dietary antioxidants (Vit-C and sulforaphane) were helpful to manage oxidative-stress-induced acute inflammatory lung injury that requires mechanical ventilation [130]. Another antioxidant, natural curcumin has also been effective against inflammation that caused during pneumonia [131]. National Institutes of Health (NIH) states that high dose IV Vit-C (1.5 g/kd body weight) is safe for good health and without side effects [116].

4. Discussion and conclusions

Over the past century, the opinion that Vit-C can be used to treat cancer and viral infection has shown promises and controversies. There are cases where high dose Vit-C has shown benefits. In some cases, there have been no benefits. However, new knowledge regarding the pharmacokinetic properties of Vit-C, and recent preclinical studies, have revived interest in the utilization of high-dose Vit-C for cancer treatment [[132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145]]. Similar is the case of using IV Vit-C as antiviral, especially for the recent Covid19 [[146], [147], [148], [149], [150]]. It is believed that IV Vit-C has been particularly effective by inhibiting the production of cytokines storm due to Corvid19.

Covid19 pneumonia is an extremely rapidly developing disease with a high mortality rate. The main pathogenesis is the acute lung injury that causes ARDS and death. Antioxidants should have a role in the management of these conditions. Appropriate clinical studies and reports demonstrate that a timely administration of high dose IV Vit-C improves the outcome of Covid19 infection.

Additional studies detailing the use of IV Vit-C for the treatment of severe Covid19 infected pneumonia are definitively warranted. Covid19 may continue to happen in the future. Since the development of clinically active vaccines or antiviral drugs targeting specific diseases may take a long time to develop, the use of IV Vit-C as a universal agent for ARDS may have benefits behind Covid19. Additional clinical studies of the IV Vit-C and oral VC (such as liposomal-encapsulated VC) targeting other situations through different mechanisms are required to develop as soon as possible.

Author contributions

A.B. wrote the first draft of the manuscript. B.K.B. first revised the manuscript. Both authors further improved the manuscript.

Declaration of Competing Interest

The authors received no funding and have no conflict of interest to declare.

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Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome

PharmaNutrition. 2020 Jun; 12: 100190.

Prince Mohammad Bin Fahd University, P.O. Box 1664, Al Khobar, 31952, Saudi Arabia

Corresponding author.

Received 2020 Mar 31; Revised 2020 Apr 5; Accepted 2020 Apr 6.

Copyright © 2020 Elsevier B.V. All rights reserved.

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Abstract

The recent outbreak of Covid19 has required urgent treatments for numerous patients. No suitable vaccines or antivirals are available for Covid19. The efficiency against Covid19 of WHO therapies of choice, that are two antivirals developed for other pathologies, is controversial. Therefore, alternative approaches are required. Intravenous (IV) Vitamin C (Vit-C) has emerged as one of the other alternatives for this purpose. Here we review the effects of IV Vit-C on the immune system response, the antiviral properties of IV Vit-C, and finally the antioxidant properties of IV Vit-C to specifically address the cytokines’ storm characteristic of the Acute Respiratory Distress Syndrome (ARDS) that occur in the later cycle of the Covid19 infectious disease.

Keywords: Vitamin C, Severe acute respiratory syndrome coronavirus, Antiviral agents, Covid19, Cytokines

1. Introduction

The recent outbreak of Covid19 has required urgent treatments for numerous patients. The Covid19 originated in Wuhan, China has spread to other continents and has caused significant harm to the public.
represents a transmission electron microscope image of Covid19 along with a 3D structure of coronavirus. No suitable vaccines or antiviral drugs exist against Covid19. At the time of writing (15 March 2020), Coronavirus cases were already 173,085 (+19 % over the last 24 h, +5% the day before), with 6664 deaths (+23 % over the last 24 h, +6% the day before) vs. 77,784 recovered (+6% over the last 24 h), with some improvements in China. However, the condition is deteriorating in Western Europe, especially Italy. No cure for Covid19 is known at this time. In addition to administering oxygen, current treatments recommended by the World Health Organization (WHO) for the serious, critical cases of Covid19 include Remdesivir, Kaletra, and Kaletra plus Interferon (France24, “Conquering the coronavirus: the most pressing goal for these researchers in Paris”, youtu.be/L0wRSKnIErk). Remdesivir is an antiviral nucleotide developed as a treatment for the Ebola virus and Marburg virus infections. Kaletra is a combination of Lopinavir and Ritonavir (LPV/r). This is also used as antiviral nucleotide analogs developed for the treatment of HIV/AIDS. The third option is a combination of Kaletra with Interferon. Interferons are signaling proteins (cytokines) that infected cells produce and release in response to viruses. Interferons activate other cells of the immune system so that a stronger immune system response can be achieved. Interferon alphas are specifically recommended for viral infections and some cancers. The efficacy of these processes for Covid19 is controversial. Therefore, alternative approaches are urgently needed.

In China, the death rate was peaked at 3% a few weeks ago but is now declined to 0.7 %. Good results are obtained using Interferon Alpha 2B (IFNrec) without any combination with Kaletra. The use of Intravenous (IV) Vitamin C (Vit-C) has shown promise in this area in China. The IV Vit-C (or Ascorbic acid) protocols are mentioned in clinicaltrials.gov, for Covid19 and other pathologies. Shanghai now utilizes IV Vit-C in the treatment for Covid-19. Many physicians in China have identified promising results using IV Vit-C against Covid19. Thus, there is a need to urgently review the uses of IV Vit-C, pre- and post-infection, and during different stages of the infection. IV Vit-C is helping to develop a stronger immune system response, reducing the cytokines storm, or increasing antiviral activities through other unknown mechanisms.

Perhaps, the reduction of the cytokines storm in the late stages of the Covid19 infection is the most significant application of IV Vit-C. Covid19 pneumonia is a complex medical disorder with high morbidity and mortality rate. This causes severe lung injury that results in Acute Respiratory Distress Syndrome (ARDS), a life-threatening lung disorder. This process prevents the necessary oxygen to enter into the lungs and ultimately causes death. Coronaviruses increase oxidative stress that promotes cellular malfunction and ultimately results in organ failure. It is believed that pulmonary failure (ARDS) is the principal cause of Covid19′s action on humans. This helps to increase oxidative stress considerably because of the generation of free radicals and cytokines. This process finally leads to serious cellular injury, organ failure and death. The administration of anti-oxidizing agents along with proven conventional supportive therapies is believed to have an important role in controlling these medical situations. Appropriate vaccines and antiviral drugs for the Covid19 epidemic are not available. IV Vitamin C and other antioxidants are extremely good agents for ARDS. These can be applied clinically. Importantly, high dose IV Vit-C is safe and effective. In this paper, we review the use of high-dose Vit-C as an efficient method of treatment for patients with cancers and infections.

The antiviral properties of Vit-C help to reduce symptoms and mortality in children and adults [[1], [2], [3], [4]]. The antiviral activities of ascorbic acid was known and it was published almost 80 years ago [[5], [6], [7], [8], [9]] when scientists were involved in work on poliomyelitis. Moreover, the use of ascorbic acid as a medicinally crucial agent against various diseases was also well established [[10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]]. Applications of Vit-C are found in poliomyelitis [[22], [23], [24], [25], [26]]. Many other uses of Vit-C include hepatitis, herpes, chickenpox and measles, infectious mononucleosis, trichinosis, urethritis, Antabuse, arthritis, and cancer. Vit-C is also helpful for the treatment of elevated cholesterol and arteriosclerosis, [[27], [28], [29], [30], [31], [32]], corneal ulcers, glaucoma, burns, heatstroke, sunburn, slipped disc, toxins, and heavy metal poisonings [[33], [34], [35]]. The appropriate clinically effective vaccines and specific antivirals may serve effectively if they are available. Considering the current situation, the use of Vit-C as an antiviral agent should also be considered. Notably, Vit-C can be used alone or in combination with other available medicines to exert positive synergistic effects. Here we review the principal mechanism of actions of IV Vit-C that helps to make the immune system stronger, reduces the cytokines storm and inhibits oxidative processes. Under the first criteria, literature knowledge on cancer treatment will be reviewed first. Then, the antiviral properties will be reviewed, with focusing on the reduction of the oxidative pathways typical of the Covid19 ARDS.

2. Cancer treatment

A review of laboratory, animal and human studies and current clinical trials is provided regarding cancer treatments [36]. Vit-C is a crucial nutrient with redox properties, a cofactor of numerous enzymes, and it plays an important role in the synthesis of collagen [37]. A deficiency of Vit-C may result in scurvy [38]. Scurvy can cause collagen structure narrow and thin. It has been found that normal healthy situation can be maintained with the administration of Vit-C. In the mid-20th century, a study hypothesized that cancer can originate due to the alterations of the structures in connective tissues caused by Vit-C deficiency [39]. A review suggested that a high-dose of ascorbic acid can enhance host resistance. This study also identified the use of ascorbic acid in cancer therapy [40]. In general, Vit-C is synthesized from isomeric sugars d-glucose or d-galactose by numerous plants and animals. Interestingly, humans lack the enzyme l-gulonolactone oxidase which is required for ascorbic acid synthesis. On this basis, humans need Vit-C through food or other supplements [37].

Vit-C is an essential nutrient with redox properties in normal physiological situations [36]. Some cancer patients were treated successfully with high-dose of oral and/or IV Vit-C. However, two early randomized placebo-controlled studies of high-dose oral Vit-C (10 g/d) indicated no significant effects against cancers. These studies indicated marginal medical benefits between ascorbate- and placebo-treated groups. Laboratory experiments reported that high-dose of Vit-C can decrease cell proliferation in prostate, pancreatic, colon, mesothelioma, and neuroblastoma cancer cell lines. Studies of Vit-C combined with other medicines in animal models demonstrated inconclusive results. Importantly, IV Vit-C was well-tolerated in clinical trials. An IV administration of Vit-C (500 mg) was found to be more effective than oral administration since a higher blood concentration of ascorbate was found through the IV route. A study with Vit-C as ascorbate versus ascorbate formulations along with standard cancer therapies was performed in clinical trials. Two studies of high-dose Vit-C confirmed a better quality of life and fewer cancer-related toxicities. These results from preclinical and clinical trials of high-dose Vit-C with and without standard cancer therapies are note-worthy. However, it may be challenged that these investigations have a few shortcomings.

The use of high-dose Vit-C (IV and oral) for the management of cancer was started five decades ago [41]. The application of Vit-C therapy in the treatment of various cancers was promoted [42,43]. For example, two clinical trials of Vit-C were conducted many years ago [44,45]. Pharmacokinetic experiments identified considerable differences in the maximum achieved blood concentrations of Vit-C. It was found that the nature of the route of delivery was relevant. For example, if Vit-C was taken orally, plasma concentrations are controlled with a peak achievable concentration of less than 300 μM. However, this control was bypassed with IV administration of the vitamin, resulting in a very high level of Vit-C plasma concentration (up to 20 mM) [46,47]. Additional research suggested that pharmacological concentrations of ascorbate as achieved with IV administration may result in cell death in numerous cancer cell lines [48]. Health care practitioners who had participated in complementary and alternative medicine conferences in 2006 and 2008 were debated on the benefits/risks of high-dose IV Vit-C in patients. A total of 199 participants were chosen and out of which 172 were taken Vit-C. Specifically, IV Vit-C was recommended to fight against infection, cancer, and fatigue [49].

In the early 1970s, a case study was conducted with 50 cancer patients who were taken a high dose of ascorbic acid [41]. Conventional therapies were applied to these patients, but these were not successful. On this basis, these patients were recommended to take ascorbic acid. Different doses and schedules were used. For example, some patients were given IV ascorbic acid (10 g/day for 10 successive days), a few were given higher dose amounts, and some were chosen to give oral ascorbic acid (10 g/day) or a combination of both. A wide variety of responses were found. Dome of them had no or minimal response and some of them had tumor regression and tumor hemorrhage. Despite this important observation, a lack of control study prevented making any conclusion on the health benefits of ascorbic acid treatment. From a limited study published in 1975, it is apparent that one of the patients experienced tumor regression [60]. The patient who had reticulum cell sarcoma exhibited improvement due to the treatment with ascorbic acid. A reduction of the daily dose of ascorbic acid was not helpful since symptoms of the disease appeared. Notably, remission was successfully achieved again after the same patient was given a higher initial dose of ascorbic acid.

A larger study of terminal cancer patients treated with ascorbate was conducted in 1976. In this investigation, 100 terminal cancer patients [41] were given ascorbate through an acceptable and scientific way (10 g/day for 10 days IV, then repeated orally). The health conditions of these patients were evaluated concerning 1000 matched control patients from the same clinic. Interestingly, the average survival time for ascorbate-treated patients was considerably much higher (300 days) than that of the matched control group [42,43].

Two randomized investigations using placebo-controlled trials were performed. In these studies, cancer patients were taken either 10 g of oral Vit-C or placebo daily until signs of cancer go away. At the end of these investigations, no significant differences in clinical results were found between the two ascorbate- and placebo-treated groups [44,45].

A study disclosed three case reports on cancer patients who received IV Vit-C as their main medicines. During Vit-C uptake, the patients were also given other materials including vitamins, minerals, and botanicals. It was claimed that the cases are analyzed following the National Cancer Institute (NCI) Best Case Series procedures. Histopathologic tests found weak prognoses for these patients. But the survival period of these patients went up after being treated with IV Vit-C [61]. Vit-C was given from 15 g to 65 g, once or twice a week, for several months to these patients. Two studies demonstrated that IV Vit-C treatment helps to improve the quality of life and decreases the side effects associated with cancer [62,63].

Systematic studies identified that the doses of Vit-C to volunteers or cancer patients can be up to 1.5 g/kg. No toxicity risks were seen (for example, glucose-6-phosphate dehydrogenase deficiency, renal diseases or urolithiasis). These studies identified that plasma concentrations of Vit-C can be much higher with IV administration than that of oral administration. The concentration was maintained for approximately 4 h [46,47].

A phase I study investigated the safety and efficiency of dual drug therapy by combining IV ascorbate with gemcitabine and erlotinib in stage IV pancreatic cancer patients. Fourteen subjects were evaluated in this study. The patients received IV gemcitabine (1000 mg for 30 min, once a week for 7 weeks), oral erlotinib (100 mg daily for 8 weeks), and IV ascorbate (50 g/infusion, 75 g/infusion, or 100 g/infusion 3 times per week for 8 weeks). No adverse effects were observed for ascorbic acid treatment. Five subjects received fewer than 18 of the proposed 24 ascorbate infusions. In three patients the disease was continued. Imaging tests were performed on nine patients to assess tumor size. This showed that the health situation was stable in each of them [64].

A 2013 phase I clinical investigation studied the effects of combining ascorbate with gemcitabine in the treatment of stage IV pancreatic cancer. During each 4-week cycle, patients were given gemcitabine weekly for 3 weeks and ascorbate for 4 weeks with a specific dose. This study found a progression-free and overall survival period. The combination of drug treatment was acceptable well [54].

In 2014, a phase I/IIA clinical trial measured the toxicities of two systems. The first one was combined IV ascorbate with carboplatin and the second one was ascorbate paclitaxel in stage III/IV ovarian cancer. More than 24 patients were chosen to receive either chemotherapy alone or chemotherapy and IV Vit-C. The chemotherapy was given for 6 months and IV Vit-C was continued for 12 months. Interestingly, IV Vit-C reduced chemotherapy-related toxicities [65].

A phase I/II clinical trial of high-dose IV Vit-C with numerous chemotherapeutic agents was conducted in 2015. This study was performed to evaluate multiple factors. Some important targets were to evaluate associated adverse effects, to determine the pharmacokinetic activities of Vit-C, to understand the clinical potential, to evaluate changes in mood and behavior and to assess the lifestyle [66].

A high-dose of IV Vit-C was analyzed in 14 patients. The procedures performed were tolerated well and were safe. A few temporary side effects were seen: increased urinary flow, thirst, nausea, vomiting, and chilling. It was important to note that an administration of chemotherapeutic agents did not alter the plasma concentration of Vit-C. A few patients were benefitted from this treatment because they experience temporary stable disease, demonstrate more activity with additional energy. However, since the group was small, no general conclusions from this study were drawn [66].

Recently, [67], a phase I study was evaluated to evaluate the safety, bioavailability, and efficiency of high-dose IV Vit-C in combination with chemotherapy regimens mFOLFOX6 or FOLFIRI. These were a combination of well-known agents: oxaliplatin, leucovorin, and 5-fluorouracil or leucovorin, 5-fluorouracil and irinotecan hydrochloride. This study was conducted on 36 patients with metastatic colorectal or gastric cancer. The principal aims were to evaluate the maximum-tolerated dose. Another goal was to determine the phase II dose of ascorbic acid with co-administration with mFOLFOX6 or FOLFIRI. Initially, all patients were given an identical chemotherapy treatment for 14 days with Vit-C infusions. Later, the concentration of ascorbic acid was altered for the dose-escalation investigation. This study demonstrated no dose-limiting toxicity. Therefore, a maximum-tolerated dose was not identified from this investigation. However, a dose of 1.5 g/kg for ascorbic acid was recommended for this phase II study. No adverse side effects were observed and the treatments were acceptable to the patients. Based on the success, a randomized phase III investigation is under progress. The goal of this study is to determine the clinical power of ascorbic acid against metastatic colorectal cancer in combination with mFOLFOX6 with or without bevacizumab [67].

Several studies were performed small doses of IV ascorbic acid treatment (1000 mg) with arsenic trioxide regimens, and mixed results were obtained [[68], [69], [70]].

Clinical investigations of ascorbate in combination with arsenic trioxide were reported [36]. Patients with non-small cell lung carcinoma (NSCLC) and glioblastoma multiforme (GBM) were treated in two clinical trials [71,72]. The patients in both of these trials were undergone conventional therapy along with IV Vit-C. IV Vit-C was administered under radiation therapy and in the presence of temozolomide. The toxicity and overall survival rate of the patients were favorable. The NSCLC clinical trial was a phase II procedure that has 14 patients with advanced cancer. These patients were also given both chemotherapy and IV Vit-C. The results of this investigation were also favorable.

Many trials with IV Vit-C in a combination with other medicines are under active investigation. Accordingly, 5 trials are being conducted by scientists at Iowa University, 4 phase II studies and 1 phase IB/II trial. The 4 phase II clinical trials are focused to identify the efficiency of high-dose ascorbic acid combined with common anticancer molecules. These studies with ascorbate are also progressing with many cancer cell lines. These include studies on non-small cell lung cancer therapy under radiation therapy and in the presence of carboplatin and paclitaxel; metastatic pancreatic adenocarcinoma in the presence of gemcitabine and nab-paclitaxel; pancreatic adenocarcinoma in the presence of gemcitabine and radiation therapy, and glioblastoma in the presence of temozolomide and radiation therapy. Another phase IB/II trial is investigating the safety and clinical performance of high-dose ascorbate with radiation therapy against soft tissue sarcoma.

Numerous studies used IV ascorbic acid at a fixed dose of 1000 mg with various amounts of arsenic trioxide as anticancer therapy. It was expected that the pro-oxidant character of IV ascorbic acid can improve the effects of arsenic trioxide by a sensitization process of the malignant cells to arsenic’s cytotoxic nature [72]. The combination therapies worked well. Some benefits against multiple myeloma were observed. However, the role of Vit-C in this was not determined [[73], [74], [75]]. In contrast, similar combination regimens were not effective and resulted in side effects, including the progression of the disease with particular cancer. Moreover, no anticancer effects against metastatic colorectal cancer [76] and metastatic melanoma were determined [77]. Since these trials were not placebo-controlled, the role of ascorbic acid to the results is unclear.

Intravenous (IV) high-dose ascorbic acid was well-tolerated in clinical trials [46], [78], [74], [71], [73], [64]. It was speculated that ascorbic acid may accelerate renal failure in patients with preexisting renal disorders [49]. Glucose-6-phosphate dehydrogenase (G-6-PD) deficient patients were not good candidates to have high doses of Vit-C due to hemolysis [[50], [51], [52]]. Vit-C was able to improve the bioavailability of iron. A large dose of Vit-C was not recommended for patients with hemochromatosis [53].

Vit-C in high doses reacted with a few anticancer compounds. These interactions were detected in preclinical studies. A phase I clinical investigation examined the feasibility of using high-dose IV ascorbate and gemcitabine in stage IV pancreatic cancer patients. It was important to know that the combination formula was well tolerated by patients. No adverse effects were observed [54].

In vitro and in vivo animal studies indicated ascorbate can alter the mechanism of the drug. For example, ascorbate with bortezomib altered the action of the medicine as a proteasome inhibiting agent and blocked bortezomib-mediated cell death [[55], [56], [57]]. This interaction was observed with a low concentration of Vit-C (40 mg/kg/day) to animals. The cell culture study on blood plasma with Vit-C (1 g/day) also demonstrated a large decrease in bortezomib’s growth inhibitory effect against multiple myeloma cells. The plasma of healthy volunteers was analyzed. Bortezomib growth inhibition on multiple myeloma cells was observed when a person takes 1 g of oral Vit-C per day. This amount had blocked the drug’s inhibitory properties against the 20S proteasome [57]. On the other hand, a study that utilized mice harboring human prostate cancer cell xenografts did not find any good effect of oral Vit-C (40 mg/kg/day or 500 mg/kg/day) on the tumor growth inhibitory action of this medicine [58]. Studies showed that dehydroascorbic acid, an oxidized form of Vit-C alters the cytotoxic properties of some chemotherapy drugs [59]. But, the concentration of dehydroascorbic acid is found to be low in dietary supplements and foods.

Despite some controversial results over the years, Vit-C had proven to have anticancer effects when given intravenously at high concentrations [79]. Some reports on the anticancer activities of Vit-C were dependent on the use of immune-deficient mice. These studies were conducted to examine the direct effects of ascorbate on tumors. It was found that the effects of Vitamin C are much stronger in the presence of an intact immune system [79]. These observations suggested a combination treatment which requires evaluation in patients.

3. Treatment of viral infections

The antiviral properties of Vit-C were recently reviewed [80]. Vit-C was used for the treatment of hypovitaminosis C in malnourished patients. A combination of hydrocortisone, ascorbic acid, and thiamine (HAT therapy) worked well in the treatment of patients with sepsis and septic shock [81]. There were 29 ongoing or completed clinical trials with Vit-C administration in sepsis. The effectiveness of Vit-C in preventing common cold [82] and other health disorders was questioned [83,84]. The ascorbic acid therapy for acute inflammatory disorders was based upon numerous biological studies following many decades of research. The current interest in Vit-C focuses on bacterial sepsis and septic shock in patients. More than 300 scientific and clinical studies supported mechanistic data to use Vit-C against this disease [85,86]. Some other additional role of Vit-C in the treatment of viral diseases is also possible. The biological concepts and evidence for the use of Vit-C in viral infections are described here.

Numerous studies identified that Vit-C in high dosages is virucidal [83]. This conclusion was based on in-vitro experiments. In the presence of copper and/or iron, high doses of Vit-C showed virucidal activity. This was explained through the formation of hydrogen peroxide and other radical initiators [87,88]. Moreover, the low pH value of the system was responsible for the in-vitro antiviral effects of Vit-C. Despite these studies, the in vivo virucidal activity of Vit-C was not confirmed. It was well established that Vit-C is a powerful antioxidant and it can exert pro-oxidant effects at high concentrations. The generation of reactive oxygen species through the reduction of transition metal is possible [89]. It was found that a very high-dose of one sodium salt of ascorbic acid (90 mM) kills Candida albicans in-vitro through an iron-catalyzed Fenton reaction [90]. An iron chelator 2,2′-bipyridyl inhibited this effect. An experiment demonstrated that Vit-C can decrease the viral load of the Ebstein-Barr virus (EBV) [91]. This observation suggested multiple mechanisms are involved in Vit-C-controlled anti-vital therapy. The activity of antigens and load was reduced through pre-treatment of human foreskin fibroblast and endothelial cells with ascorbate before cytomegalovirus (CMV) infection [92]. This observation was failed to reproduce when ascorbate is added after the infection. The immunomodulatory activities of Vit-C were responsible for this effect. In general, Ascorbic acid is concentrated in leucocytes, lymphocytes, and macrophages [93,94]. Chemotaxis was improved by Vit-C [[95], [96], [97]]. The neutrophil phagocytic activity and oxidative death were also enhanced [[95], [96], [97]]. Lymphocyte proliferation was also accelerated [[95], [96], [97]].

The rate-determining last step of ascorbic acid biosynthesis in animals is l-Gulono-γ-lactone oxidase or the isomeric Gulo form. Mutations in the gene of this enzyme prevented anthropoid primates and guinea pigs to synthesize this molecule. The effects of Vit-C in viral infections were studied via a Gulo (-/-) knockout mice system. It was shown that nasal inoculation of the h4N2 influenza virus is fatal in Gulo (-/-) mice in comparison to wild type mice [97]. Anti-viral cytokine interferon (IFN)-α/β became lower. However, the viral titers in the lung of ascorbic acid-insufficient Gulo (-/-) mice became more abundant [97]. The pro-inflammatory cytokines, tumor necrosis factor (TNF), interleukin-1 (IL-1)-α/β, and infiltration of inflammatory cells was increased in the lung. These results were corrected in Gulo (-/-) mice repleted with ascorbic acid before viral exposure occurs. Most probably, an impaired phosphorylation process of signal transducers and activators of transcription (STATs) was responsible for the decreased generation of IFN in Gulo (-/-) mice [98]. It was found that Gulo (-/-) mice as compared to wild type mice have an impaired immune response with higher lung pathological dysfunction when exposed to influenza h2N1 virus [98]. It was shown that restraint-stressed mice with h2N1-induced pneumonia have a dose-dependent reduction of mortality in the presence of ascorbate. Histopathological lung sections also demonstrated reduced problems in the treated mice [99]. An administration of Vit-C was helpful to recover mitochondrial membrane potential and gene expression of pro-inflammatory cytokines. Ascorbic acid was reported to have clinical activity against numerous other viruses including poliovirus, Venezuelan equine encephalitis, human lymphotropic virus type 1 (HTLV-1), human immunodeficiency virus (HIV) and rabies virus in addition to demonstrating activity against influenza and herpes virus [[100], [101], [102], [103], [104], [105], [106], [107]].

It is known that most of the infections activate phagocytes with the generation of reactive oxygen species (ROS). The ROS has a key role in deactivating viruses. Some of the ROS harm the host cells that cause viral-induced host injury. Respiratory syncytial virus (RSV) infects the upper and lower respiratory tract in infants and children. RSV infection of airway epithelial cells accelerates ROS production and this inhibits the concentration of the lung antioxidant enzymes. The oxidant-antioxidant amount and proportion in cells are critical to RSV pulmonary toxicity [108]. Lung pulmonary inflammation and injury are considerably reduced by the administration of antioxidants [109]. Ascorbic acid is a powerful antioxidant and therefore, it scavenges oxygen free radicals and restores other cellular antioxidants. These include tetrahydrobiopterin and α-tocopherol [94]. The hypothesis that Vit-C may become beneficial in the treatment of viral infections is based on two concepts. Patients with infectious diseases do not have a sufficient level of Vit-C due to metabolic consumption [110]. Vit-C has immunomodulating properties in patients with viral infections. This is possible by increasing the production of α/β interferons and downregulating the synthesis of pro-inflammatory cytokines. Despite that Vit-C have beneficial effects in viral infections no solid clinical data exists on this topic. Pauling suggested that Vit-C can be used for the treatment of the common cold. On this basis, most of the randomized controlled trials (RCTs’) targeted the role of Vit-C in the prevention and treatment of the cold symptoms. In an analysis of 29 RCTs, Vit-C failed to reduce cold disease [82]. No consistent effects of Vit-C were observed also on the duration of colds in patients. Several studies, however, complicated the interpretation of these data.

Ascorbic acid may have clinical effects in patients with infections caused by herpes viruses. Herpes zoster (HZV) infection takes place due to the reactivation of the latent Varicella-Zoster virus (VZV). This is particularly predominant because of the loss of cell-induced immunity with age. The concentration of ascorbic acid in plasma is decreased in post-herpetic neuralgia patients compared to healthy persons [111]. An RCT study was conducted with 41 patients who were subjected to IV Vit-C (50 mg/kg on days 1, 3 and 5) or placebo [111]. It was found that those patients who were taken IV Vit-C have experienced less pain. In a non-blinded RCT, the role of ascorbic acid on acute herpetic pain and postherpetic neuralgia were evaluated [112]. Eighty-seven patients were given 5 g of IV ascorbic acid on the first, third and fifth days or placebo. Interestingly, a few differences between the groups were observed. The treated group with Vit-C demonstrated a lower incidence of postherpetic neuralgia and a lower pain score. Vit-C is mostly concentrated in the aqueous humor of the anterior chamber of the eye. A retrospective cohort investigation indicated that oral Vit-C reduced the risk of herpes simplex keratitis in combination with an oral antiviral drug [111].

It was concluded only a few months before the start of the CoV19 epidemic that there is an urgent need for novel research about the application of IV Vit-C, targeting the management of infectious diseases [80]. Influenza A virus causes epidemics and pandemics that kill thousands of people every year. Experimental studies demonstrate a beneficial effect of ascorbic acid against influenza. Patients with respiratory disorders due to infection by influenza were treated with histone acetyltransferase (HAT) without corticosteroids. Remarkably, these patients showed rapid improvement after the initiation of HAT. Corticosteroids, on the other hand, have a complex role in the treatment of infection. As a result, corticosteroids may not be a standard choice in patients with influenza A infection [113,114]. Effective clinical trials are necessary to investigate the use of Vit-C against infections due to influenza, RSV, herpes, and other viral illnesses.

A large dose of IV ascorbic acid can be one treatment of choices for Covid19 pneumonia [115]. A report on this disease indicates the severity. For example, a 26 % ICU admission and a 4.3 % mortality rate are observed among 138 cases [116]. It is believed that ARDS is the main mechanism for Covid19′s action. This is followed by increased oxidative stress because of the release of free radicals and cytokines. Considering this mechanism of the process, a large dose of Vit-C should play a key role in the management of Covid19. A study indicates out of 99 Covid19 patients, 17 of them developed ARDS [117]. Eleven patients passed away due to multiple organ failure [117]. This death was explained due to increased oxidative stress and cytokine generation that lead to ARDS. Like influenza, coronaviruses are pandemic viruses that injure lung drastically [118]. This viral infection generates a “storm” of cytokines that reacts with the endothelial cells of the lung. This interaction causes neutrophil infiltration and enhances oxidative stress and damages the function of the lung barrier [118]. ARDS is characterized by strong hypoxemia. This is propagated because of multiple reasons. Uncontrolled inflammation, oxidative injury, and damage to the alveolar-capillary barrier are the main reasons [119]. The severe increased oxidative stress causes pulmonary injuries: lung injury (ALI) and ARDS. ALI and ARDS are key factors responsible for substantially high morbidity and mortality [120,121]. An increase of C-reactive protein (hsCRP), an indicator of inflammation and oxidative stress is seen among Covid19 patients [122]. The transcription factor nuclear factor-erythroid-2–related factor 2 (Nrf2) is a major regulator of antioxidant response element (ARE) driven cytoprotective protein expression. It is believed that the activation of Nrf2 signaling pathways plays a crucial role in preventing cells and tissues to undergo oxidative stress.

Ascorbic acid is a key compound of the antioxidant system in cells and tissues [123]. The biological and medicinal properties of Vit-C in critical care management are documented [124]. It is now accepted that both viral and bacterial infections result in the production of excess cytokine [118]. Antioxidants should be given to control pandemics (Covid19) because of the non-availability of pathogen-specific vaccines and drugs. This is further strengthened by the fact that a large dose of IV Vit-C has shown successful clinical results in viral ARDS and influenza [125].

A report is known that a 26-year-old woman developed viral ARDS (rhinovirus and enterovirus-D68) [118]. She was admitted to ICU and was not responsive to routine treatment. She was then placed on ECMO on day 3, a high dose of IV (200 mg/kg body/24 h, 4 doses, one every 6 h) was initiated on ECMO. Amazingly, the lungs of the patients showed excellent improvement on day 2 of high dose IV Vit-C infusion. This improvement was characterized by X-ray imaging. She was then continued to improve and was discharged from the hospital, without the requirement of additional oxygen. After a month, X-ray of her lungs indicated a complete cure. A severe medical problem of influenza was treated with high dose IV Vit-C successfully [125]. A young patient was recommended to take a high dose of IV Vit-C (50,000 mg of Vit-C in 1000 ml Ringer’s solution, infused over 90 min) and the condition of the patient improved notably by the next day. He was continued to take oral VC (2000 mg twice daily) [125].

The protective action of ascorbic acid is shown in [126]. A high dose IV Vit-C was used in 2009 to treat a New Zealand farmer (Primal Panacea) [127]. Vit-C was able to cut down ICU stay through an analysis of 18 clinical studies on 2004 ICU patients [128]. It was found that 17,000 mg/day IV Vit-C had shortened the ICU stay by 44 %. The use of IV Vit-C in 47 sepsis ICU cases was reported and a major reduction in death was possible [129]. Dietary antioxidants (Vit-C and sulforaphane) were helpful to manage oxidative-stress-induced acute inflammatory lung injury that requires mechanical ventilation [130]. Another antioxidant, natural curcumin has also been effective against inflammation that caused during pneumonia [131]. National Institutes of Health (NIH) states that high dose IV Vit-C (1.5 g/kd body weight) is safe for good health and without side effects [116].

4. Discussion and conclusions

Over the past century, the opinion that Vit-C can be used to treat cancer and viral infection has shown promises and controversies. There are cases where high dose Vit-C has shown benefits. In some cases, there have been no benefits. However, new knowledge regarding the pharmacokinetic properties of Vit-C, and recent preclinical studies, have revived interest in the utilization of high-dose Vit-C for cancer treatment [[132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145]]. Similar is the case of using IV Vit-C as antiviral, especially for the recent Covid19 [[146], [147], [148], [149], [150]]. It is believed that IV Vit-C has been particularly effective by inhibiting the production of cytokines storm due to Corvid19.

Covid19 pneumonia is an extremely rapidly developing disease with a high mortality rate. The main pathogenesis is the acute lung injury that causes ARDS and death. Antioxidants should have a role in the management of these conditions. Appropriate clinical studies and reports demonstrate that a timely administration of high dose IV Vit-C improves the outcome of Covid19 infection.

Additional studies detailing the use of IV Vit-C for the treatment of severe Covid19 infected pneumonia are definitively warranted. Covid19 may continue to happen in the future. Since the development of clinically active vaccines or antiviral drugs targeting specific diseases may take a long time to develop, the use of IV Vit-C as a universal agent for ARDS may have benefits behind Covid19. Additional clinical studies of the IV Vit-C and oral VC (such as liposomal-encapsulated VC) targeting other situations through different mechanisms are required to develop as soon as possible.

Author contributions

A.B. wrote the first draft of the manuscript. B.K.B. first revised the manuscript. Both authors further improved the manuscript.

Declaration of Competing Interest

The authors received no funding and have no conflict of interest to declare.

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Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome

PharmaNutrition. 2020 Jun; 12: 100190.

Prince Mohammad Bin Fahd University, P.O. Box 1664, Al Khobar, 31952, Saudi Arabia

Corresponding author.

Received 2020 Mar 31; Revised 2020 Apr 5; Accepted 2020 Apr 6.

Copyright © 2020 Elsevier B.V. All rights reserved.

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Abstract

The recent outbreak of Covid19 has required urgent treatments for numerous patients. No suitable vaccines or antivirals are available for Covid19. The efficiency against Covid19 of WHO therapies of choice, that are two antivirals developed for other pathologies, is controversial. Therefore, alternative approaches are required. Intravenous (IV) Vitamin C (Vit-C) has emerged as one of the other alternatives for this purpose. Here we review the effects of IV Vit-C on the immune system response, the antiviral properties of IV Vit-C, and finally the antioxidant properties of IV Vit-C to specifically address the cytokines’ storm characteristic of the Acute Respiratory Distress Syndrome (ARDS) that occur in the later cycle of the Covid19 infectious disease.

Keywords: Vitamin C, Severe acute respiratory syndrome coronavirus, Antiviral agents, Covid19, Cytokines

1. Introduction

The recent outbreak of Covid19 has required urgent treatments for numerous patients. The Covid19 originated in Wuhan, China has spread to other continents and has caused significant harm to the public.
represents a transmission electron microscope image of Covid19 along with a 3D structure of coronavirus. No suitable vaccines or antiviral drugs exist against Covid19. At the time of writing (15 March 2020), Coronavirus cases were already 173,085 (+19 % over the last 24 h, +5% the day before), with 6664 deaths (+23 % over the last 24 h, +6% the day before) vs. 77,784 recovered (+6% over the last 24 h), with some improvements in China. However, the condition is deteriorating in Western Europe, especially Italy. No cure for Covid19 is known at this time. In addition to administering oxygen, current treatments recommended by the World Health Organization (WHO) for the serious, critical cases of Covid19 include Remdesivir, Kaletra, and Kaletra plus Interferon (France24, “Conquering the coronavirus: the most pressing goal for these researchers in Paris”, youtu.be/L0wRSKnIErk). Remdesivir is an antiviral nucleotide developed as a treatment for the Ebola virus and Marburg virus infections. Kaletra is a combination of Lopinavir and Ritonavir (LPV/r). This is also used as antiviral nucleotide analogs developed for the treatment of HIV/AIDS. The third option is a combination of Kaletra with Interferon. Interferons are signaling proteins (cytokines) that infected cells produce and release in response to viruses. Interferons activate other cells of the immune system so that a stronger immune system response can be achieved. Interferon alphas are specifically recommended for viral infections and some cancers. The efficacy of these processes for Covid19 is controversial. Therefore, alternative approaches are urgently needed.

In China, the death rate was peaked at 3% a few weeks ago but is now declined to 0.7 %. Good results are obtained using Interferon Alpha 2B (IFNrec) without any combination with Kaletra. The use of Intravenous (IV) Vitamin C (Vit-C) has shown promise in this area in China. The IV Vit-C (or Ascorbic acid) protocols are mentioned in clinicaltrials.gov, for Covid19 and other pathologies. Shanghai now utilizes IV Vit-C in the treatment for Covid-19. Many physicians in China have identified promising results using IV Vit-C against Covid19. Thus, there is a need to urgently review the uses of IV Vit-C, pre- and post-infection, and during different stages of the infection. IV Vit-C is helping to develop a stronger immune system response, reducing the cytokines storm, or increasing antiviral activities through other unknown mechanisms.

Perhaps, the reduction of the cytokines storm in the late stages of the Covid19 infection is the most significant application of IV Vit-C. Covid19 pneumonia is a complex medical disorder with high morbidity and mortality rate. This causes severe lung injury that results in Acute Respiratory Distress Syndrome (ARDS), a life-threatening lung disorder. This process prevents the necessary oxygen to enter into the lungs and ultimately causes death. Coronaviruses increase oxidative stress that promotes cellular malfunction and ultimately results in organ failure. It is believed that pulmonary failure (ARDS) is the principal cause of Covid19′s action on humans. This helps to increase oxidative stress considerably because of the generation of free radicals and cytokines. This process finally leads to serious cellular injury, organ failure and death. The administration of anti-oxidizing agents along with proven conventional supportive therapies is believed to have an important role in controlling these medical situations. Appropriate vaccines and antiviral drugs for the Covid19 epidemic are not available. IV Vitamin C and other antioxidants are extremely good agents for ARDS. These can be applied clinically. Importantly, high dose IV Vit-C is safe and effective. In this paper, we review the use of high-dose Vit-C as an efficient method of treatment for patients with cancers and infections.

The antiviral properties of Vit-C help to reduce symptoms and mortality in children and adults [[1], [2], [3], [4]]. The antiviral activities of ascorbic acid was known and it was published almost 80 years ago [[5], [6], [7], [8], [9]] when scientists were involved in work on poliomyelitis. Moreover, the use of ascorbic acid as a medicinally crucial agent against various diseases was also well established [[10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]]. Applications of Vit-C are found in poliomyelitis [[22], [23], [24], [25], [26]]. Many other uses of Vit-C include hepatitis, herpes, chickenpox and measles, infectious mononucleosis, trichinosis, urethritis, Antabuse, arthritis, and cancer. Vit-C is also helpful for the treatment of elevated cholesterol and arteriosclerosis, [[27], [28], [29], [30], [31], [32]], corneal ulcers, glaucoma, burns, heatstroke, sunburn, slipped disc, toxins, and heavy metal poisonings [[33], [34], [35]]. The appropriate clinically effective vaccines and specific antivirals may serve effectively if they are available. Considering the current situation, the use of Vit-C as an antiviral agent should also be considered. Notably, Vit-C can be used alone or in combination with other available medicines to exert positive synergistic effects. Here we review the principal mechanism of actions of IV Vit-C that helps to make the immune system stronger, reduces the cytokines storm and inhibits oxidative processes. Under the first criteria, literature knowledge on cancer treatment will be reviewed first. Then, the antiviral properties will be reviewed, with focusing on the reduction of the oxidative pathways typical of the Covid19 ARDS.

2. Cancer treatment

A review of laboratory, animal and human studies and current clinical trials is provided regarding cancer treatments [36]. Vit-C is a crucial nutrient with redox properties, a cofactor of numerous enzymes, and it plays an important role in the synthesis of collagen [37]. A deficiency of Vit-C may result in scurvy [38]. Scurvy can cause collagen structure narrow and thin. It has been found that normal healthy situation can be maintained with the administration of Vit-C. In the mid-20th century, a study hypothesized that cancer can originate due to the alterations of the structures in connective tissues caused by Vit-C deficiency [39]. A review suggested that a high-dose of ascorbic acid can enhance host resistance. This study also identified the use of ascorbic acid in cancer therapy [40]. In general, Vit-C is synthesized from isomeric sugars d-glucose or d-galactose by numerous plants and animals. Interestingly, humans lack the enzyme l-gulonolactone oxidase which is required for ascorbic acid synthesis. On this basis, humans need Vit-C through food or other supplements [37].

Vit-C is an essential nutrient with redox properties in normal physiological situations [36]. Some cancer patients were treated successfully with high-dose of oral and/or IV Vit-C. However, two early randomized placebo-controlled studies of high-dose oral Vit-C (10 g/d) indicated no significant effects against cancers. These studies indicated marginal medical benefits between ascorbate- and placebo-treated groups. Laboratory experiments reported that high-dose of Vit-C can decrease cell proliferation in prostate, pancreatic, colon, mesothelioma, and neuroblastoma cancer cell lines. Studies of Vit-C combined with other medicines in animal models demonstrated inconclusive results. Importantly, IV Vit-C was well-tolerated in clinical trials. An IV administration of Vit-C (500 mg) was found to be more effective than oral administration since a higher blood concentration of ascorbate was found through the IV route. A study with Vit-C as ascorbate versus ascorbate formulations along with standard cancer therapies was performed in clinical trials. Two studies of high-dose Vit-C confirmed a better quality of life and fewer cancer-related toxicities. These results from preclinical and clinical trials of high-dose Vit-C with and without standard cancer therapies are note-worthy. However, it may be challenged that these investigations have a few shortcomings.

The use of high-dose Vit-C (IV and oral) for the management of cancer was started five decades ago [41]. The application of Vit-C therapy in the treatment of various cancers was promoted [42,43]. For example, two clinical trials of Vit-C were conducted many years ago [44,45]. Pharmacokinetic experiments identified considerable differences in the maximum achieved blood concentrations of Vit-C. It was found that the nature of the route of delivery was relevant. For example, if Vit-C was taken orally, plasma concentrations are controlled with a peak achievable concentration of less than 300 μM. However, this control was bypassed with IV administration of the vitamin, resulting in a very high level of Vit-C plasma concentration (up to 20 mM) [46,47]. Additional research suggested that pharmacological concentrations of ascorbate as achieved with IV administration may result in cell death in numerous cancer cell lines [48]. Health care practitioners who had participated in complementary and alternative medicine conferences in 2006 and 2008 were debated on the benefits/risks of high-dose IV Vit-C in patients. A total of 199 participants were chosen and out of which 172 were taken Vit-C. Specifically, IV Vit-C was recommended to fight against infection, cancer, and fatigue [49].

In the early 1970s, a case study was conducted with 50 cancer patients who were taken a high dose of ascorbic acid [41]. Conventional therapies were applied to these patients, but these were not successful. On this basis, these patients were recommended to take ascorbic acid. Different doses and schedules were used. For example, some patients were given IV ascorbic acid (10 g/day for 10 successive days), a few were given higher dose amounts, and some were chosen to give oral ascorbic acid (10 g/day) or a combination of both. A wide variety of responses were found. Dome of them had no or minimal response and some of them had tumor regression and tumor hemorrhage. Despite this important observation, a lack of control study prevented making any conclusion on the health benefits of ascorbic acid treatment. From a limited study published in 1975, it is apparent that one of the patients experienced tumor regression [60]. The patient who had reticulum cell sarcoma exhibited improvement due to the treatment with ascorbic acid. A reduction of the daily dose of ascorbic acid was not helpful since symptoms of the disease appeared. Notably, remission was successfully achieved again after the same patient was given a higher initial dose of ascorbic acid.

A larger study of terminal cancer patients treated with ascorbate was conducted in 1976. In this investigation, 100 terminal cancer patients [41] were given ascorbate through an acceptable and scientific way (10 g/day for 10 days IV, then repeated orally). The health conditions of these patients were evaluated concerning 1000 matched control patients from the same clinic. Interestingly, the average survival time for ascorbate-treated patients was considerably much higher (300 days) than that of the matched control group [42,43].

Two randomized investigations using placebo-controlled trials were performed. In these studies, cancer patients were taken either 10 g of oral Vit-C or placebo daily until signs of cancer go away. At the end of these investigations, no significant differences in clinical results were found between the two ascorbate- and placebo-treated groups [44,45].

A study disclosed three case reports on cancer patients who received IV Vit-C as their main medicines. During Vit-C uptake, the patients were also given other materials including vitamins, minerals, and botanicals. It was claimed that the cases are analyzed following the National Cancer Institute (NCI) Best Case Series procedures. Histopathologic tests found weak prognoses for these patients. But the survival period of these patients went up after being treated with IV Vit-C [61]. Vit-C was given from 15 g to 65 g, once or twice a week, for several months to these patients. Two studies demonstrated that IV Vit-C treatment helps to improve the quality of life and decreases the side effects associated with cancer [62,63].

Systematic studies identified that the doses of Vit-C to volunteers or cancer patients can be up to 1.5 g/kg. No toxicity risks were seen (for example, glucose-6-phosphate dehydrogenase deficiency, renal diseases or urolithiasis). These studies identified that plasma concentrations of Vit-C can be much higher with IV administration than that of oral administration. The concentration was maintained for approximately 4 h [46,47].

A phase I study investigated the safety and efficiency of dual drug therapy by combining IV ascorbate with gemcitabine and erlotinib in stage IV pancreatic cancer patients. Fourteen subjects were evaluated in this study. The patients received IV gemcitabine (1000 mg for 30 min, once a week for 7 weeks), oral erlotinib (100 mg daily for 8 weeks), and IV ascorbate (50 g/infusion, 75 g/infusion, or 100 g/infusion 3 times per week for 8 weeks). No adverse effects were observed for ascorbic acid treatment. Five subjects received fewer than 18 of the proposed 24 ascorbate infusions. In three patients the disease was continued. Imaging tests were performed on nine patients to assess tumor size. This showed that the health situation was stable in each of them [64].

A 2013 phase I clinical investigation studied the effects of combining ascorbate with gemcitabine in the treatment of stage IV pancreatic cancer. During each 4-week cycle, patients were given gemcitabine weekly for 3 weeks and ascorbate for 4 weeks with a specific dose. This study found a progression-free and overall survival period. The combination of drug treatment was acceptable well [54].

In 2014, a phase I/IIA clinical trial measured the toxicities of two systems. The first one was combined IV ascorbate with carboplatin and the second one was ascorbate paclitaxel in stage III/IV ovarian cancer. More than 24 patients were chosen to receive either chemotherapy alone or chemotherapy and IV Vit-C. The chemotherapy was given for 6 months and IV Vit-C was continued for 12 months. Interestingly, IV Vit-C reduced chemotherapy-related toxicities [65].

A phase I/II clinical trial of high-dose IV Vit-C with numerous chemotherapeutic agents was conducted in 2015. This study was performed to evaluate multiple factors. Some important targets were to evaluate associated adverse effects, to determine the pharmacokinetic activities of Vit-C, to understand the clinical potential, to evaluate changes in mood and behavior and to assess the lifestyle [66].

A high-dose of IV Vit-C was analyzed in 14 patients. The procedures performed were tolerated well and were safe. A few temporary side effects were seen: increased urinary flow, thirst, nausea, vomiting, and chilling. It was important to note that an administration of chemotherapeutic agents did not alter the plasma concentration of Vit-C. A few patients were benefitted from this treatment because they experience temporary stable disease, demonstrate more activity with additional energy. However, since the group was small, no general conclusions from this study were drawn [66].

Recently, [67], a phase I study was evaluated to evaluate the safety, bioavailability, and efficiency of high-dose IV Vit-C in combination with chemotherapy regimens mFOLFOX6 or FOLFIRI. These were a combination of well-known agents: oxaliplatin, leucovorin, and 5-fluorouracil or leucovorin, 5-fluorouracil and irinotecan hydrochloride. This study was conducted on 36 patients with metastatic colorectal or gastric cancer. The principal aims were to evaluate the maximum-tolerated dose. Another goal was to determine the phase II dose of ascorbic acid with co-administration with mFOLFOX6 or FOLFIRI. Initially, all patients were given an identical chemotherapy treatment for 14 days with Vit-C infusions. Later, the concentration of ascorbic acid was altered for the dose-escalation investigation. This study demonstrated no dose-limiting toxicity. Therefore, a maximum-tolerated dose was not identified from this investigation. However, a dose of 1.5 g/kg for ascorbic acid was recommended for this phase II study. No adverse side effects were observed and the treatments were acceptable to the patients. Based on the success, a randomized phase III investigation is under progress. The goal of this study is to determine the clinical power of ascorbic acid against metastatic colorectal cancer in combination with mFOLFOX6 with or without bevacizumab [67].

Several studies were performed small doses of IV ascorbic acid treatment (1000 mg) with arsenic trioxide regimens, and mixed results were obtained [[68], [69], [70]].

Clinical investigations of ascorbate in combination with arsenic trioxide were reported [36]. Patients with non-small cell lung carcinoma (NSCLC) and glioblastoma multiforme (GBM) were treated in two clinical trials [71,72]. The patients in both of these trials were undergone conventional therapy along with IV Vit-C. IV Vit-C was administered under radiation therapy and in the presence of temozolomide. The toxicity and overall survival rate of the patients were favorable. The NSCLC clinical trial was a phase II procedure that has 14 patients with advanced cancer. These patients were also given both chemotherapy and IV Vit-C. The results of this investigation were also favorable.

Many trials with IV Vit-C in a combination with other medicines are under active investigation. Accordingly, 5 trials are being conducted by scientists at Iowa University, 4 phase II studies and 1 phase IB/II trial. The 4 phase II clinical trials are focused to identify the efficiency of high-dose ascorbic acid combined with common anticancer molecules. These studies with ascorbate are also progressing with many cancer cell lines. These include studies on non-small cell lung cancer therapy under radiation therapy and in the presence of carboplatin and paclitaxel; metastatic pancreatic adenocarcinoma in the presence of gemcitabine and nab-paclitaxel; pancreatic adenocarcinoma in the presence of gemcitabine and radiation therapy, and glioblastoma in the presence of temozolomide and radiation therapy. Another phase IB/II trial is investigating the safety and clinical performance of high-dose ascorbate with radiation therapy against soft tissue sarcoma.

Numerous studies used IV ascorbic acid at a fixed dose of 1000 mg with various amounts of arsenic trioxide as anticancer therapy. It was expected that the pro-oxidant character of IV ascorbic acid can improve the effects of arsenic trioxide by a sensitization process of the malignant cells to arsenic’s cytotoxic nature [72]. The combination therapies worked well. Some benefits against multiple myeloma were observed. However, the role of Vit-C in this was not determined [[73], [74], [75]]. In contrast, similar combination regimens were not effective and resulted in side effects, including the progression of the disease with particular cancer. Moreover, no anticancer effects against metastatic colorectal cancer [76] and metastatic melanoma were determined [77]. Since these trials were not placebo-controlled, the role of ascorbic acid to the results is unclear.

Intravenous (IV) high-dose ascorbic acid was well-tolerated in clinical trials [46], [78], [74], [71], [73], [64]. It was speculated that ascorbic acid may accelerate renal failure in patients with preexisting renal disorders [49]. Glucose-6-phosphate dehydrogenase (G-6-PD) deficient patients were not good candidates to have high doses of Vit-C due to hemolysis [[50], [51], [52]]. Vit-C was able to improve the bioavailability of iron. A large dose of Vit-C was not recommended for patients with hemochromatosis [53].

Vit-C in high doses reacted with a few anticancer compounds. These interactions were detected in preclinical studies. A phase I clinical investigation examined the feasibility of using high-dose IV ascorbate and gemcitabine in stage IV pancreatic cancer patients. It was important to know that the combination formula was well tolerated by patients. No adverse effects were observed [54].

In vitro and in vivo animal studies indicated ascorbate can alter the mechanism of the drug. For example, ascorbate with bortezomib altered the action of the medicine as a proteasome inhibiting agent and blocked bortezomib-mediated cell death [[55], [56], [57]]. This interaction was observed with a low concentration of Vit-C (40 mg/kg/day) to animals. The cell culture study on blood plasma with Vit-C (1 g/day) also demonstrated a large decrease in bortezomib’s growth inhibitory effect against multiple myeloma cells. The plasma of healthy volunteers was analyzed. Bortezomib growth inhibition on multiple myeloma cells was observed when a person takes 1 g of oral Vit-C per day. This amount had blocked the drug’s inhibitory properties against the 20S proteasome [57]. On the other hand, a study that utilized mice harboring human prostate cancer cell xenografts did not find any good effect of oral Vit-C (40 mg/kg/day or 500 mg/kg/day) on the tumor growth inhibitory action of this medicine [58]. Studies showed that dehydroascorbic acid, an oxidized form of Vit-C alters the cytotoxic properties of some chemotherapy drugs [59]. But, the concentration of dehydroascorbic acid is found to be low in dietary supplements and foods.

Despite some controversial results over the years, Vit-C had proven to have anticancer effects when given intravenously at high concentrations [79]. Some reports on the anticancer activities of Vit-C were dependent on the use of immune-deficient mice. These studies were conducted to examine the direct effects of ascorbate on tumors. It was found that the effects of Vitamin C are much stronger in the presence of an intact immune system [79]. These observations suggested a combination treatment which requires evaluation in patients.

3. Treatment of viral infections

The antiviral properties of Vit-C were recently reviewed [80]. Vit-C was used for the treatment of hypovitaminosis C in malnourished patients. A combination of hydrocortisone, ascorbic acid, and thiamine (HAT therapy) worked well in the treatment of patients with sepsis and septic shock [81]. There were 29 ongoing or completed clinical trials with Vit-C administration in sepsis. The effectiveness of Vit-C in preventing common cold [82] and other health disorders was questioned [83,84]. The ascorbic acid therapy for acute inflammatory disorders was based upon numerous biological studies following many decades of research. The current interest in Vit-C focuses on bacterial sepsis and septic shock in patients. More than 300 scientific and clinical studies supported mechanistic data to use Vit-C against this disease [85,86]. Some other additional role of Vit-C in the treatment of viral diseases is also possible. The biological concepts and evidence for the use of Vit-C in viral infections are described here.

Numerous studies identified that Vit-C in high dosages is virucidal [83]. This conclusion was based on in-vitro experiments. In the presence of copper and/or iron, high doses of Vit-C showed virucidal activity. This was explained through the formation of hydrogen peroxide and other radical initiators [87,88]. Moreover, the low pH value of the system was responsible for the in-vitro antiviral effects of Vit-C. Despite these studies, the in vivo virucidal activity of Vit-C was not confirmed. It was well established that Vit-C is a powerful antioxidant and it can exert pro-oxidant effects at high concentrations. The generation of reactive oxygen species through the reduction of transition metal is possible [89]. It was found that a very high-dose of one sodium salt of ascorbic acid (90 mM) kills Candida albicans in-vitro through an iron-catalyzed Fenton reaction [90]. An iron chelator 2,2′-bipyridyl inhibited this effect. An experiment demonstrated that Vit-C can decrease the viral load of the Ebstein-Barr virus (EBV) [91]. This observation suggested multiple mechanisms are involved in Vit-C-controlled anti-vital therapy. The activity of antigens and load was reduced through pre-treatment of human foreskin fibroblast and endothelial cells with ascorbate before cytomegalovirus (CMV) infection [92]. This observation was failed to reproduce when ascorbate is added after the infection. The immunomodulatory activities of Vit-C were responsible for this effect. In general, Ascorbic acid is concentrated in leucocytes, lymphocytes, and macrophages [93,94]. Chemotaxis was improved by Vit-C [[95], [96], [97]]. The neutrophil phagocytic activity and oxidative death were also enhanced [[95], [96], [97]]. Lymphocyte proliferation was also accelerated [[95], [96], [97]].

The rate-determining last step of ascorbic acid biosynthesis in animals is l-Gulono-γ-lactone oxidase or the isomeric Gulo form. Mutations in the gene of this enzyme prevented anthropoid primates and guinea pigs to synthesize this molecule. The effects of Vit-C in viral infections were studied via a Gulo (-/-) knockout mice system. It was shown that nasal inoculation of the h4N2 influenza virus is fatal in Gulo (-/-) mice in comparison to wild type mice [97]. Anti-viral cytokine interferon (IFN)-α/β became lower. However, the viral titers in the lung of ascorbic acid-insufficient Gulo (-/-) mice became more abundant [97]. The pro-inflammatory cytokines, tumor necrosis factor (TNF), interleukin-1 (IL-1)-α/β, and infiltration of inflammatory cells was increased in the lung. These results were corrected in Gulo (-/-) mice repleted with ascorbic acid before viral exposure occurs. Most probably, an impaired phosphorylation process of signal transducers and activators of transcription (STATs) was responsible for the decreased generation of IFN in Gulo (-/-) mice [98]. It was found that Gulo (-/-) mice as compared to wild type mice have an impaired immune response with higher lung pathological dysfunction when exposed to influenza h2N1 virus [98]. It was shown that restraint-stressed mice with h2N1-induced pneumonia have a dose-dependent reduction of mortality in the presence of ascorbate. Histopathological lung sections also demonstrated reduced problems in the treated mice [99]. An administration of Vit-C was helpful to recover mitochondrial membrane potential and gene expression of pro-inflammatory cytokines. Ascorbic acid was reported to have clinical activity against numerous other viruses including poliovirus, Venezuelan equine encephalitis, human lymphotropic virus type 1 (HTLV-1), human immunodeficiency virus (HIV) and rabies virus in addition to demonstrating activity against influenza and herpes virus [[100], [101], [102], [103], [104], [105], [106], [107]].

It is known that most of the infections activate phagocytes with the generation of reactive oxygen species (ROS). The ROS has a key role in deactivating viruses. Some of the ROS harm the host cells that cause viral-induced host injury. Respiratory syncytial virus (RSV) infects the upper and lower respiratory tract in infants and children. RSV infection of airway epithelial cells accelerates ROS production and this inhibits the concentration of the lung antioxidant enzymes. The oxidant-antioxidant amount and proportion in cells are critical to RSV pulmonary toxicity [108]. Lung pulmonary inflammation and injury are considerably reduced by the administration of antioxidants [109]. Ascorbic acid is a powerful antioxidant and therefore, it scavenges oxygen free radicals and restores other cellular antioxidants. These include tetrahydrobiopterin and α-tocopherol [94]. The hypothesis that Vit-C may become beneficial in the treatment of viral infections is based on two concepts. Patients with infectious diseases do not have a sufficient level of Vit-C due to metabolic consumption [110]. Vit-C has immunomodulating properties in patients with viral infections. This is possible by increasing the production of α/β interferons and downregulating the synthesis of pro-inflammatory cytokines. Despite that Vit-C have beneficial effects in viral infections no solid clinical data exists on this topic. Pauling suggested that Vit-C can be used for the treatment of the common cold. On this basis, most of the randomized controlled trials (RCTs’) targeted the role of Vit-C in the prevention and treatment of the cold symptoms. In an analysis of 29 RCTs, Vit-C failed to reduce cold disease [82]. No consistent effects of Vit-C were observed also on the duration of colds in patients. Several studies, however, complicated the interpretation of these data.

Ascorbic acid may have clinical effects in patients with infections caused by herpes viruses. Herpes zoster (HZV) infection takes place due to the reactivation of the latent Varicella-Zoster virus (VZV). This is particularly predominant because of the loss of cell-induced immunity with age. The concentration of ascorbic acid in plasma is decreased in post-herpetic neuralgia patients compared to healthy persons [111]. An RCT study was conducted with 41 patients who were subjected to IV Vit-C (50 mg/kg on days 1, 3 and 5) or placebo [111]. It was found that those patients who were taken IV Vit-C have experienced less pain. In a non-blinded RCT, the role of ascorbic acid on acute herpetic pain and postherpetic neuralgia were evaluated [112]. Eighty-seven patients were given 5 g of IV ascorbic acid on the first, third and fifth days or placebo. Interestingly, a few differences between the groups were observed. The treated group with Vit-C demonstrated a lower incidence of postherpetic neuralgia and a lower pain score. Vit-C is mostly concentrated in the aqueous humor of the anterior chamber of the eye. A retrospective cohort investigation indicated that oral Vit-C reduced the risk of herpes simplex keratitis in combination with an oral antiviral drug [111].

It was concluded only a few months before the start of the CoV19 epidemic that there is an urgent need for novel research about the application of IV Vit-C, targeting the management of infectious diseases [80]. Influenza A virus causes epidemics and pandemics that kill thousands of people every year. Experimental studies demonstrate a beneficial effect of ascorbic acid against influenza. Patients with respiratory disorders due to infection by influenza were treated with histone acetyltransferase (HAT) without corticosteroids. Remarkably, these patients showed rapid improvement after the initiation of HAT. Corticosteroids, on the other hand, have a complex role in the treatment of infection. As a result, corticosteroids may not be a standard choice in patients with influenza A infection [113,114]. Effective clinical trials are necessary to investigate the use of Vit-C against infections due to influenza, RSV, herpes, and other viral illnesses.

A large dose of IV ascorbic acid can be one treatment of choices for Covid19 pneumonia [115]. A report on this disease indicates the severity. For example, a 26 % ICU admission and a 4.3 % mortality rate are observed among 138 cases [116]. It is believed that ARDS is the main mechanism for Covid19′s action. This is followed by increased oxidative stress because of the release of free radicals and cytokines. Considering this mechanism of the process, a large dose of Vit-C should play a key role in the management of Covid19. A study indicates out of 99 Covid19 patients, 17 of them developed ARDS [117]. Eleven patients passed away due to multiple organ failure [117]. This death was explained due to increased oxidative stress and cytokine generation that lead to ARDS. Like influenza, coronaviruses are pandemic viruses that injure lung drastically [118]. This viral infection generates a “storm” of cytokines that reacts with the endothelial cells of the lung. This interaction causes neutrophil infiltration and enhances oxidative stress and damages the function of the lung barrier [118]. ARDS is characterized by strong hypoxemia. This is propagated because of multiple reasons. Uncontrolled inflammation, oxidative injury, and damage to the alveolar-capillary barrier are the main reasons [119]. The severe increased oxidative stress causes pulmonary injuries: lung injury (ALI) and ARDS. ALI and ARDS are key factors responsible for substantially high morbidity and mortality [120,121]. An increase of C-reactive protein (hsCRP), an indicator of inflammation and oxidative stress is seen among Covid19 patients [122]. The transcription factor nuclear factor-erythroid-2–related factor 2 (Nrf2) is a major regulator of antioxidant response element (ARE) driven cytoprotective protein expression. It is believed that the activation of Nrf2 signaling pathways plays a crucial role in preventing cells and tissues to undergo oxidative stress.

Ascorbic acid is a key compound of the antioxidant system in cells and tissues [123]. The biological and medicinal properties of Vit-C in critical care management are documented [124]. It is now accepted that both viral and bacterial infections result in the production of excess cytokine [118]. Antioxidants should be given to control pandemics (Covid19) because of the non-availability of pathogen-specific vaccines and drugs. This is further strengthened by the fact that a large dose of IV Vit-C has shown successful clinical results in viral ARDS and influenza [125].

A report is known that a 26-year-old woman developed viral ARDS (rhinovirus and enterovirus-D68) [118]. She was admitted to ICU and was not responsive to routine treatment. She was then placed on ECMO on day 3, a high dose of IV (200 mg/kg body/24 h, 4 doses, one every 6 h) was initiated on ECMO. Amazingly, the lungs of the patients showed excellent improvement on day 2 of high dose IV Vit-C infusion. This improvement was characterized by X-ray imaging. She was then continued to improve and was discharged from the hospital, without the requirement of additional oxygen. After a month, X-ray of her lungs indicated a complete cure. A severe medical problem of influenza was treated with high dose IV Vit-C successfully [125]. A young patient was recommended to take a high dose of IV Vit-C (50,000 mg of Vit-C in 1000 ml Ringer’s solution, infused over 90 min) and the condition of the patient improved notably by the next day. He was continued to take oral VC (2000 mg twice daily) [125].

The protective action of ascorbic acid is shown in [126]. A high dose IV Vit-C was used in 2009 to treat a New Zealand farmer (Primal Panacea) [127]. Vit-C was able to cut down ICU stay through an analysis of 18 clinical studies on 2004 ICU patients [128]. It was found that 17,000 mg/day IV Vit-C had shortened the ICU stay by 44 %. The use of IV Vit-C in 47 sepsis ICU cases was reported and a major reduction in death was possible [129]. Dietary antioxidants (Vit-C and sulforaphane) were helpful to manage oxidative-stress-induced acute inflammatory lung injury that requires mechanical ventilation [130]. Another antioxidant, natural curcumin has also been effective against inflammation that caused during pneumonia [131]. National Institutes of Health (NIH) states that high dose IV Vit-C (1.5 g/kd body weight) is safe for good health and without side effects [116].

4. Discussion and conclusions

Over the past century, the opinion that Vit-C can be used to treat cancer and viral infection has shown promises and controversies. There are cases where high dose Vit-C has shown benefits. In some cases, there have been no benefits. However, new knowledge regarding the pharmacokinetic properties of Vit-C, and recent preclinical studies, have revived interest in the utilization of high-dose Vit-C for cancer treatment [[132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145]]. Similar is the case of using IV Vit-C as antiviral, especially for the recent Covid19 [[146], [147], [148], [149], [150]]. It is believed that IV Vit-C has been particularly effective by inhibiting the production of cytokines storm due to Corvid19.

Covid19 pneumonia is an extremely rapidly developing disease with a high mortality rate. The main pathogenesis is the acute lung injury that causes ARDS and death. Antioxidants should have a role in the management of these conditions. Appropriate clinical studies and reports demonstrate that a timely administration of high dose IV Vit-C improves the outcome of Covid19 infection.

Additional studies detailing the use of IV Vit-C for the treatment of severe Covid19 infected pneumonia are definitively warranted. Covid19 may continue to happen in the future. Since the development of clinically active vaccines or antiviral drugs targeting specific diseases may take a long time to develop, the use of IV Vit-C as a universal agent for ARDS may have benefits behind Covid19. Additional clinical studies of the IV Vit-C and oral VC (such as liposomal-encapsulated VC) targeting other situations through different mechanisms are required to develop as soon as possible.

Author contributions

A.B. wrote the first draft of the manuscript. B.K.B. first revised the manuscript. Both authors further improved the manuscript.

Declaration of Competing Interest

The authors received no funding and have no conflict of interest to declare.

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Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome

PharmaNutrition. 2020 Jun; 12: 100190.

Prince Mohammad Bin Fahd University, P.O. Box 1664, Al Khobar, 31952, Saudi Arabia

Corresponding author.

Received 2020 Mar 31; Revised 2020 Apr 5; Accepted 2020 Apr 6.

Copyright © 2020 Elsevier B.V. All rights reserved.

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Abstract

The recent outbreak of Covid19 has required urgent treatments for numerous patients. No suitable vaccines or antivirals are available for Covid19. The efficiency against Covid19 of WHO therapies of choice, that are two antivirals developed for other pathologies, is controversial. Therefore, alternative approaches are required. Intravenous (IV) Vitamin C (Vit-C) has emerged as one of the other alternatives for this purpose. Here we review the effects of IV Vit-C on the immune system response, the antiviral properties of IV Vit-C, and finally the antioxidant properties of IV Vit-C to specifically address the cytokines’ storm characteristic of the Acute Respiratory Distress Syndrome (ARDS) that occur in the later cycle of the Covid19 infectious disease.

Keywords: Vitamin C, Severe acute respiratory syndrome coronavirus, Antiviral agents, Covid19, Cytokines

1. Introduction

The recent outbreak of Covid19 has required urgent treatments for numerous patients. The Covid19 originated in Wuhan, China has spread to other continents and has caused significant harm to the public.
represents a transmission electron microscope image of Covid19 along with a 3D structure of coronavirus. No suitable vaccines or antiviral drugs exist against Covid19. At the time of writing (15 March 2020), Coronavirus cases were already 173,085 (+19 % over the last 24 h, +5% the day before), with 6664 deaths (+23 % over the last 24 h, +6% the day before) vs. 77,784 recovered (+6% over the last 24 h), with some improvements in China. However, the condition is deteriorating in Western Europe, especially Italy. No cure for Covid19 is known at this time. In addition to administering oxygen, current treatments recommended by the World Health Organization (WHO) for the serious, critical cases of Covid19 include Remdesivir, Kaletra, and Kaletra plus Interferon (France24, “Conquering the coronavirus: the most pressing goal for these researchers in Paris”, youtu.be/L0wRSKnIErk). Remdesivir is an antiviral nucleotide developed as a treatment for the Ebola virus and Marburg virus infections. Kaletra is a combination of Lopinavir and Ritonavir (LPV/r). This is also used as antiviral nucleotide analogs developed for the treatment of HIV/AIDS. The third option is a combination of Kaletra with Interferon. Interferons are signaling proteins (cytokines) that infected cells produce and release in response to viruses. Interferons activate other cells of the immune system so that a stronger immune system response can be achieved. Interferon alphas are specifically recommended for viral infections and some cancers. The efficacy of these processes for Covid19 is controversial. Therefore, alternative approaches are urgently needed.

In China, the death rate was peaked at 3% a few weeks ago but is now declined to 0.7 %. Good results are obtained using Interferon Alpha 2B (IFNrec) without any combination with Kaletra. The use of Intravenous (IV) Vitamin C (Vit-C) has shown promise in this area in China. The IV Vit-C (or Ascorbic acid) protocols are mentioned in clinicaltrials.gov, for Covid19 and other pathologies. Shanghai now utilizes IV Vit-C in the treatment for Covid-19. Many physicians in China have identified promising results using IV Vit-C against Covid19. Thus, there is a need to urgently review the uses of IV Vit-C, pre- and post-infection, and during different stages of the infection. IV Vit-C is helping to develop a stronger immune system response, reducing the cytokines storm, or increasing antiviral activities through other unknown mechanisms.

Perhaps, the reduction of the cytokines storm in the late stages of the Covid19 infection is the most significant application of IV Vit-C. Covid19 pneumonia is a complex medical disorder with high morbidity and mortality rate. This causes severe lung injury that results in Acute Respiratory Distress Syndrome (ARDS), a life-threatening lung disorder. This process prevents the necessary oxygen to enter into the lungs and ultimately causes death. Coronaviruses increase oxidative stress that promotes cellular malfunction and ultimately results in organ failure. It is believed that pulmonary failure (ARDS) is the principal cause of Covid19′s action on humans. This helps to increase oxidative stress considerably because of the generation of free radicals and cytokines. This process finally leads to serious cellular injury, organ failure and death. The administration of anti-oxidizing agents along with proven conventional supportive therapies is believed to have an important role in controlling these medical situations. Appropriate vaccines and antiviral drugs for the Covid19 epidemic are not available. IV Vitamin C and other antioxidants are extremely good agents for ARDS. These can be applied clinically. Importantly, high dose IV Vit-C is safe and effective. In this paper, we review the use of high-dose Vit-C as an efficient method of treatment for patients with cancers and infections.

The antiviral properties of Vit-C help to reduce symptoms and mortality in children and adults [[1], [2], [3], [4]]. The antiviral activities of ascorbic acid was known and it was published almost 80 years ago [[5], [6], [7], [8], [9]] when scientists were involved in work on poliomyelitis. Moreover, the use of ascorbic acid as a medicinally crucial agent against various diseases was also well established [[10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]]. Applications of Vit-C are found in poliomyelitis [[22], [23], [24], [25], [26]]. Many other uses of Vit-C include hepatitis, herpes, chickenpox and measles, infectious mononucleosis, trichinosis, urethritis, Antabuse, arthritis, and cancer. Vit-C is also helpful for the treatment of elevated cholesterol and arteriosclerosis, [[27], [28], [29], [30], [31], [32]], corneal ulcers, glaucoma, burns, heatstroke, sunburn, slipped disc, toxins, and heavy metal poisonings [[33], [34], [35]]. The appropriate clinically effective vaccines and specific antivirals may serve effectively if they are available. Considering the current situation, the use of Vit-C as an antiviral agent should also be considered. Notably, Vit-C can be used alone or in combination with other available medicines to exert positive synergistic effects. Here we review the principal mechanism of actions of IV Vit-C that helps to make the immune system stronger, reduces the cytokines storm and inhibits oxidative processes. Under the first criteria, literature knowledge on cancer treatment will be reviewed first. Then, the antiviral properties will be reviewed, with focusing on the reduction of the oxidative pathways typical of the Covid19 ARDS.

2. Cancer treatment

A review of laboratory, animal and human studies and current clinical trials is provided regarding cancer treatments [36]. Vit-C is a crucial nutrient with redox properties, a cofactor of numerous enzymes, and it plays an important role in the synthesis of collagen [37]. A deficiency of Vit-C may result in scurvy [38]. Scurvy can cause collagen structure narrow and thin. It has been found that normal healthy situation can be maintained with the administration of Vit-C. In the mid-20th century, a study hypothesized that cancer can originate due to the alterations of the structures in connective tissues caused by Vit-C deficiency [39]. A review suggested that a high-dose of ascorbic acid can enhance host resistance. This study also identified the use of ascorbic acid in cancer therapy [40]. In general, Vit-C is synthesized from isomeric sugars d-glucose or d-galactose by numerous plants and animals. Interestingly, humans lack the enzyme l-gulonolactone oxidase which is required for ascorbic acid synthesis. On this basis, humans need Vit-C through food or other supplements [37].

Vit-C is an essential nutrient with redox properties in normal physiological situations [36]. Some cancer patients were treated successfully with high-dose of oral and/or IV Vit-C. However, two early randomized placebo-controlled studies of high-dose oral Vit-C (10 g/d) indicated no significant effects against cancers. These studies indicated marginal medical benefits between ascorbate- and placebo-treated groups. Laboratory experiments reported that high-dose of Vit-C can decrease cell proliferation in prostate, pancreatic, colon, mesothelioma, and neuroblastoma cancer cell lines. Studies of Vit-C combined with other medicines in animal models demonstrated inconclusive results. Importantly, IV Vit-C was well-tolerated in clinical trials. An IV administration of Vit-C (500 mg) was found to be more effective than oral administration since a higher blood concentration of ascorbate was found through the IV route. A study with Vit-C as ascorbate versus ascorbate formulations along with standard cancer therapies was performed in clinical trials. Two studies of high-dose Vit-C confirmed a better quality of life and fewer cancer-related toxicities. These results from preclinical and clinical trials of high-dose Vit-C with and without standard cancer therapies are note-worthy. However, it may be challenged that these investigations have a few shortcomings.

The use of high-dose Vit-C (IV and oral) for the management of cancer was started five decades ago [41]. The application of Vit-C therapy in the treatment of various cancers was promoted [42,43]. For example, two clinical trials of Vit-C were conducted many years ago [44,45]. Pharmacokinetic experiments identified considerable differences in the maximum achieved blood concentrations of Vit-C. It was found that the nature of the route of delivery was relevant. For example, if Vit-C was taken orally, plasma concentrations are controlled with a peak achievable concentration of less than 300 μM. However, this control was bypassed with IV administration of the vitamin, resulting in a very high level of Vit-C plasma concentration (up to 20 mM) [46,47]. Additional research suggested that pharmacological concentrations of ascorbate as achieved with IV administration may result in cell death in numerous cancer cell lines [48]. Health care practitioners who had participated in complementary and alternative medicine conferences in 2006 and 2008 were debated on the benefits/risks of high-dose IV Vit-C in patients. A total of 199 participants were chosen and out of which 172 were taken Vit-C. Specifically, IV Vit-C was recommended to fight against infection, cancer, and fatigue [49].

In the early 1970s, a case study was conducted with 50 cancer patients who were taken a high dose of ascorbic acid [41]. Conventional therapies were applied to these patients, but these were not successful. On this basis, these patients were recommended to take ascorbic acid. Different doses and schedules were used. For example, some patients were given IV ascorbic acid (10 g/day for 10 successive days), a few were given higher dose amounts, and some were chosen to give oral ascorbic acid (10 g/day) or a combination of both. A wide variety of responses were found. Dome of them had no or minimal response and some of them had tumor regression and tumor hemorrhage. Despite this important observation, a lack of control study prevented making any conclusion on the health benefits of ascorbic acid treatment. From a limited study published in 1975, it is apparent that one of the patients experienced tumor regression [60]. The patient who had reticulum cell sarcoma exhibited improvement due to the treatment with ascorbic acid. A reduction of the daily dose of ascorbic acid was not helpful since symptoms of the disease appeared. Notably, remission was successfully achieved again after the same patient was given a higher initial dose of ascorbic acid.

A larger study of terminal cancer patients treated with ascorbate was conducted in 1976. In this investigation, 100 terminal cancer patients [41] were given ascorbate through an acceptable and scientific way (10 g/day for 10 days IV, then repeated orally). The health conditions of these patients were evaluated concerning 1000 matched control patients from the same clinic. Interestingly, the average survival time for ascorbate-treated patients was considerably much higher (300 days) than that of the matched control group [42,43].

Two randomized investigations using placebo-controlled trials were performed. In these studies, cancer patients were taken either 10 g of oral Vit-C or placebo daily until signs of cancer go away. At the end of these investigations, no significant differences in clinical results were found between the two ascorbate- and placebo-treated groups [44,45].

A study disclosed three case reports on cancer patients who received IV Vit-C as their main medicines. During Vit-C uptake, the patients were also given other materials including vitamins, minerals, and botanicals. It was claimed that the cases are analyzed following the National Cancer Institute (NCI) Best Case Series procedures. Histopathologic tests found weak prognoses for these patients. But the survival period of these patients went up after being treated with IV Vit-C [61]. Vit-C was given from 15 g to 65 g, once or twice a week, for several months to these patients. Two studies demonstrated that IV Vit-C treatment helps to improve the quality of life and decreases the side effects associated with cancer [62,63].

Systematic studies identified that the doses of Vit-C to volunteers or cancer patients can be up to 1.5 g/kg. No toxicity risks were seen (for example, glucose-6-phosphate dehydrogenase deficiency, renal diseases or urolithiasis). These studies identified that plasma concentrations of Vit-C can be much higher with IV administration than that of oral administration. The concentration was maintained for approximately 4 h [46,47].

A phase I study investigated the safety and efficiency of dual drug therapy by combining IV ascorbate with gemcitabine and erlotinib in stage IV pancreatic cancer patients. Fourteen subjects were evaluated in this study. The patients received IV gemcitabine (1000 mg for 30 min, once a week for 7 weeks), oral erlotinib (100 mg daily for 8 weeks), and IV ascorbate (50 g/infusion, 75 g/infusion, or 100 g/infusion 3 times per week for 8 weeks). No adverse effects were observed for ascorbic acid treatment. Five subjects received fewer than 18 of the proposed 24 ascorbate infusions. In three patients the disease was continued. Imaging tests were performed on nine patients to assess tumor size. This showed that the health situation was stable in each of them [64].

A 2013 phase I clinical investigation studied the effects of combining ascorbate with gemcitabine in the treatment of stage IV pancreatic cancer. During each 4-week cycle, patients were given gemcitabine weekly for 3 weeks and ascorbate for 4 weeks with a specific dose. This study found a progression-free and overall survival period. The combination of drug treatment was acceptable well [54].

In 2014, a phase I/IIA clinical trial measured the toxicities of two systems. The first one was combined IV ascorbate with carboplatin and the second one was ascorbate paclitaxel in stage III/IV ovarian cancer. More than 24 patients were chosen to receive either chemotherapy alone or chemotherapy and IV Vit-C. The chemotherapy was given for 6 months and IV Vit-C was continued for 12 months. Interestingly, IV Vit-C reduced chemotherapy-related toxicities [65].

A phase I/II clinical trial of high-dose IV Vit-C with numerous chemotherapeutic agents was conducted in 2015. This study was performed to evaluate multiple factors. Some important targets were to evaluate associated adverse effects, to determine the pharmacokinetic activities of Vit-C, to understand the clinical potential, to evaluate changes in mood and behavior and to assess the lifestyle [66].

A high-dose of IV Vit-C was analyzed in 14 patients. The procedures performed were tolerated well and were safe. A few temporary side effects were seen: increased urinary flow, thirst, nausea, vomiting, and chilling. It was important to note that an administration of chemotherapeutic agents did not alter the plasma concentration of Vit-C. A few patients were benefitted from this treatment because they experience temporary stable disease, demonstrate more activity with additional energy. However, since the group was small, no general conclusions from this study were drawn [66].

Recently, [67], a phase I study was evaluated to evaluate the safety, bioavailability, and efficiency of high-dose IV Vit-C in combination with chemotherapy regimens mFOLFOX6 or FOLFIRI. These were a combination of well-known agents: oxaliplatin, leucovorin, and 5-fluorouracil or leucovorin, 5-fluorouracil and irinotecan hydrochloride. This study was conducted on 36 patients with metastatic colorectal or gastric cancer. The principal aims were to evaluate the maximum-tolerated dose. Another goal was to determine the phase II dose of ascorbic acid with co-administration with mFOLFOX6 or FOLFIRI. Initially, all patients were given an identical chemotherapy treatment for 14 days with Vit-C infusions. Later, the concentration of ascorbic acid was altered for the dose-escalation investigation. This study demonstrated no dose-limiting toxicity. Therefore, a maximum-tolerated dose was not identified from this investigation. However, a dose of 1.5 g/kg for ascorbic acid was recommended for this phase II study. No adverse side effects were observed and the treatments were acceptable to the patients. Based on the success, a randomized phase III investigation is under progress. The goal of this study is to determine the clinical power of ascorbic acid against metastatic colorectal cancer in combination with mFOLFOX6 with or without bevacizumab [67].

Several studies were performed small doses of IV ascorbic acid treatment (1000 mg) with arsenic trioxide regimens, and mixed results were obtained [[68], [69], [70]].

Clinical investigations of ascorbate in combination with arsenic trioxide were reported [36]. Patients with non-small cell lung carcinoma (NSCLC) and glioblastoma multiforme (GBM) were treated in two clinical trials [71,72]. The patients in both of these trials were undergone conventional therapy along with IV Vit-C. IV Vit-C was administered under radiation therapy and in the presence of temozolomide. The toxicity and overall survival rate of the patients were favorable. The NSCLC clinical trial was a phase II procedure that has 14 patients with advanced cancer. These patients were also given both chemotherapy and IV Vit-C. The results of this investigation were also favorable.

Many trials with IV Vit-C in a combination with other medicines are under active investigation. Accordingly, 5 trials are being conducted by scientists at Iowa University, 4 phase II studies and 1 phase IB/II trial. The 4 phase II clinical trials are focused to identify the efficiency of high-dose ascorbic acid combined with common anticancer molecules. These studies with ascorbate are also progressing with many cancer cell lines. These include studies on non-small cell lung cancer therapy under radiation therapy and in the presence of carboplatin and paclitaxel; metastatic pancreatic adenocarcinoma in the presence of gemcitabine and nab-paclitaxel; pancreatic adenocarcinoma in the presence of gemcitabine and radiation therapy, and glioblastoma in the presence of temozolomide and radiation therapy. Another phase IB/II trial is investigating the safety and clinical performance of high-dose ascorbate with radiation therapy against soft tissue sarcoma.

Numerous studies used IV ascorbic acid at a fixed dose of 1000 mg with various amounts of arsenic trioxide as anticancer therapy. It was expected that the pro-oxidant character of IV ascorbic acid can improve the effects of arsenic trioxide by a sensitization process of the malignant cells to arsenic’s cytotoxic nature [72]. The combination therapies worked well. Some benefits against multiple myeloma were observed. However, the role of Vit-C in this was not determined [[73], [74], [75]]. In contrast, similar combination regimens were not effective and resulted in side effects, including the progression of the disease with particular cancer. Moreover, no anticancer effects against metastatic colorectal cancer [76] and metastatic melanoma were determined [77]. Since these trials were not placebo-controlled, the role of ascorbic acid to the results is unclear.

Intravenous (IV) high-dose ascorbic acid was well-tolerated in clinical trials [46], [78], [74], [71], [73], [64]. It was speculated that ascorbic acid may accelerate renal failure in patients with preexisting renal disorders [49]. Glucose-6-phosphate dehydrogenase (G-6-PD) deficient patients were not good candidates to have high doses of Vit-C due to hemolysis [[50], [51], [52]]. Vit-C was able to improve the bioavailability of iron. A large dose of Vit-C was not recommended for patients with hemochromatosis [53].

Vit-C in high doses reacted with a few anticancer compounds. These interactions were detected in preclinical studies. A phase I clinical investigation examined the feasibility of using high-dose IV ascorbate and gemcitabine in stage IV pancreatic cancer patients. It was important to know that the combination formula was well tolerated by patients. No adverse effects were observed [54].

In vitro and in vivo animal studies indicated ascorbate can alter the mechanism of the drug. For example, ascorbate with bortezomib altered the action of the medicine as a proteasome inhibiting agent and blocked bortezomib-mediated cell death [[55], [56], [57]]. This interaction was observed with a low concentration of Vit-C (40 mg/kg/day) to animals. The cell culture study on blood plasma with Vit-C (1 g/day) also demonstrated a large decrease in bortezomib’s growth inhibitory effect against multiple myeloma cells. The plasma of healthy volunteers was analyzed. Bortezomib growth inhibition on multiple myeloma cells was observed when a person takes 1 g of oral Vit-C per day. This amount had blocked the drug’s inhibitory properties against the 20S proteasome [57]. On the other hand, a study that utilized mice harboring human prostate cancer cell xenografts did not find any good effect of oral Vit-C (40 mg/kg/day or 500 mg/kg/day) on the tumor growth inhibitory action of this medicine [58]. Studies showed that dehydroascorbic acid, an oxidized form of Vit-C alters the cytotoxic properties of some chemotherapy drugs [59]. But, the concentration of dehydroascorbic acid is found to be low in dietary supplements and foods.

Despite some controversial results over the years, Vit-C had proven to have anticancer effects when given intravenously at high concentrations [79]. Some reports on the anticancer activities of Vit-C were dependent on the use of immune-deficient mice. These studies were conducted to examine the direct effects of ascorbate on tumors. It was found that the effects of Vitamin C are much stronger in the presence of an intact immune system [79]. These observations suggested a combination treatment which requires evaluation in patients.

3. Treatment of viral infections

The antiviral properties of Vit-C were recently reviewed [80]. Vit-C was used for the treatment of hypovitaminosis C in malnourished patients. A combination of hydrocortisone, ascorbic acid, and thiamine (HAT therapy) worked well in the treatment of patients with sepsis and septic shock [81]. There were 29 ongoing or completed clinical trials with Vit-C administration in sepsis. The effectiveness of Vit-C in preventing common cold [82] and other health disorders was questioned [83,84]. The ascorbic acid therapy for acute inflammatory disorders was based upon numerous biological studies following many decades of research. The current interest in Vit-C focuses on bacterial sepsis and septic shock in patients. More than 300 scientific and clinical studies supported mechanistic data to use Vit-C against this disease [85,86]. Some other additional role of Vit-C in the treatment of viral diseases is also possible. The biological concepts and evidence for the use of Vit-C in viral infections are described here.

Numerous studies identified that Vit-C in high dosages is virucidal [83]. This conclusion was based on in-vitro experiments. In the presence of copper and/or iron, high doses of Vit-C showed virucidal activity. This was explained through the formation of hydrogen peroxide and other radical initiators [87,88]. Moreover, the low pH value of the system was responsible for the in-vitro antiviral effects of Vit-C. Despite these studies, the in vivo virucidal activity of Vit-C was not confirmed. It was well established that Vit-C is a powerful antioxidant and it can exert pro-oxidant effects at high concentrations. The generation of reactive oxygen species through the reduction of transition metal is possible [89]. It was found that a very high-dose of one sodium salt of ascorbic acid (90 mM) kills Candida albicans in-vitro through an iron-catalyzed Fenton reaction [90]. An iron chelator 2,2′-bipyridyl inhibited this effect. An experiment demonstrated that Vit-C can decrease the viral load of the Ebstein-Barr virus (EBV) [91]. This observation suggested multiple mechanisms are involved in Vit-C-controlled anti-vital therapy. The activity of antigens and load was reduced through pre-treatment of human foreskin fibroblast and endothelial cells with ascorbate before cytomegalovirus (CMV) infection [92]. This observation was failed to reproduce when ascorbate is added after the infection. The immunomodulatory activities of Vit-C were responsible for this effect. In general, Ascorbic acid is concentrated in leucocytes, lymphocytes, and macrophages [93,94]. Chemotaxis was improved by Vit-C [[95], [96], [97]]. The neutrophil phagocytic activity and oxidative death were also enhanced [[95], [96], [97]]. Lymphocyte proliferation was also accelerated [[95], [96], [97]].

The rate-determining last step of ascorbic acid biosynthesis in animals is l-Gulono-γ-lactone oxidase or the isomeric Gulo form. Mutations in the gene of this enzyme prevented anthropoid primates and guinea pigs to synthesize this molecule. The effects of Vit-C in viral infections were studied via a Gulo (-/-) knockout mice system. It was shown that nasal inoculation of the h4N2 influenza virus is fatal in Gulo (-/-) mice in comparison to wild type mice [97]. Anti-viral cytokine interferon (IFN)-α/β became lower. However, the viral titers in the lung of ascorbic acid-insufficient Gulo (-/-) mice became more abundant [97]. The pro-inflammatory cytokines, tumor necrosis factor (TNF), interleukin-1 (IL-1)-α/β, and infiltration of inflammatory cells was increased in the lung. These results were corrected in Gulo (-/-) mice repleted with ascorbic acid before viral exposure occurs. Most probably, an impaired phosphorylation process of signal transducers and activators of transcription (STATs) was responsible for the decreased generation of IFN in Gulo (-/-) mice [98]. It was found that Gulo (-/-) mice as compared to wild type mice have an impaired immune response with higher lung pathological dysfunction when exposed to influenza h2N1 virus [98]. It was shown that restraint-stressed mice with h2N1-induced pneumonia have a dose-dependent reduction of mortality in the presence of ascorbate. Histopathological lung sections also demonstrated reduced problems in the treated mice [99]. An administration of Vit-C was helpful to recover mitochondrial membrane potential and gene expression of pro-inflammatory cytokines. Ascorbic acid was reported to have clinical activity against numerous other viruses including poliovirus, Venezuelan equine encephalitis, human lymphotropic virus type 1 (HTLV-1), human immunodeficiency virus (HIV) and rabies virus in addition to demonstrating activity against influenza and herpes virus [[100], [101], [102], [103], [104], [105], [106], [107]].

It is known that most of the infections activate phagocytes with the generation of reactive oxygen species (ROS). The ROS has a key role in deactivating viruses. Some of the ROS harm the host cells that cause viral-induced host injury. Respiratory syncytial virus (RSV) infects the upper and lower respiratory tract in infants and children. RSV infection of airway epithelial cells accelerates ROS production and this inhibits the concentration of the lung antioxidant enzymes. The oxidant-antioxidant amount and proportion in cells are critical to RSV pulmonary toxicity [108]. Lung pulmonary inflammation and injury are considerably reduced by the administration of antioxidants [109]. Ascorbic acid is a powerful antioxidant and therefore, it scavenges oxygen free radicals and restores other cellular antioxidants. These include tetrahydrobiopterin and α-tocopherol [94]. The hypothesis that Vit-C may become beneficial in the treatment of viral infections is based on two concepts. Patients with infectious diseases do not have a sufficient level of Vit-C due to metabolic consumption [110]. Vit-C has immunomodulating properties in patients with viral infections. This is possible by increasing the production of α/β interferons and downregulating the synthesis of pro-inflammatory cytokines. Despite that Vit-C have beneficial effects in viral infections no solid clinical data exists on this topic. Pauling suggested that Vit-C can be used for the treatment of the common cold. On this basis, most of the randomized controlled trials (RCTs’) targeted the role of Vit-C in the prevention and treatment of the cold symptoms. In an analysis of 29 RCTs, Vit-C failed to reduce cold disease [82]. No consistent effects of Vit-C were observed also on the duration of colds in patients. Several studies, however, complicated the interpretation of these data.

Ascorbic acid may have clinical effects in patients with infections caused by herpes viruses. Herpes zoster (HZV) infection takes place due to the reactivation of the latent Varicella-Zoster virus (VZV). This is particularly predominant because of the loss of cell-induced immunity with age. The concentration of ascorbic acid in plasma is decreased in post-herpetic neuralgia patients compared to healthy persons [111]. An RCT study was conducted with 41 patients who were subjected to IV Vit-C (50 mg/kg on days 1, 3 and 5) or placebo [111]. It was found that those patients who were taken IV Vit-C have experienced less pain. In a non-blinded RCT, the role of ascorbic acid on acute herpetic pain and postherpetic neuralgia were evaluated [112]. Eighty-seven patients were given 5 g of IV ascorbic acid on the first, third and fifth days or placebo. Interestingly, a few differences between the groups were observed. The treated group with Vit-C demonstrated a lower incidence of postherpetic neuralgia and a lower pain score. Vit-C is mostly concentrated in the aqueous humor of the anterior chamber of the eye. A retrospective cohort investigation indicated that oral Vit-C reduced the risk of herpes simplex keratitis in combination with an oral antiviral drug [111].

It was concluded only a few months before the start of the CoV19 epidemic that there is an urgent need for novel research about the application of IV Vit-C, targeting the management of infectious diseases [80]. Influenza A virus causes epidemics and pandemics that kill thousands of people every year. Experimental studies demonstrate a beneficial effect of ascorbic acid against influenza. Patients with respiratory disorders due to infection by influenza were treated with histone acetyltransferase (HAT) without corticosteroids. Remarkably, these patients showed rapid improvement after the initiation of HAT. Corticosteroids, on the other hand, have a complex role in the treatment of infection. As a result, corticosteroids may not be a standard choice in patients with influenza A infection [113,114]. Effective clinical trials are necessary to investigate the use of Vit-C against infections due to influenza, RSV, herpes, and other viral illnesses.

A large dose of IV ascorbic acid can be one treatment of choices for Covid19 pneumonia [115]. A report on this disease indicates the severity. For example, a 26 % ICU admission and a 4.3 % mortality rate are observed among 138 cases [116]. It is believed that ARDS is the main mechanism for Covid19′s action. This is followed by increased oxidative stress because of the release of free radicals and cytokines. Considering this mechanism of the process, a large dose of Vit-C should play a key role in the management of Covid19. A study indicates out of 99 Covid19 patients, 17 of them developed ARDS [117]. Eleven patients passed away due to multiple organ failure [117]. This death was explained due to increased oxidative stress and cytokine generation that lead to ARDS. Like influenza, coronaviruses are pandemic viruses that injure lung drastically [118]. This viral infection generates a “storm” of cytokines that reacts with the endothelial cells of the lung. This interaction causes neutrophil infiltration and enhances oxidative stress and damages the function of the lung barrier [118]. ARDS is characterized by strong hypoxemia. This is propagated because of multiple reasons. Uncontrolled inflammation, oxidative injury, and damage to the alveolar-capillary barrier are the main reasons [119]. The severe increased oxidative stress causes pulmonary injuries: lung injury (ALI) and ARDS. ALI and ARDS are key factors responsible for substantially high morbidity and mortality [120,121]. An increase of C-reactive protein (hsCRP), an indicator of inflammation and oxidative stress is seen among Covid19 patients [122]. The transcription factor nuclear factor-erythroid-2–related factor 2 (Nrf2) is a major regulator of antioxidant response element (ARE) driven cytoprotective protein expression. It is believed that the activation of Nrf2 signaling pathways plays a crucial role in preventing cells and tissues to undergo oxidative stress.

Ascorbic acid is a key compound of the antioxidant system in cells and tissues [123]. The biological and medicinal properties of Vit-C in critical care management are documented [124]. It is now accepted that both viral and bacterial infections result in the production of excess cytokine [118]. Antioxidants should be given to control pandemics (Covid19) because of the non-availability of pathogen-specific vaccines and drugs. This is further strengthened by the fact that a large dose of IV Vit-C has shown successful clinical results in viral ARDS and influenza [125].

A report is known that a 26-year-old woman developed viral ARDS (rhinovirus and enterovirus-D68) [118]. She was admitted to ICU and was not responsive to routine treatment. She was then placed on ECMO on day 3, a high dose of IV (200 mg/kg body/24 h, 4 doses, one every 6 h) was initiated on ECMO. Amazingly, the lungs of the patients showed excellent improvement on day 2 of high dose IV Vit-C infusion. This improvement was characterized by X-ray imaging. She was then continued to improve and was discharged from the hospital, without the requirement of additional oxygen. After a month, X-ray of her lungs indicated a complete cure. A severe medical problem of influenza was treated with high dose IV Vit-C successfully [125]. A young patient was recommended to take a high dose of IV Vit-C (50,000 mg of Vit-C in 1000 ml Ringer’s solution, infused over 90 min) and the condition of the patient improved notably by the next day. He was continued to take oral VC (2000 mg twice daily) [125].

The protective action of ascorbic acid is shown in [126]. A high dose IV Vit-C was used in 2009 to treat a New Zealand farmer (Primal Panacea) [127]. Vit-C was able to cut down ICU stay through an analysis of 18 clinical studies on 2004 ICU patients [128]. It was found that 17,000 mg/day IV Vit-C had shortened the ICU stay by 44 %. The use of IV Vit-C in 47 sepsis ICU cases was reported and a major reduction in death was possible [129]. Dietary antioxidants (Vit-C and sulforaphane) were helpful to manage oxidative-stress-induced acute inflammatory lung injury that requires mechanical ventilation [130]. Another antioxidant, natural curcumin has also been effective against inflammation that caused during pneumonia [131]. National Institutes of Health (NIH) states that high dose IV Vit-C (1.5 g/kd body weight) is safe for good health and without side effects [116].

4. Discussion and conclusions

Over the past century, the opinion that Vit-C can be used to treat cancer and viral infection has shown promises and controversies. There are cases where high dose Vit-C has shown benefits. In some cases, there have been no benefits. However, new knowledge regarding the pharmacokinetic properties of Vit-C, and recent preclinical studies, have revived interest in the utilization of high-dose Vit-C for cancer treatment [[132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145]]. Similar is the case of using IV Vit-C as antiviral, especially for the recent Covid19 [[146], [147], [148], [149], [150]]. It is believed that IV Vit-C has been particularly effective by inhibiting the production of cytokines storm due to Corvid19.

Covid19 pneumonia is an extremely rapidly developing disease with a high mortality rate. The main pathogenesis is the acute lung injury that causes ARDS and death. Antioxidants should have a role in the management of these conditions. Appropriate clinical studies and reports demonstrate that a timely administration of high dose IV Vit-C improves the outcome of Covid19 infection.

Additional studies detailing the use of IV Vit-C for the treatment of severe Covid19 infected pneumonia are definitively warranted. Covid19 may continue to happen in the future. Since the development of clinically active vaccines or antiviral drugs targeting specific diseases may take a long time to develop, the use of IV Vit-C as a universal agent for ARDS may have benefits behind Covid19. Additional clinical studies of the IV Vit-C and oral VC (such as liposomal-encapsulated VC) targeting other situations through different mechanisms are required to develop as soon as possible.

Author contributions

A.B. wrote the first draft of the manuscript. B.K.B. first revised the manuscript. Both authors further improved the manuscript.

Declaration of Competing Interest

The authors received no funding and have no conflict of interest to declare.

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Frontiers | Intravenous Vitamin C for Cancer Therapy – Identifying the Current Gaps in Our Knowledge

Introduction

Over the years, numerous epidemiological studies have highlighted a decreased incidence of cancer and improved survival in patients with higher dietary intakes of vitamin C or higher plasma levels of the vitamin (Carr and Frei, 1999b; Harris et al., 2014). Although vitamin C is often considered a good marker of fruit and vegetable intake (Block et al., 2001), the vitamin has essential functions within the body, including integral roles in various anti-cancer mechanisms (Du et al., 2012). Because of the pleiotropic functions of vitamin C, optimizing its levels in the body through diet and supplementation is likely to be of benefit to oncology patients. In support of this premise, studies in a vitamin C-requiring mouse model indicate that oral vitamin C supplementation of these animals can impair the development of tumors and can also increase the rejection rate of implanted tumor cells (Campbell et al., 2016a; Cha et al., 2016). This suggests an important role for vitamin C in host defense against cancer.

Treatment of cancer, in contrast, is thought to require much higher doses of vitamin C than normal dietary intakes (Parrow et al., 2013). In fact, high dose intravenous vitamin C (IVC) has been administered by physicians for many decades as a complementary and alternative therapy for oncology patients (Padayatty et al., 2010). This practice has continued despite significant controversy in the field as a result of two high profile Mayo Clinic trials carried out in the late 1970s which debunked the initially encouraging findings of Cameron and Pauling (1976, 1978; Creagan et al., 1979; Moertel et al., 1985). Due to the paucity of a strong evidence base for informing appropriate clinical practice, there are significant inconsistencies in administration of IVC therapy to oncology patients (Padayatty et al., 2010). These include huge variability in the dose, frequency, and duration of vitamin C administration.

Research in the 1990s highlighting the important differences between oral and IVC pharmacokinetics resulted in a surge of new research in the IVC field with numerous in vitro, preclinical and clinical studies being undertaken (Parrow et al., 2013; Fritz et al., 2014). The in vitro studies have provided useful insights into potential mechanisms of action and pre-clinical studies have indicated promising efficacy of IVC, however, clinical studies have so far been limited primarily to Phase I safety and pharmacokinetic trials (Du et al., 2012; Parrow et al., 2013). As a result of study design issues with many of the earlier clinical trials there remains controversy as to the efficacy of IVC in the treatment of cancer (Wilson et al., 2014). Many of these trials recruited terminal or end-stage patients, for whom any sort of treatment is unlikely to have an effect, and they often recruited cohorts with mixed cancers, which may respond differentially to IVC depending on the underlying mechanisms involved.

In this review, we pose a series of questions, both clinically relevant and patient centered, related to IVC use in cancer therapy in order to identify the current gaps in our knowledge. Although many of these questions have been adequately addressed, some require further research in order to provide the essential data required to inform good clinical practice.

Q1. Do Oncology Patients Have Compromised Vitamin C Status?

Vitamin C supports many important biological functions through its action as an electron donor (Du et al., 2012), however, the vitamin C status of oncology patients is often not assessed in clinical trials or in clinical practice. Many studies (shown in Table 1) have consistently shown that patients with cancer have lower mean plasma vitamin C status than healthy controls (Torun et al., 1995; Choi et al., 1999; Mahdavi et al., 2009; Sharma et al., 2009; Emri et al., 2012; Mehdi et al., 2013; Huijskens et al., 2016), and a large proportion of them present with hypovitaminosis C (<23 μmol/L) and outright deficiency (<11 μmol/L) (Anthony and Schorah, 1982; Fain et al., 1998; Mayland et al., 2005; Riordan et al., 2005; Hoffer et al., 2015; Liu et al., 2016; Shenoy et al., 2017). Although other case control studies have confirmed lower vitamin C status in patients with cancer (Khanzode et al., 2003; Gupta et al., 2009), their control values were also quite low indicating possible issues with sample collection and/or analysis (Pullar et al., 2018). Severity of the disease also appears to impact on vitamin C status with the proportion of lymphoma patients with hypovitaminosis C being significantly elevated for those with high-burden disease (Shenoy et al., 2017). Furthermore, patients with higher stage breast and cervical cancers had significantly lower vitamin C status than patients with lower stage disease (Ramaswamy and Krishnamoorthy, 1996; Khanzode et al., 2004). Ex vivo studies indicate that tumors from patients with colorectal cancer contained lower vitamin C concentrations than matched normal tissue (Kuiper et al., 2014a), and higher grade colorectal and endometrial tumors had proportionately less vitamin C than lower grade tumors (Kuiper et al., 2010, 2014a).

TABLE 1. Vitamin C levels in plasma or serum of oncology patients.

This observational data supports the premise that oncology patients have compromised vitamin C status, which is likely due to enhanced metabolic turnover as a result of oxidative and inflammatory aspects of the disease process (Reuter et al., 2010). Enhanced oxidative stress and pro-inflammatory biomarkers can also result from chemotherapy (Hunnisett et al., 1995; Nannya et al., 2014). Administration of IVC to oncology patients results in lower circulating vitamin C levels compared with administration of the same amount to healthy controls (Mikirova et al., 2013). The finding that oncology patients have a higher requirement for vitamin C is thought to indicate a lower body pool and/or the higher oxidative and pro-inflammatory status of these patients, as indicated by elevated lipid oxidation products or C-reactive protein concentrations (Torun et al., 1995; Mayland et al., 2005; Mahdavi et al., 2009; Sharma et al., 2009; Mehdi et al., 2013; Mikirova et al., 2013). It is interesting to note that animals which can synthesize their own vitamin C in their livers increase their endogenous vitamin C levels when under a tumor burden suggesting enhanced requirements (Campbell et al., 2015; Cha et al., 2016).

There is evidence that adjunctive cancer therapies may impact negatively on vitamin C status (Table 2). It has been noted that administration of some anticancer therapies, such as cisplatin, fluorouracil, nilotinib, and interleukin-2, can significantly lower the vitamin C status of oncology patients and result in scurvy-like symptoms in some cases (Marcus et al., 1991; Fain et al., 1998; Weijl et al., 1998; Alexandrescu et al., 2009; Oak et al., 2016). Chemotherapy drugs such as cisplatin are known to generate off-target oxidative stress which could contribute to the depletion of vitamin C (Chirino and Pedraza-Chaverri, 2009). Discontinuation of the chemotherapy or administration of supplemental vitamin C to these patients resolved the deficiency symptoms (Fain et al., 1998; Alexandrescu et al., 2009; Oak et al., 2016). Patients with hematopoietic cancers typically undergo conditioning with multiple chemotherapy agents and a number of studies have shown significantly lower vitamin C status following the conditioning regimens (Hunnisett et al., 1995; Goncalves et al., 2009; Nannya et al., 2014; Huijskens et al., 2016; Liu et al., 2016; Rasheed et al., 2017). Although plasma vitamin C levels appear to return to baseline values approximately 1 month following chemotherapy (Mehdi et al., 2013; Rasheed et al., 2017), these values are still well below optimal. Administration of IVC to these patients has been shown to increase their circulating vitamin C levels and decrease markers of lipid oxidation (Hunnisett et al., 1995; Jonas et al., 2000).

TABLE 2. Effects of chemotherapeutic agents on plasma vitamin C levels in oncology patients.

Q2. Is IV the Optimal Route for Vitamin C Administration?

Much of the controversy around vitamin C use in cancer therapy has arisen from early misunderstandings around the pharmacokinetics of oral and IVC. In the mid 1970s Cameron and Pauling (1976, 1978) published findings from 100 terminal cancer patients who had been administered 10 g/d IVC for approximately 10 days, followed by 10 g/d oral vitamin C thereafter. Their work showed significantly enhanced survival in these patients compared with two retrospective cohorts of 1,000 patients who did not receive vitamin C. Subsequently, researchers at the Mayo Clinic attempted to reproduce these results with two randomized controlled trials (RCTs) carried out in 123 patients with advanced malignancies and 100 patients with advanced colorectal cancer (Creagan et al., 1979; Moertel et al., 1985). Neither study showed a significant survival advantage in the patients who received vitamin C.

The negative results of the Mayo Clinic RCTs relegated the use of vitamin C to the arena of complementary and alternative medicine (Padayatty et al., 2010). It wasn’t until the mid 1990s, when the seminal work by Mark Levine’s group highlighted the dramatic differences between the pharmacokinetics of oral and IVC, that the discrepancies between the original Cameron and Pauling studies and the Mayo Clinic RCTs were explained (Levine et al., 1996). While Cameron and Pauling (1976, 1978) had used IVC with subsequent oral maintenance, the Mayo Clinic RCTs comprised divided daily doses of oral vitamin C only (Creagan et al., 1979; Moertel et al., 1985). Intestinal uptake of oral vitamin C is regulated via the sodium-dependent vitamin C transporter-1 (SVCT1) (Savini et al., 2008), which is bypassed with IVC administration, resulting in significantly higher plasma concentrations (Levine et al., 1996). Peak plasma concentrations from oral ingestion rarely exceed 200 μmol/L (Padayatty et al., 2004), however, IVC administration can result in peak plasma concentrations of 20 mmol/L (Table 3). These high concentrations are relatively transient, however, due to rapid clearance by the kidneys, resulting in a half-life of about 2 h in circulation (Stephenson et al., 2013; Nielsen et al., 2015). The realization that IVC may be more effective than oral vitamin C in oncology patients sparked a surge of new research in the field over the past 20 years, particularly around plausible mechanisms of action (Parrow et al., 2013; Fritz et al., 2014).

TABLE 3. Pharmacokinetics of high dose vitamin C in preclinical cancer models and oncology patients with and without chemotherapy.

Q3. Is IVC Safe?

High dose IVC has been used for many decades by complementary and alternative medicine providers and physicians, with few side effects reported (Padayatty et al., 2010). Of 9,328 patients surveyed, only 1% reported minor side effects that included lethargy, fatigue, change in mental status and vein irritation. More recent Phase 1 safety trials of high dose IVC indicate only minor side effects and no adverse events over and above what would be expected from the underlying disease or chemotherapy side effects (Hoffer et al., 2008; Monti et al., 2012; Stephenson et al., 2013; Welsh et al., 2013).

A minor product of vitamin C metabolism is oxalate which has the potential to form calcium oxalate crystals in individuals predisposed to renal stone formation. One patient with a history of renal calculi developed a kidney stone following 2 weeks of continuous IVC infusion (Riordan et al., 2005). Acute oxalate nephropathy has also been reported in several cases following high dose IVC administration, however, the patients all exhibited existing renal dysfunction (Lawton et al., 1985; Wong et al., 1994; Cossey et al., 2013). Therefore, high dose IVC is contraindicated for patients with renal dysfunction due to the inability of the kidneys to clear high circulating concentrations. However, in individuals with normal renal function, IVC infusions of up to 1.5 g/kg body weight resulted in less than 0.5% conversion into oxalic acid (Robitaille et al., 2009).

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is typically screened for prior to high dose IVC administration, due to two case reports of hemolytic anemia in G6PD deficient individuals following 80 g IVC administration (Rees et al., 1993; Quinn et al., 2017). The lower IVC doses typically used for quality of life improvement (e.g., ≤10 g/d) would be unlikely to precipitate hemolytic anemia in G6PD deficient individuals due to lack of in vivo hydrogen peroxide generation at these doses.

Intravenous vitamin C has been shown to interfere with many point-of-care glucose meters, even at low gram doses (Tang et al., 2000). IVC can cause either false positive or false negative results depending on the biochemistry utilized in the monitor, therefore, caution is required for patients needing regular glucose monitoring. However, IVC does not interfere with laboratory-based glucose tests which utilize absorbance photometric rather than electrochemical detection (Tang et al., 2000; Kahn and Lentz, 2015). Some clinicians have used the detection of IVC by point-of-care glucose monitors as a convenient method for determining peak plasma vitamin C concentrations in patients receiving IVC infusions (Ma et al., 2013).

Q4. Does IVC Interfere With Chemotherapy or Radiotherapy?

Potential interactions between vitamin C and chemotherapeutic agents have long been a matter of debate (D’Andrea, 2005; Simone et al., 2007; Lawenda et al., 2008; Verrax and Calderon, 2008). Because of vitamin C’s potent antioxidant activity, many clinicians believe they have to avoid the concurrent use of IVC during all chemotherapy regimens. However, different chemotherapeutic agents act via different mechanisms, and only some act via oxidative mechanisms (Simone et al., 2007). Nevertheless, it has been recommended for administered natural therapies to allow five half-lives to elapse prior to administration of chemotherapeutic agents to eliminate potential interactions (Seely et al., 2007). Because vitamin C has a relatively short half-life of <2 h in circulation due to rapid renal clearance, IVC is typically administered the day before or after chemotherapy administration (Stephenson et al., 2013; Nielsen et al., 2015). However, if the chemotherapeutic agent does not act via oxidative mechanisms, then concurrent IVC administration may not be an issue and would be more patient centered.

Animal studies have indicated that concurrent administration of vitamin C to numerous different chemotherapeutic agents (e.g., gemcitabine, paclitaxel, carboplatin, melphalan, carfilzomib, bortezomib, cisplatin, and temozolomide) synergistically decreased xenograft tumor growth, including in a chemotherapy resistant pancreatic tumor model, and synergistically increased survival (Table 4) (Espey et al., 2011; Ma et al., 2014; Wang C. et al., 2017; Xia et al., 2017). No difference in the anti-tumor activity of the chemotherapeutic agents dacarbazine and valproic acid was observed when combined with high dose parenteral vitamin C in a murine melanoma model (Serrano et al., 2015). Administration of vitamin C to mice and guinea pigs reduced the toxic side effects of paclitaxel and doxorubicin without interfering with their antitumor effects (Fujita et al., 1982; Park et al., 2012). Interestingly, many of the pre-clinical studies showed that administration of IVC alone was as effective at decreasing tumor growth and promoting survival as the chemotherapeutic agents themselves (Table 4).

TABLE 4. Summary of the effects of high-dose vitamin C administration in pre-clinical cancer models.

Human trials have shown no adverse effects from combining IVC with a number of different chemotherapeutic agents (e.g., carboplatin, paclitaxel, decitabine, cytarabine, aclarubicin, gemcitabine, erlotinib, and temozolomide; Table 5), and in many cases decreased off-target toxicity and improved health-related quality of life were observed (Welsh et al., 2013; Kawada et al., 2014; Ma et al., 2014; Hoffer et al., 2015; Polireddy et al., 2017; Zhao et al., 2018). Vitamin C is routinely administered in combination with arsenic trioxide to enhance its efficacy in the treatment of refractory multiple myeloma (Fritz et al., 2014). Although co-administration of high dose thiol antioxidants, such as glutathione and N-acetyl cysteine, was contraindicated in animal models (Chen et al., 2011; Yun et al., 2015), normal supplemental intakes of these antioxidants (e.g., 1–1.5 g/d) by patients would be unlikely to interact with high dose IVC treatments (Padayatty et al., 2006).

TABLE 5. Summary of the effects of IVC administration in clinical studies.

Radiotherapy with ionizing radiation generates free radicals and also increases levels of catalytic transition metal ions in tissues (Cieslak and Cullen, 2015). Cell culture studies have shown radio-sensitizing effects of high dose vitamin C in combination with ionizing irradiation (Shinozaki et al., 2011; Herst et al., 2012; Hosokawa et al., 2015). Only a few studies have been carried out in animal models, with most showing radio-sensitizing effects of vitamin C (Du et al., 2015; Cieslak et al., 2016), although one model showed radio-protective effects (Grasso et al., 2014). These differences likely reflect the timing of the radiation treatment relative to vitamin C administration. For example, in the Grasso et al. (2014) study, radiation treatment was carried out only 2 h after intraperitoneal administration of vitamin C, while in the other studies radiation treatment was carried out on days 3 or 5 following initiation of high dose vitamin C administration (Du et al., 2015; Cieslak et al., 2016). In these latter studies, high dose vitamin C administration was shown to act synergistically with radiotherapy, decreasing tumor growth and enhancing survival (Cieslak and Cullen, 2015; Cieslak et al., 2016). PET imaging showed tumoristatic activity of vitamin C administration alone and radiation therapy alone, however, the two combined showed tumoricidal activity (Cieslak et al., 2016). Addition of vitamin C to radiotherapy and chemotherapy combinations further improved anti-tumor activity and survival (Cieslak and Cullen, 2015; Schoenfeld et al., 2017). Clearly, more studies need to be carried out to determine appropriate tumor models and optimal timing and dosing of IVC combined with radiotherapy.

Q5. Does IVC Decrease the Toxic Side Effects of Chemotherapy and Improve Quality of Life?

Numerous animal studies have shown decreased off-target toxicity of chemotherapeutic agents following administration of oral and IVC (Table 4). Vitamin C administration decreased white blood cell loss, weight loss, ascites accumulation, hepatotoxicity, reticulocytosis, lipid oxidation, and cardiomyopathy induced by the chemotherapeutic agents. In a murine ovarian cancer model, a synergistic decrease in ascites accumulation was observed with high dose vitamin C administration in combination with carboplatin and paclitaxel (Ma et al., 2014). Administration of vitamin C also decreased the toxic side effects of doxorubicin and paclitaxel, as well as cisplatin, which is known to cause off-target oxidative stress (Fujita et al., 1982; Park et al., 2012; Chen et al., 2014). It has been noted that combination therapy with vitamin C enhances sensitivity to specific anti-cancer drugs, thus potentially decreasing the required dosage and ameliorating associated side-effects (Cimmino et al., 2017; Wang G. et al., 2017). Low dose IVC (e.g., 1 g/infusion) is often administered with arsenic trioxide for multiple myeloma or leukemia to improve tolerability of the chemotherapeutic agent (Fritz et al., 2014).

Decreased chemotherapy-related toxicity has been demonstrated in patients with stage III–IV ovarian cancer receiving chemotherapy (carboplatin and paclitaxel) in conjunction with high-dose IVC (75–100 g two times per week) (Ma et al., 2014). Adverse events were evaluated and grade 1 and 2 toxicities were found to be significantly decreased in the group receiving IVC. Decreased toxicities were observed in almost all the evaluated organ systems, e.g., neurological, bone marrow, hepatobiliary/pancreatic, renal/genitourinary, infection, pulmonary, gastrointestinal, and dermatological. Interestingly, despite decreasing chemotherapy-related toxicity, IVC did not appear to adversely affect the anti-cancer activity of the drugs as assessed by survival of the patients or time to disease relapse or progression (Ma et al., 2014). In support of a role for vitamin C in decreasing chemotherapy-related toxicity, a Phase I clinical study of patients with pancreatic cancer treated with gemcitabine reported decreased plasma F2-isoprostanes, an established oxidative stress biomarker, following administration of high dose IVC (Welsh et al., 2013). Thus, IVC is a potentially useful adjunctive therapy to decrease off-target toxicity of chemotherapeutic agents and as a result may also improve the health-related quality of life of oncology patients (Carr et al., 2014; Carr and McCall, 2017).

Since the early 1970s and 1980s, clinicians have reported improved subjective quality of life in patients following administration of both high dose oral and IVC (Cameron and Campbell, 1974; Murata et al., 1982). More recent studies specifically assessing the effects of IVC administration on cancer- and chemotherapy-related quality of life using validated questionnaires have shown decreases in common symptoms, such as fatigue, pain, nausea/vomiting, insomnia and appetite loss, following administration of IVC (Yeom et al., 2007; Takahashi et al., 2012; Stephenson et al., 2013). These studies also demonstrated improvements in overall health and, specifically, enhanced physical, emotional, cognitive, and social functioning. Interestingly, even relatively low IVC doses of 2.5–10 g/infusion provided decreased symptoms and improved quality of life (Yeom et al., 2007; Vollbracht et al., 2011; Kiziltan et al., 2014; Gunes-Bayir and Kiziltan, 2015), suggesting that anti-oxidant/anti-inflammatory functions and/or enzyme cofactor mechanisms of vitamin C may be involved in the quality of life improvements (Carr et al., 2014; Carr and McCall, 2017).

Q6. What Are the Relevant Mechanisms of Action of IVC?

I. Generation of Hydrogen Peroxide

Currently, one of the most widely accepted anti-cancer mechanisms proposed for vitamin C is based on its so-called ‘pro-oxidant’ activity (Parrow et al., 2013). However, this terminology can be misleading as vitamin C itself always acts as an antioxidant, through donation of electrons; the ‘pro-oxidant’ action occurs subsequently and is therefore an indirect effect. As such, the term ‘pro-drug’ has been adopted by some researchers (Chen et al., 2005). In vitro, vitamin C (in the form of the ascorbate anion) is able to reduce transition metal ions, such as ferric and cupric cations, which are present in buffers or in cell culture media. The reduced transition metal ions are then able to generate hydrogen peroxide through reduction of oxygen to the superoxide radical, which can react with itself to form hydrogen peroxide. However, whether catalytically available transition metal ions are found in vivo and can cause enhanced oxidative stress is still a matter of some debate since iron and copper are normally sequestered in transport and storage proteins such as transferrin, ferritin and ceruloplasmin (Carr and Frei, 1999a). Nevertheless, in some pathological situations, such as iron and copper-overload diseases and during tissue injury, free transition metal ions may become more catalytically available (Du et al., 2012). It has also been postulated that transition metal ions are catalytically more available in the extracellular fluid of the tumor microenvironment (Chen et al., 2005).

In vitro studies have shown that addition of high (millimolar) concentrations of vitamin C to cell culture media exhibits differential cytotoxicity toward various cancer cell lines, but not toward normal cultured cells (Chen et al., 2005, 2008). This cytotoxic effect appears to be primarily due to generation of hydrogen peroxide (Figure 1), as evidenced by protection via exogenously added catalase (Sestili et al., 1996; Clement et al., 2001). The differential sensitivity of cancer cell lines to vitamin C-generated hydrogen peroxide may reflect their endogenous catalase content (Doskey et al., 2016). Recently, generation of dehydroascorbic acid from vitamin C added to culture media and subsequent uptake of the dehydroascorbic acid into colorectal cancer cells overexpressing glucose transporter 1 was proposed to increase intracellular oxidative stress through oxidation of glutathione (Yun et al., 2015). However, because catalase was not added to the cell cultures, generation of hydrogen peroxide and subsequent oxidative stress due to this reactive oxygen species, rather than dehydroascorbic acid, cannot be ruled out. Furthermore, recent research has shown that addition of vitamin C is more effective than comparable concentrations of enzymatically generated hydrogen peroxide, and addition of non-cytotoxic concentrations of vitamin C with hydrogen peroxide exhibits synergistic effects (Rouleau et al., 2016). This indicates that additional vitamin-dependent anti-tumor mechanisms are occurring.

FIGURE 1. Proposed mechanisms of action of intravenous vitamin C in cancer cells. (a) Transition metal ion-dependent generation of hydrogen peroxide (H2O2) and oxidation of intracellular glutathione (GSH) which causes enhanced oxidative stress and potential cell death. (b) Enhances ten-eleven translocation (TET) DNA hydroxylase activity and jumonji histone demethylase (JHDM) activity which alters gene transcription. (c) Decreases HIF protein levels which decreases gene transcription. (d) Increases collagen synthesis resulting in decreased tumor invasion and metastasis.

Pharmacokinetic studies in oncology patients have provided insight into the doses of IVC required to generate high (millimolar) concentrations of vitamin C in plasma (Table 3) (Hoffer et al., 2008; Stephenson et al., 2013; Welsh et al., 2013; Nielsen et al., 2015). It is generally believed that plasma vitamin C concentrations > 20 mmol/L are required for hydrogen peroxide generation in vivo (Chen et al., 2008). However, it should be noted that hydrogen peroxide generated in the circulation will be rapidly detoxified by antioxidant enzymes present in erythrocytes, including catalase, glutathione peroxidase, and peroxiredoxin-2 (Guemouri et al., 1991; Low et al., 2008). Thus, erythrocytes will act as a sink for hydrogen peroxide generated in the circulation (Zhang et al., 2016). This premise has been confirmed in animal studies whereby low concentrations of hydrogen peroxide were detected in extracellular fluid, but not in blood, following administration of high dose parenteral vitamin C (Chen et al., 2007, 2008).

Administration of high dose parenteral vitamin C (i.e., 1–8 g/kg/d) to murine models has been shown to decrease tumor growth and enhance survival (Table 4) (Du et al., 2012; Campbell and Dachs, 2014). The ‘pro-oxidant’ activity of vitamin C is thought to predominate at these higher doses as low levels of hydrogen peroxide and the ascorbyl radical intermediate were detected in the extracellular fluid of rodent models (Chen et al., 2007, 2008). Furthermore, co-administration of high dose thiol antioxidants such as glutathione and N-acetyl cysteine inhibited the anti-tumor effect of high-dose vitamin C administration (Chen et al., 2011; Yun et al., 2015). As such, in animal models administered very high dose vitamin C, there is some evidence to suggest that a ‘pro-oxidant’ mechanism is occurring. However, it should be noted that the doses of vitamin C administered to animal models are typically four to eight times higher and more frequent (daily vs. twice a week) than those administered to patients. It should also be noted that most of the animal models used (other than Gulo knockout mice and guinea pigs) can also synthesize their own vitamin C. As yet, there is little evidence to indicate that the proposed ‘pro-oxidant’ mechanism is occurring in oncology patients administered IVC (Welsh et al., 2013).

II. Enzyme Cofactor Activities

Animal studies, particularly in vitamin C-requiring animals such as Gulo knockout mice and guinea pigs, have indicated that oral dosing (e.g., 0.3–5 g/L) (Casciari et al., 2005; Gao et al., 2007; Campbell et al., 2015, 2016a; Yang et al., 2017) and low parenteral doses of vitamin C (e.g., 0.1 g/kg/d) (Belin et al., 2009) exhibit comparable decreases in tumor growth to high dose parenteral vitamin C (i.e., 1–8 g/kg/d; Table 4). Since hydrogen peroxide is not detected following oral or low dose IVC administration (Chen et al., 2007), this suggests possible tumor growth inhibition mechanisms other than hydrogen peroxide generation are likely operating in these situations. Numerous cell culture and pre-clinical studies have shown regulatory effects of vitamin C administration on various transcription factors and cell signaling pathways, with subsequent effects on cell cycle, angiogenesis, and cell death pathways (Parrow et al., 2013). Analysis of tissues from various animal models has indicated regulation of numerous genes and their products following administration of vitamin C (Gao et al., 2007; Belin et al., 2009; Park et al., 2009; Yeom et al., 2009; Lee et al., 2012; Ma et al., 2014; Campbell et al., 2015, 2016a,b). Thus, it appears that vitamin C administration, particularly at lower doses, has gene-regulatory effects.

Vitamin C is a cofactor for a family of metalloenzymes with pleotropic biosynthetic and gene regulatory roles (Du et al., 2012). It has long been known to be a cofactor for the three hydroxylase enzymes essential for the stabilization of collagen tertiary structure (Englard and Seifter, 1986). Research has shown increased collagen encapsulation of tumors in Gulo knockout mice with melanoma and breast tumors following supplementation with low dose oral vitamin C (0.15 g/L, Figure 1) (Cha et al., 2011, 2013). Decreased metastases were also observed in these models. This work has been confirmed recently in a pancreatic cancer model (Polireddy et al., 2017). Increased levels of collagen were detected in tumor stroma of vitamin C-treated mice and this was associated with decreased tumor invasion. Resected tumors from pancreatic cancer patients treated with IVC also exhibited increased collagen content (Polireddy et al., 2017). Since enhanced collagen mRNA levels were also observed in the tumors from vitamin C-treated mice, this suggests that gene regulatory mechanisms are also involved.

In the early 2000s, vitamin C was demonstrated to regulate the transcription factor hypoxia inducible factor-1α (HIF-1α) (Hirsila et al., 2003; Koivunen et al., 2004; Hirota and Semenza, 2005). HIF-1α is a constitutively expressed transcription factor which regulates numerous pro-survival genes. Under normoxic conditions, HIF-1α is downregulated via hydroxylase-mediated modifications which prevents coactivator binding and targets HIF for proteosomal degradation. In the hypoxic core of solid tumors HIF-1α is upregulated due to the absence of substrates and cofactors required for hydroxylase-dependent downregulation. Vitamin C is a cofactor for the HIF hydroxylases (Kuiper and Vissers, 2014). Animal studies have shown downregulation of HIF-1α and downstream pro-survival proteins (e.g., glucose transporter 1, vascular epithelial growth factor, and carbonic anhydrase) following administration of oral or parenteral vitamin C (Figure 1) (Campbell et al., 2015, 2016a,b). In human colorectal tumors and other tumors there was an inverse association between tumor vitamin C levels and expression of HIF and related downstream proteins (Kuiper et al., 2010, 2014a; Jozwiak et al., 2017), and enhanced disease-free survival was observed in patients who had higher vitamin C levels in their tumors (Kuiper et al., 2014a).

Recent research has uncovered a role for vitamin C in epigenetic regulation via acting as a cofactor for DNA and histone demethylases which belong to the same family of enzymes as the collagen and HIF hydroxylases (Camarena and Wang, 2016; Gillberg et al., 2017). Vitamin C acts as a cofactor for the ten-eleven translocation (TET) dioxygenases which hydroxylate methylated cytosine moieties in DNA (Blaschke et al., 2013; Minor et al., 2013; Yin et al., 2013). The hydroxymethylcytosine mark can be further oxidized and subsequently removed through both active and passive DNA repair mechanisms, but may also represent an epigenetic mark in its own right (Camarena and Wang, 2016). It is noteworthy that a decrease in DNA hydroxymethylation has been observed in cancer cells and tumors (Haffner et al., 2011; Kudo et al., 2012; Lian et al., 2012; Kroeze et al., 2015). Recent research has indicated that vitamin C can modulate the epigenome of leukemia cells and regulate hematopoietic stem cell function in a TET-dependent fashion, suppressing leukemia progression in pre-clinical models (Figure 1) (Agathocleous et al., 2017; Cimmino et al., 2017; Mingay et al., 2017; Zhao et al., 2018). Research has also indicated that vitamin C treatment increases hydroxymethylation in lymphoma and melanoma cells, and causes a decrease in tumor-cell invasiveness and clonogenic growth (Gustafson et al., 2015; Shenoy et al., 2017). Thus, epigenetic mechanisms may be involved in the attenuated metastasis that has been observed in animal models and patients following administration of vitamin C (Padayatty et al., 2006; Pollard et al., 2010; Cha et al., 2013; Polireddy et al., 2017).

Vitamin C is also a cofactor for several Jumonji C domain-containing histone demethylases (JHDM) that catalyze histone demethylation (Camarena and Wang, 2016). Methylation of lysine and arginine residues on histones is closely associated with activation or silencing of transcription. JHDM can demethylate mono-, di-, and trimethylated histone lysine and arginine residues (Klose et al., 2006). Vitamin C is required for optimal catalytic activity and demethylation by JHDM (Tsukada et al., 2006). The involvement of vitamin C in JHDM-dependent histone demethylation was confirmed in somatic cell reprogramming and T-cell maturation (Wang et al., 2011; Manning et al., 2013; Ebata et al., 2017). Thus, it appears that vitamin C can regulate the epigenome via acting as a cofactor for both DNA and histone demethylases. Due to the multitude of genes regulated through both DNA and histone demethylation, it is likely that epigenomic regulation by vitamin C may play a major role in its pleiotropic health promoting and disease modifying effects. Continuing research in this field will no doubt reveal exciting insights and treatment possibilities.

III. Antioxidant and Anti-inflammatory Activities

It has been suggested that oxidative stress, chronic inflammation, and cancer are closely linked (Reuter et al., 2010). Oxidative stress can activate a variety of transcription factors, leading to the expression of hundreds of different genes, including those of pro-inflammatory cytokines. Vitamin C is a potent antioxidant both in plasma and within cells due to its ability to scavenge a wide range of reactive oxygen species, thereby protecting important biomolecules from oxidative damage (Carr and Frei, 1999a). Patients with cancer tend to have elevated markers of oxidative stress, such as malondialdehyde (Hunnisett et al., 1995; Torun et al., 1995; Mahdavi et al., 2009; Sharma et al., 2009; Mehdi et al., 2013). An early study in healthy volunteers administered low dose IVC showed a decrease in lipid oxidation biomarkers (Muhlhofer et al., 2004). More recently, administration of high dose IVC to patients with pancreatic cancer produced a decrease in F2-isoprostanes, a marker of systemic oxidative stress (Welsh et al., 2013), suggesting a systemic antioxidant effect of IVC. Detection of ascorbyl radicals in the blood and extracellular fluid of animal models has been used as evidence for a ‘pro-oxidant’ role for vitamin C, i.e., they are an intermediate in the reduction of transition metal ions (Chen et al., 2007, 2008). Although very low (nanomolar) levels of ascorbyl radical were detected in the circulation of patients in the human intervention study (Welsh et al., 2013), these radicals can also be formed through vitamin C’s oxidant scavenging function (Carr and Frei, 1999a). Thus, detection of low level ascorbyl radicals, which parallels ascorbate concentrations, could instead be indicative of oxidant scavenging, i.e., an antioxidant, role of vitamin C (Muhlhofer et al., 2004).

Elevated markers of inflammation, such as C-reactive protein and various cytokines, have been reported in oncology patients (Mayland et al., 2005; Mikirova et al., 2012, 2013, 2016; Nannya et al., 2014). Vitamin C exhibits anti-inflammatory functions via modulating cytokine levels (Carr and Maggini, 2017) and animal models of melanoma and breast cancer have indicated decreased pro-inflammatory cytokine (interleukin-6, interleukin-1) levels following vitamin C administration (Cha et al., 2011, 2013). In patients with various cancers, administration of 25–50 g IVC decreased a number of different inflammatory mediators (such as C-reactive protein) and pro-inflammatory cytokines (Mikirova et al., 2012, 2016). Because oxidants can enhance inflammation, it is not clear if the cytokine-modulatory effects of vitamin C are due to its oxidant scavenging function or its gene regulatory cofactor functions (Song et al., 2017). It is noteworthy that patients with higher levels of inflammation also appear to have a higher requirement for vitamin C (Mikirova et al., 2013).

Q7. What Are the Optimal Doses, Frequency, and Duration of IVC Therapy?

Intravenous vitamin C has been used for decades by health care professionals with very little consistency in the dose, frequency, or duration of use. A survey of complementary and alternative medicine practitioners showed an average dose of 28 g/infusion (range of 1–200 g/infusion), a frequency of approximately twice a week (range of 1–7 times per week), and about 19 treatments per patient (range of 1–80 treatments) (Padayatty et al., 2010). Because of the prevailing ‘pro-oxidant’ paradigm of IVC, it is generally believed that ‘more is better’ and doses as high as 200 g/infusion have been administered to oncology patients (Table 5) (Padayatty et al., 2010; Stephenson et al., 2013). Lower IVC doses of 2.5–10 g/infusion have been shown to decrease common cancer- and chemotherapy-related symptoms and improve health-related quality of life (Carr et al., 2014).

Although the ‘pro-oxidant’ activity of IVC has yet to be conclusively demonstrated in humans, there may be alternate rationales for administering high dose IVC. Solid tumors exhibit dysregulated blood supply which limits diffusion of oxygen and other nutrients to the core of the tumors. Utilizing a well-established multicell-layered, three-dimensional pharmacokinetic model, Kuiper et al. (2014b) measured vitamin C diffusion and transport parameters through dense tissue. The investigators demonstrated that supra-physiological plasma concentrations (i.e., up to 500 μmol/L) were required to achieve effective delivery of vitamin C to poorly vascularized tumor tissue. Enhanced delivery of vitamin C to the hypoxic core of solid tumors would facilitate down-regulation of the HIF-driven hypoxic response (Kuiper and Vissers, 2014). The efficacy of IVC against metastatic tumors could also be due, in part, to the generally smaller size of metastases allowing better diffusion of vitamin C into the tumor, thus facilitating its various gene-regulatory mechanisms. Uptake of vitamin C into tumor cells may also be dependent upon vitamin C transporter (SVCT2) status and polymorphisms, which is an area that warrants further investigation (Wang C. et al., 2017; Wohlrab et al., 2017).

Preclinical studies indicate that a single infusion of vitamin C is not as effective as multiple infusions and a higher frequency of administration appears to be more beneficial (Takemura et al., 2010; Campbell et al., 2016b). For example, daily intraperitoneal injections of vitamin C slowed tumor growth in the mice and downregulated HIF-1α and downstream gene products to a greater extent than injections every other day (Campbell et al., 2016b). A trial of castration-resistant prostate cancer patients who were administered only one 60 g infusion per week did not show diminished PSA levels or disease remission after 12 weeks (Nielsen et al., 2017). However, daily administration of high dose IVC to rodents with implanted prostate tumor cells showed decreased tumor growth and lung metastases (Pollard et al., 2010). Although continuous vitamin C infusion has been piloted (Riordan et al., 2005), this is usually only practical if the patients are hospitalized. However, because IVC solutions are remarkably stable, even at ambient temperature and in the light (Carr et al., 2018), it might be possible to utilize continuous infusion bottles typically used for home intravenous antibiotic administration. However, since intermittent infusions allow for high peak plasma concentrations (de Grooth et al., 2018), there is debate as to whether continuous infusion is better than intermittent infusions over a longer period (Cameron, 1991; Gonzalez et al., 2012). As mentioned above, high peak concentrations may be required to facilitate uptake of vitamin C into solid tumors.

Conclusion

• Do oncology patients have compromised vitamin C status? Yes, studies consistently show that patients with cancer have lower mean circulating vitamin C levels than healthy volunteers. These patients also exhibit higher rates of hypovitaminosis C and deficiency. Furthermore, chemotherapy can impact negatively on the vitamin C status of oncology patients. Because of vitamin C’s supportive functions in the body, increasing the vitamin C status of oncology patients is likely to be of benefit.

• Is IV the optimal route for vitamin C administration? Yes, IV administration of vitamin C can provide significantly higher peak plasma concentrations because it bypasses the regulated intestinal uptake of oral vitamin C. These higher concentrations are believed to be required for some of the proposed anti-cancer mechanisms of vitamin C and may also enhance diffusion of the vitamin into the hypoxic core of solid tumors.

• Is IVC safe? Yes, IVC is remarkably safe, considering the massive (>75 g) doses that are often administered. However, there are several currently known situations where caution is warranted. These include patients with impaired renal function due to their inability to adequately clear high IVC doses from circulation, and patients with G6PD deficiency due to inability to detoxify oxidative stress generated by high dose IVC administration. Caution is also required for patients requiring regular glucose monitoring due to the potential for IVC to interfere with point-of-care glucose monitors.

• Does IVC interfere with chemotherapy or radiotherapy? Clinical trials indicate that IVC does not adversely interfere with chemotherapy and pre-clinical studies indicate that it may in fact act synergistically in combination with different chemotherapeutic agents. There is as yet limited research around interference with radiotherapy, with conflicting results likely due to the timing of the interventions.

• Does IVC decrease the toxic side effects of chemotherapy and improve quality of life? Both pre-clinical and clinical studies indicate that IVC can decrease the off-target toxicity of chemotherapeutic agents, likely through its antioxidant and anti-inflammatory activities, without affecting the anti-cancer activities of the chemotherapeutic agents. The reduction in specific chemotherapy-related side-effects results in an overall improvement in the health-related quality of life of oncology patients.

• What are the relevant mechanisms of action of IVC? A number of plausible anti-cancer mechanisms have been proposed, such as indirect generation of hydrogen peroxide, enzyme cofactor activities (e.g., collagen synthesis, HIF hypoxic response regulation, TET and JHDM epigenetic regulation), as well as antioxidant and anti-inflammatory functions. Different cancers likely respond differently to IVC therapy depending upon their underlying mechanisms. Thus, future work should focus on tailoring IVC regimens to specific cancers or cancer subtypes, e.g., hematological cancers that are driven specifically by TET mutations may respond more readily to IVC therapy.

• What are the optimal doses, frequency, and duration of IVC therapy? Although these are the most relevant questions clinically, there is still little consensus as to how much, how often and for how long to administer IVC to oncology patients. The different proposed mechanisms of action provide some insight into dosing, with higher doses (>50 g/d) being required for some anti-cancer mechanisms, and lower doses (≤10 g/d) being sufficient for decreasing symptoms and improving quality of life. Pre-clinical studies indicate that more frequent dosing exhibits enhanced efficacy. However, depending on the underlying mechanisms involved, it is possible that anti-tumor activity may require long term treatment and follow-up, e.g., over years rather than just the few weeks or months of most clinical trials. It is unlikely that future large scale IVC RCTs will be carried out due to the prohibitive costs. Nevertheless, smaller scale studies, if well designed, have the potential to contribute relevant and translatable findings to inform good clinical practice.

Author Contributions

AC conceived and wrote the review. JC contributed clinical input.

Funding

AC was supported by a Health Research Council of New Zealand Sir Charles Hercus Health Research Fellowship (#16/037).

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Administration of Intravenous Vitamin C in Novel Coronavirus Infection (COVID-19) and Decreased Oxygenation – Full Text View

Previous research has shown that high dose intravenous vitamin C (HDIVC) may benefit patients with sepsis, acute lung injury (ALI), and the acute respiratory distress syndrome (ARDS). However, it is not known if early administration of HDIVC could prevent progression to ARDS.

We hypothesize that HDIVC is safe and tolerable in Coronavirus disease 2019 (COVID-19) subjects given early or late in the disease course and may reduce the risk of respiratory failure requiring mechanical ventilation and development of ARDS along with reductions in supplemental oxygen demand and inflammatory markers.

The purpose of this study is to assess the safety, tolerability, potential efficacy of high dose intravenous vitamin C (HDIVC) therapy for patients with COVID-19 and decreased oxygenation. COVID-19 is a rapidly evolving pandemic with numerous prediction models suggesting potential shortages in ventilators, ICU beds, and high rates of hospital mortality. Case-series suggest sepsis and the acute respiratory distress syndrome (ARDS) are driving hospitalizations, morbidity (ICU beds, ventilator use, organ failures), and mortality. A therapy is urgently needed to be given early in the disease course in order to attenuate the infectious and inflammatory process, reduce risk of intubation, and reduce progression of organ failure and ARDS. By administering HDIVC at the first objective sign of worsening oxygenation, documented by change in peripheral capillary oxygen saturation (SpO2) to fraction of inspired oxygen (FIO2) ratio (S/F) or decreased SpO2 at baseline (mild hypoxia group), HDIVC may reduce the inflammatory process and development of respiratory failure requiring intubation. We will also enroll patients already in respiratory failure on ventilators (severe hypoxia group) and document safety and tolerability in both cohorts. By calculating ventilator and ICU-free days, we can potentially signal clinically relevant endpoints that could be used in larger trials needed to answer a crucial therapeutic question-can early administration of HDIVC in COVID-19 lead to faster recovery or improve outcomes? Moreover, we will document change in inflammatory markers that are elevated in COVID-19 (d-dimer, CRP, LDH, liver enzymes, and ferritin) to develop a mechanistic understanding and risk stratification of response to HDIVC infusion. Ultimately, if HDIVC is deemed safe and tolerable in hospitalized COVID-19 subjects, a larger clinical trial will be indicated. AVoCaDO will produce safety and tolerability data to test HDIVC in a multi-center, rapid, randomized, placebo-controlled trial of subjects with COVID-19.

90,000 🧬 Should you take vitamin D?

Doctors often advise drinking this vitamin, although its usefulness in preventing or treating disease has not been proven. We figure out in what cases its deficiency is really dangerous to health.

What is it

Vitamin D is the collective name for a group of calciferols – fat-soluble organic compounds. For humans, the most significant active varieties of D2 are ergocalciferol, which enters the body only with food, and D3, cholecalciferol, which comes both with food or supplements and is synthesized by skin cells in the light.Some researchers even find support for the hypothesis that vitamin D can be considered an indicator of impaired health and a potential universal remedy for its recovery.

Vitamin D is necessary for the full absorption and assimilation of calcium, without which mineralization and bone growth is impossible. D also regulates the metabolic exchange of phosphorus compounds and is involved in several other biochemical reactions, the research of which is ongoing.

“Vitamin D is for the body like gasoline for the engine,” explains endocrinologist Olga Shamrina.- In fact, it is a prohormone, it has effects similar to hormonal ones. For example, it regulates the formation of the sex hormones testosterone and estrogen from cholesterol. Participates in the synthesis of thyroid hormones – the main anti-stress center of the body, responsible for reducing the perception of stress. Vitamin D corrects the level of insulin in the blood, speeds up the metabolism, promotes the absorption of useful elements from food and, at the same time, weight loss. It regulates all human activity at the cellular level, including acting as an immunomodulator. “

Why did people decide to take vitamins

Nitrogenous organic substances, which are essential for vital activity – amines, which are not produced in the body, were once called vitamins. They were investigated and determined, which enzyme in the cell provides each of them. Signs of a deficiency of one or another vitamin in the diet were formulated: if symptoms of a specific disease appear with a lack of a substance, and after replenishing the amount of vitamin they disappear, the ailment is due to a deficiency and vitaminization is a direct treatment.This was the case, for example, with vitamin C, which cures scurvy.

In the middle of the twentieth century, the range of vitamins expanded, at the same time a new concept appeared: even if a minor deficiency does not cause symptoms, a generous vitamin supplement to the body can improve well-being and have a beneficial effect on related ailments. Numerous attempts to treat any disease with horse doses of vitamin C in clinical practice did not take root. Vitamin A in large doses turned out to be simply toxic to the body.

“D is the only vitamin that has an effect on immunity, and this has been confirmed in many studies,” says Olga Sidorovich, allergist-immunologist at GMS Clinic. – I personally take only it from vitamins from October to March. The effect of other vitamins for the prevention of colds, including the widely used vitamin C for this purpose, has not been proven.

Doctors favor vitamin D mainly because in northern latitudes, the vast majority of the population cannot get the normal amount of vitamin D, either from food or sunlight.In the autumn-winter period, vitamin D deficiency becomes especially acute. A deficiency is considered to be less than 30 ng / ml.

Why deficit is dangerous

“Very often in winter and spring, patients come to a neurologist with muscle pain or incomprehensible fatigue,” confirms Varvara Khaletskaya, a neurologist at the Fantasy Children’s Clinic. – On research it turns out that the level of vitamin D is lowered. Although in the summer such patients sometimes come for an appointment, so not all of this is due to the length of daylight hours. “

According to Olga Shamrina, over the past 8 years of practice, she only twice got patients without a vitamin D deficiency, and both times they were not Russians. For southerners, prolonged exposure to the sun causes tanning, in which D3 synthesis is slowed down by the body in order to avoid overdose. Also, with age, the sensitivity of the receptors in the skin, which are responsible for the absorption of vitamin D in the light, decreases.

Vitamin D deficiency is critical in young children.This is the main reason for the development of rickets. Also, in the case of a deficiency, there is a high risk of developing respiratory infections, asthma, autoimmune diseases, or the development of insulin resistance. But this problem has been reliably solved for today.

“For many years I have not seen children with rickets due to vitamin D deficiency,” says Vladimir Yagodkin, pediatrician of the Fantasy clinic. – A sign that a child lacks vitamin D may be a fontanelle that does not overgrow for a long time or the absence of hair on the back of the head.If there are still children with a deficit, then perhaps in a distant wilderness or in third world countries. I myself take vitamin D as a preventive measure and I advise all the adults I know to do it. ”

Olga Shamrina says that in the United States and Great Britain, most endocrinologists and general practitioners do not accept those who complain of general ill health without testing for vitamin D. load.The analysis itself is quite expensive and is not included in the regulations for the provision of free medical care.

“The analysis is needed so that the doctor can prescribe the correct form and individual dosage of external vitamin D,” adds Dr. Shamrina. – It depends on the function of the parathyroid gland, age, excess weight. After all, vitamin D can accumulate in adipose tissue and not work, so a large dosage is required for overweight people. In those suffering from gastritis or gastroduodenitis, the vitamin may not be absorbed in the gastrointestinal tract.A 78-year-old patient of mine with abnormal parathyroid hormone function has been receiving vitamin D in fat-soluble form for a long time without any benefit. After replacing it with a water-soluble form, which is metabolized by the kidneys, the state of health immediately improved. ”

Criticism

The wave of publications about the healing properties of vitamin D in medical, paramedical and non-medical publications began about 30 years ago and does not think to subside. If you type “vitamin D” next to the name of any disease on an Internet search engine, you will find many articles about the beneficial effects of treatment or the effect of a deficiency in the course of the disease.For example, here is a study that a lack of vitamin D can lead to a more severe course of coronavirus infection. But some experts disagree on the absolute benefits of taking it.

“All statements about the direct effect of vitamin D on immunity, insulin and general well-being have nothing to do with evidence-based medicine,” says Vasily Vlasov, vice president of the Society of Evidence-Based Medicine Specialists, MD. – There are no convincing reproducible studies on the healing properties of calciferols in the prevention, and even more so in the treatment of real diseases.Over the past two to three decades, there have been hundreds of articles on the successful use of vitamin D in the treatment of diseases ranging from baldness and impotence to strokes and hypertension. All of them have not been verified by subsequent clinical trials. Therefore, when now similar articles appear every year, the attitude towards them is rather skeptical. ”

Severe vitamin D deficiency is common in a wide variety of conditions, such as obesity and type 2 diabetes.But doctors look at restoring normal levels differently.

“The importance of vitamin D for the body is just a fashionable topic,” says Aleksandr Lavrischev, therapist at the Semeynaya clinic. As a few years ago, vitamin E was fashionable among hepatologists, after a series of publications on this topic. If the doctor wanted to look progressive, he had to try large doses of vitamin E on the patient. 90% of the Russian population live with vitamin D deficiency. It is easy and inexpensive to synthesize it, and if there is a huge market, then big business appears.As a medicine, vitamin D is hardly effective: I know of no cases when a patient with an unclear illness would recover only from filling the deficiency of this substance. ”

I do not quite agree with her colleague Olga Shamrina, who has repeatedly taken exhausted patients with a noticeable deficiency of vitamin D, who have previously bypassed many doctors who have not found any pathologies.

“If a person has no complaints, this does not mean that there is no vitamin D deficiency,” the doctor says.- You may never notice it. It’s just that sometimes you will get tired more than usual, it will be difficult to wake up, sometimes you will react more accentuatedly to the change of weather. A married couple accidentally came to me, having visited many doctors before. A 45-year-old woman could not get pregnant for more than 3 years, she was going to do IVF. Analysis for vitamin D showed that both spouses had a pronounced deficiency. After a short course of treatment with only vitamin D, everything went smoothly. Now the child is already one and a half years old. ”

Who is assigned

Taking vitamin D during pregnancy is recommended only in special cases, usually it is enough to balance the diet.It is usually prescribed to older people, more often women, as a therapy for osteoporosis, more precisely, for the prevention of osteoporotic fractures.

However, a meta-analysis of studies of this practice in nursing homes has shown that long-term consumption of tablets with calcium and vitamin D does not prevent fractures, but, on the contrary, increases the frequency of heart attacks. Patients with osteoporosis lack, rather, elastic cartilage tissue on which calcium could settle and accumulate.With worn out cartilage, this trace element only strengthens the bones, which become not only hard, but also fragile.

“Until the end of the twentieth century, vitamin D was used only in the treatment of rickets and osteoporosis,” recalls Vasily Vlasov. – Including because we do not know how to effectively treat osteoporosis with anything. Observations have shown that the number of fractures in the elderly is not decreasing. If there is no real, vital need for vitamin D, no amount of it will improve health.This situation is similar to the widespread use of multivitamins that has become fashionable. They are taken not for medical reasons, but for prophylaxis, often without the participation of a doctor. Dosages, as in the case of vitamin D, are much lower than therapeutic dosages. And the positive effect has also not been proven. But the market share is estimated in billions of dollars. ”

Many developed countries solve the problem of vitamin D deficiency by enriching them with food for mass consumption: milk, yoghurts and even wheat flour.In the United States and Canada, this began to be practiced back in the 1950s, and for a long time this requirement for manufacturers was in the nature of a legislative prescription. Similar programs are popular in Western Europe. In the UK, for example, it is predicted that adding 100 mcg of a vitamin (4000 IU) to 1 kg of flour will in a short time reduce the proportion of people with insufficient vitamin D intake from 93% to 50%.

Important to remember

  • vitamin D by itself does not heal or enhance immunity, but only helps the body to cope with some problems
  • Do not take vitamin D without consulting a doctor
  • there is no point in doing a vitamin D test “just in case” if you are not complaining about anything.
  • 90,087 90,000 “Supplements killed my liver and nearly killed me”

    Photo by Jim McCants

    Email before photo,

    Jim McKents had a liver transplant after taking dietary supplements

    The story of an American who had transplanting the liver after taking green tea extract in capsules, again made people talk about dietary supplements.

    When 50-year-old Jim McKents started taking green tea capsules, he hoped that antioxidants would help him avoid heart attacks and lead an active lifestyle until old age.Every day he walked (or ran) several kilometers, tried to lose weight and eat in a balanced way.

    “I was prepared for these capsules to be useless and I wasted money. I was willing to take this risk. But I never expected my liver to fail,” McKents says. On the day of his son’s high school graduation, he felt unwell.

    “You are all yellow,” his wife said to Jim, and they urgently went to the hospital.

    For several days the doctors did tests and could not make a diagnosis.Finally, McKents was told that only a liver transplant would save him. Without a transplant, he would not have lived for a week – the liver completely failed.

    By a miraculous coincidence, a donor organ suitable for transplantation was found in one day. Now, four years after the surgery, McKents is experiencing constant abdominal pain, is on constant medication, and has difficulty walking.

    He sued Vitacost, a capsule manufacturer. They are sold over the counter – because the supplement is made from tea, it is considered a food product in the United States, not a medicine, and is not certified or tested.

    “There are no warnings about possible risks or side effects in the instructions,” says McKents.

    Photo author, Getty Images

    Experts call the McKents case extremely unusual.

    However, about 80 cases of liver disease in people taking granulated green tea are annually recorded in the world: for example, liver and kidney failure occurred in a 17-year-old resident of the Canadian province of Ontario Madeleine Papineau.

    Potentially toxic green tea ingredient EGCG (epigallocatechin-3-gallate) is a potential hazard.This catechin (a substance with antioxidant properties) is found in abundance in the drink, and its concentration in granules is increased hundreds of times.

    “If you just drink reasonable amounts of green tea, you are not in danger,” Herberg Bonkowski, professor at Wake Forest School of Medicine in North Carolina, told the Air Force. He has been studying the effects of green tea supplements on the liver for nearly 20 years.

    “Those who take highly concentrated extracts are at risk. They are usually drunk by those who want to lose weight, and they often eat very little solid food during this period.We know from animal studies that the body of a hungry, emaciated animal assimilates far more catechins than the body of more well-fed individuals. Another risk factor could be the concurrent use of other drugs or alcohol, “says the professor.

    So are supplements harmful?

    In the UK, supplements must pass EU safety and health checks.

    Regulatory approved additives , purchased from reliable manufacturers, are almost always safe and complete with instructions for use, doctors assure.

    However, as noted by Dr. Wayne Carter of the University of Nottingham, it cannot be argued that food additives cannot be potentially harmful.

    For example, if you take a higher dose of such a drug, there may be a health risk.

    Photo Credit, Getty Images

    Although in many cases excess substances will be excreted from the body, this can pose a threat to the liver, which detoxifies the substances we consume.

    “It seems to me that sometimes people think like this:” This is good for me, so if I take a large dose, it will make me even better. “However, there is a risk, “says Dr. Carter.

    Taking many supplements at the same time can also be dangerous, the expert warns.

    Sometimes they can interact with each other: one drug can enhance the effect of another. In other cases, they can contain one or more of the same nutrients, which leads to an overdose.

    Some of us find it more difficult to efficiently process certain substances, and their effect on the body also depends on this.

    “The thing about these drugs is that they are safe for most people, but not for everyone,” adds Carter.

    However, if these are the potential risks, what are the health benefits?

    Vitamins required and optional

    Several dietary supplements are recognized by most experts as universally useful.

    The British National Health Service (NHS) recommends that women who wish to become pregnant take folic acid (aka vitamin B9).This recommendation is also valid for pregnant women up to 12 weeks in order to prevent a number of congenital diseases in the child.

    The British government said this week that it will discuss with experts the possibility of adding folate to flour.

    There are two more vitamins that mainstream medicine strongly recommends: D and K.

    Vitamin D is also recommended for infants, children between the ages of one and four, and people who lack sunlight.

    This applies to those who often feel weak or do not leave the house, as well as those who constantly wear closed clothes.

    In general, taking vitamin D is recommended for almost any person.

    Author of the photo, Getty Images

    Signs to the photo,

    The British Health Service notes that all vitamins and minerals that a person needs are contained in healthy food

    A lack of vitamin D, which we mainly obtain from sunlight, can lead to various types of deformations bones: rickets in children and osteomalacia in adults.

    “A hundred years ago, most of the children in London had rickets. However, the situation improved after the children were given vitamin supplements,” says Benjamin Jacobs of the Royal National Orthopedic Hospital.

    In addition to vitamin D, almost all young children in Britain are eligible for a vitamin K injection – within the first 24 hours after birth to prevent internal bleeding.

    Healthy Nutrition & Supplements

    Dr. Jacobs notes that supplements are also recommended for dieters and allergy sufferers.

    For example, the UK National Health System (NHS) recommends that vegans consume vitamin B12, which is naturally found only in animal products.

    However, for many other supplements, their universal benefits are less clear.

    For example, NHS experts say that most people do not need to take vitamin supplements, since all the necessary vitamins and minerals, except for vitamin D, are already in the food if a person eats a balanced diet.

    The benefits of fish oil capsules, which are often taken to improve heart or brain function, are also less obvious.

    So, scientists came to the conclusion that the statement about the benefits of such capsules for the heart is largely mistaken.

    As noted by Sam Jennings, head of consulting firm Berry Ottaway & Associates Ltd, nutrition is an ever-evolving science with new data emerging all the time.

    “Obviously, nutritional supplements cannot be equally beneficial to all people, as it depends on the individual’s characteristics and whether the person will benefit from any additional nutrient,” she says.

    Dr. Carter advises that you study the findings of scientists regarding a particular supplement before taking it, as well as familiarize yourself with the contraindications.

    How to Choose Foods Additives and

    • Buy Supplements from Verified Suppliers – Drugs Must Pass Quality Control
    • Check Human Clinical Trials Has Been Conducted In The People For Which They Are Designed
    • Study contraindications – for example, people with heart disease should pay attention to the effect of a drug on the functioning of this organ
    • Be careful when taking several drugs at the same time
    • Stick to recommended doses

    Source: Dr. Wayne Carter.

    Vitamin D and I – Colorado Access

    I have had periodically back pain since the third grade. I also love books. How are these two things related to each other? They are actually super connected for me. I had a ton of hardback books that I usually kept on the floor next to my bed, and I often spent hours every night reading them. One night I ran and dived into my bed and fell right on the other side, landing on my back on top of all my hardback books.I couldn’t move. My parents came, assessed the situation and helped me to go to bed. The next day I went to the doctor, who diagnosed me with a dislocated tailbone. Yes, I was that third class who had to sit on padded seats or wear a donut for weeks.

    Since then, back pain has been tormenting me here and there. I stretched, took a break from running, passed out from the pain, and changed my shoes. All of this would bring temporary relief, but back pain always came back.Over the years, as I trained for marathons, my back pain got worse. On the run, on the pain. My old doctor gave me medical advice: “Well, I don’t want to tell you to stop running, so you might have to get used to the pain.” Hmm … not sure about that.

    Last year I switched to another doctor and was referred to an endocrinologist for other medical issues. According to WebMD, endocrinologists specialize in glands and hormones. 1 Bones and bone health are not necessarily theirs.On my first visit, she did a baseline blood test, which indicated that my vitamin D levels were low, among other things. Vitamin D was kind of an afterthought as that was not the reason for my visit. She told me to take the supplements that I brushed off. I am one of those people who, if you do not tell me what to buy and take, they overwhelm me with options, and then they just shut me down and do nothing.

    On my next visit, my blood looked good, but my vitamin D levels were still low.At the time, I was training for a marathon, and I had the false impression that sun exposure would give you all the vitamin D you really need. She realized that I was not going to do anything about it, so she prescribed me a strong vitamin D prescription (yes, it does exist). It worked because all I had to do was go to the pharmacy and pick up my order, there were no options. After taking strong vitamin D for a month, I switched to the over-the-counter look that Costco sells in large bottles (she told me exactly what to get, so the likelihood that I did it is much higher, and my mom did it).easy for me and it was sent straight to my door).

    As soon as I took vitamin D for one to two weeks, I felt a change. I never told my endocrinologist about back pain, but all of a sudden I didn’t have back pain. I increased my mileage for marathon preparation and still felt good.

    When I returned to my endocrinologist for my next visit, she told me that my blood showed that my vitamin D levels were almost normal.It was still on the slightly low side, but no longer in the danger zone. I told her how my back pain was largely relieved. Then she told me something that no other doctor had mentioned: Vitamin D helps in bone health. 2

    I’m sure we’ve all heard advertisements, marketing, and printed materials that say “milk, it helps the body”. We grew up knowing that calcium comes from milk, which helps build strong bones. But my endocrinologist told me that for some people, without enough vitamin D to absorb this calcium, it can lead to poor bone health.Vitamin D is just as important as calcium. And you don’t just get it from the sun.

    My experience is that you may feel good, or you may feel that things change as you get older. I didn’t necessarily feel bad; My back just hurt from time to time. Sometimes symptoms are signs of other problems, and without a complete picture, it can be difficult to know what to do. Talk to your doctor when visiting your doctor. Hear what they have to offer and weigh your options.I felt “good” before, but after my endocrinologist went through the recommended path of treatment, I feel much better.

    1 https://www.webmd.com/diabetes/what-is-endocrinologist#1

    2 https://orthoinfo.aaos.org/en/staying-healthy/vitamin-d-for-good-bone-health/

    90,000 Scientists debated whether vitamin C protects against severe coronavirus

    Vitamin C can help not only patients with COVID-19, but also physicians treating such patients.Studies 90,099 showed 90,100 that intravenous administration of this supplement shortens the hospital stay for people infected with the coronavirus. The results of the relevant clinical trials are cited by the British newspaper The Telegraph .

    The publication claims that vitamin C can “help prevent severe COVID-19 and accelerate recovery.”Scientists believe it is necessary for its widespread use in medical institutions.

    They estimate that vitamin C can increase blood oxygen levels, suppress inflammation and shorten hospital stay.

    The authors of one of the studies mentioned in the material, conducted in Wuhan, found that vitamin C increased the rate of recovery from symptomatic infection by 70% compared to placebo.

    “Six to 24 grams intravenously administered daily to critically ill patients has been beneficial: increased survival, decreased hospital stay, improved oxygenation, and decreased markers of inflammation,” said Anitra Carr of the University of Otago in New Zealand.

    “Standard of Clinical Practice”

    At the same time, the publication indicates that the dose administered through a dropper may not be enough “to provide a long-term beneficial effect, since after the end of the procedures, 15-25% of patients may return to a state of vitamin C deficiency [scurvy] “.

    “There is always a need to be on the lookout for electrolyte, micronutrient and vitamin replenishment, including vitamins C and D. This should become the standard of clinical practice,” said Dr. Marcela Wiscaychipe of Imperial College London School of Medicine.

    Does vitamin C help

    In turn, scientists in Shanghai followed the recovery process of 110 patients with moderate severity of COVID-19.

    55 of them received a weight-based dose of vitamin C, and the rest received standard treatment. Only in one third of patients who were injected with the vitamin, the disease became severe.

    In addition, studies have shown the ability of vitamin C “to maintain positive dynamics in COVID-19 in both inpatient and outpatient settings, which leads to a beneficial effect in patients with moderate symptoms,” the article says.

    However, none of the tests carried out are exhaustive, says Navid Sattar, professor of metabolic medicine at the University of Glasgow.

    Therefore, you need to be careful in interpreting the available data, he added.

    A much larger placebo-controlled study is needed to prove the hypothesis that vitamin C is beneficial for COVID-19, he said.In the meantime, it is better to resort to activities that actually work and have an impact on the relevant clinical practice, – concluded Sattar.

    Vitamin D Myths

    Several other studies have argued that elevated vitamin D levels are said to protect against COVID-19.

    However, in June 2021, biologists from five countries denied any link between vitamin D levels and coronavirus susceptibility, hospitalization, or disease severity.

    In turn, experts warn: uncontrolled use of drugs in the treatment of COVID-19 can worsen the condition of patients. According to doctor Alexander Myasnikov, the symptoms of coronavirus can be brought down with conventional medications and bed rest.

    The most “essential vitamin”

    More recently, endocrinologists at the hospital. Semashko completed a large-scale survey of residents of Buryatia. From January 2017 to June 2018, doctors examined 1,265 patients. The results showed that 1,051, or 83%, had a vitamin D deficiency, and one in five had severe hypovitaminosis

    This is the end of such a long-awaited and, unfortunately, as usual, short summer.Someone went to the sea, someone conquered the next peak, and someone spent the whole vacation in a stuffy office and did not receive enough “solar” vitamin, which our body needs so much.

    Vitamin D is called the “sun” vitamin for a reason. Unlike other nutrients, it is practically not found in food and is only produced when our skin is exposed to ultraviolet rays. But, given our short summer, there is no need to talk about the required dose of the vitamin.Why is this vitamin so necessary for our body, and what to do if it is not always possible to bask in the sun? The endocrinologist of the RCH them will help us to understand the problem. Semashko Erzhen Balzhinimaev.

    In the deficit zone

    Scientists have long proven that sunlight is one of the main conditions for maintaining human health. On a clear day, the body produces more hormones that are responsible for our mood. In addition, the sun activates the immune system, and therefore, in warm weather, people are much less sick with colds.However, the luminary was not so favorable to the inhabitants of sunny Buryatia. Despite its “popular” title, the sun’s rays in our region are surprisingly, but not effective enough for the formation of vitamin D (!). The thing is that we are at 53 degrees north latitude.

    By the way, most regions of Russia are in the “deficit zone” – the entire territory of the country is located above 37 degrees of latitude from the equator. And from autumn to summer, we get too little of the sun’s rays for adequate synthesis of vitamin D in the skin.

    It is also necessary to take into account the fact that due to low temperatures we are always in clothes or indoors and, accordingly, do not receive this substance. It is obvious that the residents of Buryatia need an additional source of vitamin, – says Erzhena Balzhinimaeva.

    It must be said that the vitamin was discovered in the “era” of childhood rickets – a disease in which, due to a lack of lime salts in the body, bones develop incorrectly. English veterinarian Edward Mellenby then noticed: only those dogs that are fed with fish oil (and there is vitamin A there) do not suffer from rickets.To clarify this issue, in 1922, the scientist set up an experiment. He gave the dogs a portion of fish oil, after which the animals were safely cured of rickets. So it was proved that it was not vitamin A that was responsible for the successful outcome, but another, until then unknown substance. Since it was the fourth vitamin discovered by science, it was named the fourth letter of the Latin alphabet – D. And already in 1923, the American biochemist Harry Stenbock demonstrated that irradiation of food with ultraviolet light increases the content of vitamin D.Around the same time, it was also proven that a person can produce a vitamin under the influence of sunlight.

    The most important vitamin

    Today scientists call vitamin D the most important vitamin. It regulates almost all metabolic processes in our body. Primarily, vitamin D is important for young children, pregnant women, and the elderly. And also for people with dark skin, because they are at risk of deficiency more than others.

    – Melanin is a substance that affects the color of your skin.The more melanin in your body, the darker your skin. The amount of melanin in your skin affects the amount of the vitamin you can produce. The lighter it is, the easier you will be able to produce vitamin D, the specialist explains.

    What happens to our body when vitamin D is sorely lacking? According to the doctor, the answer to this question is quite simple – with hypovitaminosis, our temporary ailments turn into chronic ones.

    More recently, endocrinologists at the hospital.Semashko completed a large-scale survey of residents of Buryatia. From January 2017 to June 2018, doctors examined 1,265 patients. The results showed that 1,051, or 83%, had a vitamin D deficiency, and one in five had severe vitamin D deficiency. Such indicators are associated, first of all, with the lifestyle of the inhabitants of the republic, insufficient insolation and dietary habits.

    So, the symptoms of a lack of this vitamin include: rapid eye fatigue, decreased visual acuity, cracks in the enamel of the teeth, problems with the menstrual cycle, muscle weakness, chronic pain, chronic fatigue and frequent colds.In addition, a lack of vitamin D can lead to osteoporosis and severe fractures (such as the hip), type 1 diabetes in children, obesity, rickets, and developmental delays in toddlers. Let’s dwell on some of them.

    Top 5 most common symptoms of vitamin D deficiency

    – Frequent colds. Vitamin D is essential for the proper functioning of our immune system. Without a sufficient amount of vitamin, immune cells will not be able to respond to a threat in time, making the body more susceptible to various infections.

    – Lack of mood. Vitamin D plays a major role in maintaining healthy serotonin levels in the brain. We are talking about neurotransmitters that we need to stay in a good mood and avoid seasonal depression.

    – Chronic fatigue. Our body also needs vitamin D to convert food into energy. If you constantly feel tired, this may mean that the body is not absorbing nutrients from food, which, in turn, may be triggered by a vitamin D deficiency.

    – Weak bones. In addition to all of the above, vitamin D is essential for the regulation of calcium and phosphate in the body. These minerals are essential for healthy bones and teeth.

    – Muscle pain. Vitamin D also supports muscle function. The fact is that, getting into the cells of muscle tissue, it increases the frequency of muscle contractions, helping the muscles to remain strong and elastic. This protects them from tears and minor injuries, including during training.

    What to do?

    Today, there are three ways to “deliver” vitamin to the body.The simplest thing is to “supply” the body with a vitamin with the help of the sun’s rays.

    Experts recommend being in the sun at least three times a week – from 10 to 15 minutes in open clothing and without sunscreen. At the same time, in summer it is necessary to choose morning and evening hours for “preventive sunburn”, when ultraviolet radiation is not yet very active and does not damage the skin. Vitamin can also be obtained from tanning beds. If you decide to use it, check the expiration date of the tanning lamp, doctors advise.It is important to understand that it is impossible to store vitamin D “for the future” by regular tanning in the summer sun and in a solarium.

    The second way to obtain vitamin is food. But, according to the doctor, this is a very limited solution. Most of the vitamin D is found in fat from the liver and meat of fish: salmon, tuna and mackerel. According to scientists, two or three fish meals a week can provide the need for this vitamin.

    Vitamin D can also be obtained from butter, dairy products and egg yolk. A small amount of the vitamin is also found in plant foods such as parsley and nettle, as well as in mushrooms.

    And the third, the most reliable, according to doctors, method is taking special medications. They recommend them to all residents of Buryatia for prevention purposes.

    But everything is not so simple, taking medications should be carried out on the recommendation of a doctor and in strictly defined periods. It is worth remembering that vitamin D is able to accumulate in the body. And if you take drugs uncontrollably, there is a risk to bring the level of the vitamin to a state of hypervitaminosis, which is also bad.

    – An increased level of vitamin in the blood can lead to impaired calcium metabolism in the body, and this threatens with deposits on the walls of blood vessels.As a result, the risk of cardiovascular diseases, including heart attacks and strokes, increases, the specialist says.

    You can find out your vitamin D level by taking a blood test from a vein. As for the state medical institutions of the republic, such an analysis is done in the RCH. Semashko.

    So, what about your “main vitamin”?

    Olga Makhanova
    Tradition newspaper

    To cure a cold and earn gastritis. Why is vitamin C dangerous? | Tips | HEALTH

    In the fall, the risk of catching a cold increases sharply, and many people begin to strengthen their immunity with vitamin C: they drink tea with lemon and raspberry jam, take ascorbic acid.Such measures help to strengthen the body and avoid colds, however, doctors warn: if you get carried away with such recovery, you can earn much more serious ailments than a common cold. What happens if you oversaturate your body with vitamin C, and how many oranges a day you can eat so as not to end up in a hospital bed, therapist Alexander Zubarev told .

    One pepper or bunch of parsley

    Eating vitamin C really helps to strengthen the immune system and avoid colds.But at the same time, excessive consumption of foods containing vitamin C can be dangerous for the body and is fraught with a whole bunch of serious ailments. “The daily norm of vitamin C for an adult is 80 mg per day, in the fall – up to 100 mg,” explains the therapist. – To get such a portion, it is enough to eat one bell pepper or orange, a little spinach, parsley or broccoli, one kiwi. Unfortunately, many people mistakenly believe that vitamin C is found only in citrus fruits, and do not control their diet, and some are still starting to take ascorbic acid.Of course, thanks to such a “shock” dose, you will not get a cold, but you will still undermine your health. ”

    According to the doctor, people with an excess of vitamin C in their bodies often feel dizzy and weak. Skin rashes, headache, heartburn, indigestion may occur. If you do not pay attention to these manifestations in time, they will develop into serious diseases – gastritis or even stomach ulcers, stones in the kidneys and in the gallbladder, damage to leukocytes in the blood. And all this is from too much vitamin C in the body.All of the above can be a symptom of other diseases – for example, poisoning – but if they make themselves felt exactly during the period when you take vitamins, you should think about and revise your diet. “Improper nutrition can even lead to death if you do not stop in time,” warns the therapist.

    Will it pass by itself?

    If the excess of vitamin C in the body is small, then, most likely, all excess will leave the body naturally.If a person decided to “strengthen health” with a handful of ascorbins and a kilogram of oranges, unpleasant consequences will soon make themselves felt. To relieve discomfort, you need to drink more water and reduce your intake of vitamin C. If symptoms persist, see your doctor.

    “The maximum dose of vitamin C should not exceed one gram,” reminds Zubarev. – This portion is recommended to be taken no longer than a few days, for colds or for prevention.Then you should return to the norm of 80 mg. Otherwise, there will be an excess of ascorbic acid in the body. ”

    Ascorbinka – only as a last resort

    Additional intake of vitamin C is indicated only for certain categories of people – those who have bad habits, are undergoing a period of rehabilitation after an illness, or those whose work is related to physical exertion. But at the same time, even a slight excess of the norm of vitamin C in the body is deadly for people who suffer from diabetes mellitus, renal failure, and hypertension.

    What to do to get only benefit from vitamin C? “Try to get this vitamin only from food,” the doctor advises. – Even if you overeat fruits and vegetables that contain it, the excess will not linger in your body. In addition, vitamins of natural origin are absorbed much better! Take ascorbic acid in pills only when needed, not as candy – because you like the taste of it. Carefully study the label on the jar: ascorbic acid comes in different dosages, both 50 mg and 100 mg.The last option is already a daily dose. My recommendation: eat right, maintain hygiene and exercise – and colds will bypass you. ”

    See also:

    Outdoor alphabet – Money – Kommersant

    SANPROSVET
    Useful ABC
    Vitamin A is a group of compounds. In nature, the most common retinol (vitamin A1), dehydroretinol (vitamin A2), retinal, retinoic acid, in plants there are provitamins – carotenes.It improves tone, restores the epidermis, nourishes, softens, protects and renews the skin, exfoliates dead cells, smoothes wrinkles and other roughness, heals acne and acne, relieves inflammation and irritation, strengthens tissues, gives elasticity to hair and skin, prevents water loss.
    Vitamins of group B accelerate the regeneration and epithelization of the skin, promote its hydration, participate in fat metabolism, destroy seborrhea, and activate metabolism.
    Vitamin B1 (thiamine) heals wounds, regenerates skin and hair.Treats acne, dermatitis, age spots, seborrhea. Vitamin B2 (riboflavin) stimulates energy production in cells. Improves the condition of the skin, hair, nails, strengthens them. Prevents hair loss. Treats acne, seborrhea, cracks and sores in the mouth. Rejuvenates the skin. Vitamin B6 (pyridoxine) stimulates metabolism, prevents cracks in the corners of the mouth, hair loss, brittle nails, strengthens the epidermis and hair roots. Treats seborrhea, acne and dermatitis. Vitamin B9 or Bc (folic acid) supports healthy hair growth, prevents hair loss, wrinkles, acne and other inflammation. Vitamin B0, or H1 (para-aminobenzoic acid) is called the vitamin of beauty. Maintains the natural color of hair and skin, protects against sunburn. Vitamin B12 (cobalamin) regulates the metabolism of fats, proteins and carbohydrates, renews cells, destroys acne, seborrhea and skin atrophy, prevents hair loss. Vitamin B5 (D-panthenol, pantothenic acid) participates in the biosynthesis and transformation of fatty acids, moisturizes, soothes, relieves irritation and itching, has a strong anti-aging and smoothing effect, restores and protects the skin, relieves inflammation.Restores damaged hair structure, smoothes its surface, nourishes and strengthens the roots. It is absorbed better by the hair than other vitamins. Protects against aggressive effects of moisture and wind.
    Vitamin C (ascorbic acid) is one of the most important. Antioxidant, improves the elasticity of blood vessels, stimulates collagen synthesis, prevents the formation of carcinogens, and regenerates the skin. It activates blood microcirculation, provides photoprotection, whitens, moisturizes and nourishes the skin, protects against harmful effects and prevents aging.Strengthens tissues, gives elasticity to hair and skin. It has anti-inflammatory and anti-allergic effects. Stimulates blood supply to scalp cells, accelerates hair growth. Boosts immunity.
    Vitamin D (calciferols) regulates mineral metabolism, affects the absorption of calcium and phosphorus, promotes the regeneration of aging skin, normalizes its metabolism, maintains skin turgor (elasticity).
    Vitamin E (tocopherols) – antioxidant, prevents the formation of free radicals, heals wounds.It is indispensable in the fight against skin aging, retains natural moisture, nourishes, smoothes wrinkles, protects the skin from UV radiation. Nourishes and strengthens hair follicles, protects hair from external influences. Helps hair retain moisture and improves metabolism in the hair roots. Maintains the integrity of the hair structure.
    Vitamin K (phylloquinone, menadione) – a group of vitamins that affect blood clotting, activate blood circulation in the scalp, as a result of which the hair roots are better supplied with blood.Antioxidant.
    Vitamin H (biotin) prevents edema, restores skin color, shine of hair and strength of nails, regulates the activity of the sebaceous glands.
    Vitamin P (rutin) helps with acne, facial redness, hair loss. Reduces capillary permeability and fragility, has an anti-inflammatory effect, increases the activity of vitamin C, nourishes connective tissue and capillaries, and prevents vascular fragility. A number of plant polyphenols (flavonoids) have P-vitamin activity.
    Vitamin PP (B3) is the generic name for nicotinic acid and nicotinamide. Heals wounds and burns, eliminates acne, acne and dry skin, participates in the reactions of cellular respiration, normalizes the condition of hair follicles, accelerates hair growth, stimulates metabolic processes in their roots, prevents gray hair and hair loss.
    Vitamin U (methyl methionine) stimulates the processes of cell regeneration, has a beneficial effect on the metabolism of carbohydrates and fats, has antihistamine activity, i.e.That is, it can relieve pain and allergic reactions.
    Vitamin I (inositol) in combination with B vitamins prevents hair loss.
    Pangamic acid (B15) improves fat, protein, carbohydrate metabolism, stimulates the immune system. As an antioxidant, it increases the lifespan of cells.
    Choline (B4) is a part of phospholipids, has a pronounced lipotropic effect.
    Vitamin F – a set of essential polyunsaturated fatty acids (linoleic, linolenic, arachidonic), an important component of cell membranes.Participates in oxygen and fat metabolism, restores cells, prevents roughness, dryness, flaking, dandruff, fragility and hair loss. Protects the skin from harmful effects and household chemicals, regenerates the skin’s hydrolipid barrier.

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