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Patients with higher inflammation or tumor burdens, as measured by CRP levels or tumor antigen levels, tend to show lower peak plasma ascorbate levels after IVC.

Patients with metastatic tumors tend to achieve lower post infusion plasma ascorbate levels than those with localized tumors.

Meta-analyses of clinical studies involving cancer and vitamins also conclude that antioxidant supplementation does not interfere with the efficacy of chemotherapeutic regiments

Most of the prostate cancer patients studied, 75±19% (95% confidence), showed reductions in PSA levels during the course of their IVC therapy

Laboratory studies suggest that, at high concentrations, ascorbate does not interfere with chemotherapy or irradiation and may enhance efficacy in some situations

Cameron and Pauling observed fourfold survival times in terminal cancer patients treated with intravenous ascorbate infusions followed by oral supplementation

The inflammatory microenvironment of cancer cells leads to increasing oxidative stress, which apparently depletes vitamin C, resulting in lower plasma ascorbate concentrations in blood samples post IVC infusion. Another explanation for this finding may be that cancers are themselves more metabolically active in their uptake of vitamin C, causing subjects to absorb more of the vitamin, and as a results show lower plasma ascorbate concentrations in blood post IVC infusion.

patients with severely elevated CRP levels attain plasma ascorbate concentrations after IVC infusions that are only 65% of those attained for subjects with normal CRP levels

The finding of decreased plasma ascorbate levels in cancer patients may relate to the molecular structure of ascorbic acid; in particular, the similarity of its oxidized form, dihydroascorbic acid, to glucose

Since tumor have increased requirement for glucose [67], transport of dehydroascorbate into the cancer cells via glucose transport molecules and ascorbate through sodium-dependent transporter may be elevated

Increased accumulation of ascorbic acid in the tumor site was supported by measurements of the level of ascorbic acid in tumors in animal experiments

patients with advanced malignancies may have lower level of ascorbic acid in tissue, creating a higher demand for the vitamin C

IVC therapy appears to reduce CRP levels in cancer patients.

CRP concentrations directly correlate with disease activity in many cases and can contribute to disease progression through a range of pro-inflammatory properties.

Being an exquisitely sensitive marker of systemic inflammation and tissue damage, CRP is very useful in screening for organic disease and monitoring treatment responses

ncreases in CRP concentrations have been associated with poorer prognosis of survival in cancer patients, particularly with advance disease independent of tumor stage

Regarding inflammation, 73±13% of subjects (95% confidence) showed a reduction in CRP levels during therapy. This was an even more dramatic 86±13% (95% confidence) in subjects who started therapy with CRP levels above 10 mg/L

patients treated by IVC with follow-up several year showed that suppression of inflammation in cancer patients by high-dose IVC is feasible and potentially beneficial

Inflammation is a marker of high cancer risk, and poor treatment outcome

The subjects with highly elevated CRP concentrations have a three-fold elevation “all-cause” mortality risk and a twenty-eight fold increase in cancer mortality risk

cancer patients may need higher doses to achieve a given plasma concentration.

patients with lower vitamin C levels may see more distribution of intravenously administered ascorbate into tissues and thus attain less in plasma.

When treating patients with IVC, the first treatment likely serves to replenish depleted tissue stores, if those subjects were vitamin C deficient at the beginning of the treatment. Then, in subsequent treatments, with increasing doses, higher plasma concentrations can be attained. On-going treatments serve to progressively reduce oxidative stress in cancer patients.

large doses given intravenously may result in maximum plasma concentrations of roughly 30 mM, a level that has been shown to be sufficient for preferential cytotoxicity against cancer cells

oral intake of vitamin C exceeded 200 mg administered once daily, it was difficult to increase plasma and tissue concentrations above roughly 200 μM.

Huperzine A (a natural cholinesterase inhibitor) has been linked to improved memory performance in elderly people with benign forgetfulness, as well as patients with AD and vascular dementia

Cholinesterase inhibitors have been shown to have neuroprotective properties in patients with mild [37] as well as moderate-to-advanced AD

LPS leads to an increase in SOCS3 expression [20]. SOCS3 is a negative regulator of leptin signaling

We observed a significant increase in energy intake in the LPS-treated rats

the data provides a mechanism linking changes in gut microbiota induced by ingestion of HF diets to dysregulation of food intake and body weight

SOCS3 is an important mechanism by which leptin resistance develops in vagal afferent neurons and coincides with the onset of hyperphagia

Chronic low-dose LPS treatment induced TLR4 activation and MyD88 signaling in vagal afferent neurons, associated with increased SOCS3 expression and reduced leptin-signaling, characterized by the absence of leptin-induced pSTAT3.

We demonstrate that this chronic low dose LPS is sufficient to induce leptin–resistance in vagal afferent neurons, reduced sensitivity to the satiating effects of CCK, and loss of vagal afferent plasticity

it suggests that the increase in food intake and body weight we observed at week 6 in the LPS treated rats may be caused by LPS-induced leptin resistance.

chronic LPS treatment of mice for four weeks increased body weight

chronic LPS treatment of mice for four weeks increased subcutaneous fat

IR also indirectly induces DNA damage by stimulating reactive oxygen species (ROS) production

IR is known to induce EMT in vitro

p53 is activated in response to IR-induced DNA damage

IR paradoxically also promotes tumour recurrence and metastasis

DNA double-strand breaks (DSBs)

cancer cells undergoing EMT acquire invasive and metastatic properties

changes in the tumour microenvironment (TME)

IR seems to induce EMT and CSC phenotypes by regulating cellular metabolism

EMT, stemness, and oncogenic metabolism are known to be associated with resistance to radiotherapy and chemotherapy

Hanahan and Weinberg proposed ten hallmarks of cancer that alter cell physiology to enhance malignant growth: 1) sustained proliferation, 2) evasion of growth suppression, 3) cell death resistance, 4) replicative immortality, 5) evasion of immune destruction, 6) tumour-promoting inflammation, 7) activation of invasion and metastasis, 8) induction of angiogenesis, 9) genome instability, and 10) alteration of metabolism

EMT is a developmental process that plays critical roles in embryogenesis, wound healing, and organ fibrosis

IR is known to induce stemness and metabolic alterations in cancer cells

transforming growth factor-β [TGF-β], epidermal growth factor [EGF]) and their associated signalling proteins (Wnt, Notch, Hedgehog, nuclear-factor kappa B [NF-κB], extracellular signal-regulated kinase [ERK], and phosphatidylinositol 3-kinase [PI3K]/Akt

activate EMT-inducing transcription factors, including Snail/Slug, ZEB1/δEF1, ZEB2/SIP1, Twist1/2, and E12/E47

Loss of E-cadherin is considered a hallmark of EMT

IR has been shown to induce EMT to enhance the motility and invasiveness of several cancer cells, including those of breast, lung, and liver cancer, and glioma cells

IR may increase metastasis in both the primary tumour site and in normal tissues under some circumstance

sublethal doses of IR have been shown to enhance the migratory and invasive behaviours of glioma cells

ROS are known to play an important role in IR-induced EMT

High levels of ROS trigger cell death by causing irreversible damage to cellular components such as proteins, nucleic acids, and lipids, whereas low levels of ROS have been shown to promote tumour progression—including tumour growth, invasion, and metastasis

hypoxia-inducible factor-1 (HIF-1) is involved in IR-induced EMT

Treatment with the N-acetylcysteine (NAC), a general ROS scavenger, prevents IR-induced EMT, adhesive affinity, and invasion of breast cancer cells

Snail has been shown to play a crucial role in IR-induced EMT, migration, and invasion

IR activates the p38 MAPK pathway, which contributes to the induction of Snail expression to promote EMT and invasion

NF-κB signalling that promotes cell migration

ROS promote EMT to allow cancer cells to avoid hostile environments

HIF-1 is a heterodimer composed of an oxygen-sensitive α subunit and a constitutively expressed β subunit.

Under normoxia, HIF-1α is rapidly degraded, whereas hypoxia induces stabilisation and accumulation of HIF-1α

levels of HIF-1α mRNA are enhanced by activation of the PI3K/Akt/mammalian target of rapamycin (mTOR)

IR is known to increase stabilisation and nuclear accumulation of HIF-1α, since hypoxia is a major condition for HIF-1 activation

IR induces vascular damage that causes hypoxia

ROS is implicated in IR-induced HIF-1 activation

IR causes the reoxygenation of hypoxic cancer cells to increase ROS production, which leads to the stabilisation and nuclear accumulation of HIF-1

IR increases glucose availability under reoxygenated conditions that promote HIF-1α translation by activating the Akt/mTOR pathway

The stabilised HIF-1α then translocates to the nucleus, dimerizes with HIF-1β, and increases gene expression— including the expression of essential EMT regulators such as Snail—to induce EMT, migration, and invasion

TGF-β signalling has been shown to play a crucial role in IR-induced EMT

AP-1 transcription factor is involved in IR-induced TGF-β1 expression

Wnt/β-catenin signalling is also implicated in IR-induced EMT

Notch signalling is known to be involved in IR-induced EMT

IR also increases Notch-1 expression [99]. Notch-1 is known to induce EMT by upregulating Snail

PAI-1 signalling is also implicated in IR-induced Akt activation that increases Snail levels to induce EMT

EGFR activation is known to be associated with IR-induced EMT, cell migration, and invasion by activating two downstream pathways: PI3K/Akt and Raf/MEK/ERK

ROS and RNS are also implicated in IR-induced EGFR activation

IR has also been shown to activate Hedgehog (Hh) signalling to induce EMT

IR has been shown to induce Akt activation through several signalling pathways (EGFR, C-X-C chemokine receptor type 4 [CXCR4]/C-X-C motif chemokine 12 [CXCL12], plasminogen activator inhibitor 1 [PAI-1]) and upstream regulators (Bmi1, PTEN) that promote EMT and invasion

CSCs possess a capacity for self-renewal, and they can persistently proliferate to initiate tumours upon serial transplantation, thus enabling them to maintain the whole tumour

Conventional cancer treatments kill most cancer cells, but CSCs survive due to their resistance to therapy, eventually leading to tumour relapse and metastasis

identification of CSCs, three types of markers are utilised: cell surface molecules, transcription factors, and signalling pathway molecules

CSCs express distinct and specific surface markers; commonly used ones are CD24, CD34, CD38, CD44, CD90, CD133, and ALDH

Transcription factors, including Oct4, Sox2, Nanog, c-Myc, and Klf4,

signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, platelet-derived growth factor receptor (PDGFR), and JAK/STAT

microRNAs (miRNAs), including let-7, miR-22, miR-34a, miR-128, the miR-200 family, and miR-451

Non-CSCs can be reprogrammed to become CSCs by epigenetic and genetic changes

EMT-inducing transcription factors, such as Snail, ZEB1, and Twist1, are known to confer CSC properties

Signalling pathways involved in EMT, including those of TGF-β, Wnt, and Notch, have been shown to play important roles in inducing the CSC phenotype

TGF-β1 not only increases EMT markers (Slug, Twist1, β-catenin, N-cadherin), but also upregulates CSC markers (Oct4, Sox2, Nanog, Klf4) in breast and lung cancer cells

some CSC subpopulations arise independently of EMT

IR has been shown to induce the CSC phenotype in many cancers, including breast, lung, and prostate cancers, as well as melanoma

Genotoxic stress due to IR or chemotherapy promotes a CSC-like phenotype by increasing ROS production

IR has been shown to induce reprogramming of differentiated cancer cells into CSCs

In prostate cancer patients, radiotherapy increases the CD44+ cell population that exhibit CSC properties

IR also induces the re-expression of stem cell regulators, such as Sox2, Oct4, Nanog, and Klf4, to promote stemness in cancer cells

EMT-inducing transcription factors and signalling pathways, including Snail, STAT3, Notch signalling, the PI3K/Akt pathway, and the MAPK cascade, have been shown to play important roles in IR-induced CSC properties

STAT3 directly binds to the Snail promoter and increases Snail transcription, which induces the EMT and CSC phenotypes, in cisplatin-selected resistant cells

Other oncogenic metabolic pathways, including glutamine metabolism, the pentose phosphate pathway (PPP), and synthesis of fatty acids and cholesterol, are also enhanced in many cancers

metabolic reprogramming

HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism

metabolic reprogramming

tumour cells exhibit high mitochondrial metabolism as well as aerobic glycolysis

occurring within the same tumour

CSCs can be highly glycolytic-dependent or oxidative phosphorylation (OXPHOS)-dependen

mitochondrial function is crucial for maintaining CSC functionality

cancer cells depend on mitochondrial metabolism and increase mitochondrial production of ROS that cause pseudo-hypoxia

HIF-1 then enhances glycolysis

CAFs have defective mitochondria that lead to the cells exhibiting the Warburg effect; the cells take up glucose, and then secrete lactate to 'feed' adjacent cancer cells

lactate transporter, monocarboxylate transporter (MCT)

nutrient microenvironment

Epithelial cancer cells express MCT1, while CAFs express MCT4. MCT4-positive, hypoxic CAFs secrete lactate by aerobic glycolysis, and MCT1-expressing epithelial cancer cells then uptake and use that lactate as a substrate for the tricarboxylic acid (TCA) cycle

MCT4-positive cancer cells depend on glycolysis and then efflux lactate, while MCT1-positive cells uptake lactate and rely on OXPHOS

metabolic heterogeneity induces a lactate shuttle between hypoxic/glycolytic cells and oxidative/aerobic tumour cells

bulk tumour cells exhibit a glycolytic phenotype, with increased conversion of glucose to lactate (and enhanced lactate efflux through MCT4), CSC subsets depend on oxidative phosphorylation; most of the glucose entering the cells is converted to pyruvate to fuel the TCA cycle and the electron transport chain (ETC), thereby increasing mitochondrial ROS production

the major fraction of glucose is directed into the pentose phosphate pathway, to produce redox power through the generation of NADPH and ROS scavengers

HIF-1α, p53, and c-Myc, are known to contribute to oncogenic metabolism

regulatory molecules involved in EMT and CSCs, including Snail, Dlx-2, HIF-1, STAT3, TGF-β, Wnt, and Akt, are implicated in the metabolic reprogramming of cancer cells

HIF-1 induces the expression of glycolytic enzymes, including the glucose transporter GLUT, hexokinase, lactate dehydrogenase (LDH), and MCT, resulting in the glycolytic switch

HIF-1 represses the expression of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), thereby inhibiting mitochondrial activity

STAT3 has been implicated in EMT-induced metabolic changes as well

TGF-β and Wnt play important roles in the metabolic alteration of cancer cells

Akt is also implicated in the glycolytic switch and in promoting cancer cell invasiveness

EMT, invasion, metastasis, and stemness

pyruvate kinase M2 (PKM2), LDH, and pyruvate carboxylase (PC), are implicated in the induction of the EMT and CSC phenotypes

decreased activity of PKM2 is known to promote an overall shift in metabolism to aerobic glycolysis

LDH catalyses the bidirectional conversion of lactate to pyruvate

High levels of LDHA are positively correlated with the expression of EMT and CSC markers

IR has been shown to induce metabolic changes in cancer cells

IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate

IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate

IR also elevates MCT1 expression that exports lactate into the extracellular environment, leading to acidification of the tumour microenvironment

IR increases intracellular glucose, glucose 6-phosphate, fructose, and products of pyruvate (lactate and alanine), suggesting a role for IR in the upregulation of cytosolic aerobic glycolysis

Lactate can activate latent TGF-

lactate stimulates cell migration and enhances secretion of hyaluronan from CAF that promote tumour metastasis

promote tumour survival, growth, invasion, and metastasis; enhance the stiffness of the ECM; contribute to angiogenesis; and induce inflammation by releasing several growth factors and cytokines (TGF-β, VEGF, hepatocyte growth factor [HGF], PDGF, and stromal cell-derived factor 1 [SDF1]), as well as MMP

tumours recruit the host tissue’s blood vessel network to perform four mechanisms: angiogenesis (formation of new vessels), vasculogenesis (de novo formation of blood vessels from endothelial precursor cells), co-option, and modification of existing vessels within tissues.

immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)

immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)

intrinsic immunogenicity or induce tolerance

cancer immunoediting’

three phases: 1) elimination, 2) equilibrium, and 3) escape.

The third phase, tumour escape, is mediated by antigen loss, immunosuppressive cells (TAM, MDSCs, and regulatory T cells), and immunosuppressive cytokines (TGF-β and IL-10).

IR can elicit various changes in the TME, such as CAF activity-mediated ECM remodelling and fibrosis, cycling hypoxia, and an inflammatory response

IR activates CAFs to promote the release of growth factors and ECM modulators, including TGF-β and MMP

TGF-β directly influences tumour cells and CAFs, promotes tumour immune escape, and activates HIF-1 signalling

MMPs degrade ECM that facilitates angiogenesis, tumour cell invasion, and metastasis

IR also promotes MMP-2/9 activation in cancer cells to promote EMT, invasion, and metastasis

IR-induced Snail increases MMP-2 expression to promote EMT

Radiotherapy has the paradoxical side-effect of increasing tumour aggressiveness

IR promotes ROS production in cancer cells, which may induce the activation of oncogenes and the inactivation of tumour suppressors, which further promote oncogenic metabolism

Metabolic alterations

oncogenic metabolism

elicit various changes in the TME

Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms

catalase and SOD, GPx, GST

insulin like growth factor I, or fibroblast growth factor 2 generates ROS

Depletion of GSH increases the sensitivity of cells to ROS

diet enriched in fruits and vegetables (and consequently phytochemicals) was able to reverse the process and maintain and even elevate insulin sensitivity and glucose tolerance

LPS-mediated effects are related to an increase in TLR4 levels that triggers the activation of nuclear factor-kB (NF-kB), a transcription factor that activates a cascade of inflammatory mediators [41]. These factors control the transcription of inflammatory mediators, such as IL-1β, IL-6, TNF-α, TNF-β, INF-α, INFβ, INF-γ

Inflammation can alter insulin action and give rise to diabetes and obesity by blocking insulin receptor downstream events, impairing insulin receptor substrate 1 (IRS-1) activation and phosphatidylinositol 3-kinase-dependent (PI3K) pathways, therefore compromising insulin signaling

systemic inflammation (generated by LPS) also increased neopterin levels in the urine and resulted in altered neuronal activity by decreasing dopamine (DA) metabolism

an increase in neopterin levels has been recognized a sensitive biomarker for immune system activation

Our experiments denoted that these diets were able to diminish inflammatory mediators and oxidative damage

O3 not only remedied infection, but also had hemodynamic and anti-inflammatory properties

Stimulation of oxygen metabolism

In fungi, O3 inhibits cell growth at certain stages

With viruses, the O3 damages the viral capsid and upsets the reproductive cycle by disrupting the virus-to-cell contact with peroxidation.

Inactivation of bacteria, viruses, fungi, yeast and protozoa: Ozone therapy disrupts the integrity of the bacterial cell envelope through oxidation of the phospholipids and lipoproteins

Activation of the immune system

30 and 55 μg/cc

production of interferon and the greatest output of tumor necrosis factor and interleukin-2

Mechanism of action of O3 on the human lung

cascade of reactions like peroxidation of lipids leading to changes in membrane permeability,[41] lipid ozonation products (LOP) act as signal transducer molecules

Dietary antioxidants or free radical scavengers like vitamin E, C, etc., can prevent aforementioned effects of O3

play a role during the initial chemotactic response of neutrophils shortly after infection

following vitamin C supplementation, a 20% increase in neutrophil chemotactic activity was observed

also contributes to the phagocytosis and killing of microbes by neutrophils

low levels of vitamin C occurring in high-stress situations

maturation, proliferation, and viability of T cells have all been shown to be upregulated by the presence of normal physiologic concentrations of vitamin C

Vitamin C has been shown to directly affect the number of Igs released from B cells

vitamin C among healthy young adult males showed a significant increase in serum levels of IgA, IgG, and IgM

effects of high-dose vitamin C on cytokine levels in cancer patients, finding decreased amounts of the cytokines Interleukin-1 alpha (IL-1 alpha), IL-2, IL-8, and tumor necrosis factor-alpha (TNF-alpha) after high-dose vitamin C infusion

when vitamin C was supplemented with vitamin E in healthy adults, it increased the production of cytokines IL-1 beta and TNF-alpha

vitamin C acts to modulate the levels of cytokines to prevent them from fluctuating in either direction

vitamin C also acts as an important antioxidant to the cells of the immune system.

human leukocytes, neutrophils, in particular, possess the ability to transport the oxidized form of vitamin C across its membrane to use as a defense mechanism against ROS produced during an immune response

Vitamin C also can recover other endogenous antioxidants in the body such as vitamin E and glutathione, returning them to their active state

vitamin C can decrease the activation of NF-kB

can reduce harmful nitrogen-based compounds such as N-nitrosamines and nitrosamides, both of which are carcinogenic 

subjects taking oral vitamin C supplementation saw a 60% to 90% reduction in oxidative stress compared to a placebo control

subjects infused with vitamin C alone had a 516% increase in glutathione levels compared to subjects not provided the 500 mg daily supplementation

hydroxylating proline and lysine

mature and stabilize the tissue of a healing wound

healing

oral surgery

improved soft tissue regeneration

vitamin C increases the mRNA levels of type I and type III collagen in the human dermis

Studies have demonstrated that those with low levels of vitamin C are at a significantly higher risk of respiratory infection compared to those with normal levels

viral cold duration was reduced by about 8% in adults and 13.5% in children using prophylactic daily doses of 200 mg of oral vitamin C

prophylactically supplementing vitamin C decreases the risk of infection with respiratory viruses such as the common cold

combined with probiotics, oral vitamin C supplementation showed a 33% decrease in the incidence of respiratory tract infections in preschool-age children [

high-dose oral supplementation of vitamin C managed to prevent or reduce symptoms if taken before or just after the onset of cold- or flu-like symptoms

improvements in oxygen saturation and decreased IL-6 levels (a marker of inflammation) in the treatment group compared to the control group

8 g doses of oral vitamin C

there is a negative correlation between age and serum levels of vitamin C

Patients with COVID-19 will likely also experience depletion in serum levels of vitamin C as a direct result of the upregulation of the immune system to combat the infection

Colunga et al. suggested that oral vitamin C can be combined with oral Quercetin, an antiviral flavonoid, to improve Quercetin’s ability to block viral membrane fusion of SARS-CoV-2

high doses of 1-2 g/day of oral vitamin C could prevent other upper respiratory infections

It appears vitamin C supplementation by itself does not provide a striking benefit in preventing COVID-19 infection for those without a deficiency

Hiedra et al. were able to show decreases in inflammatory biomarkers, such as D-dimer and ferritin

some evidence to support that prophylactic use of vitamin C helps reduce the severity of respiratory infection symptoms once a subject has already been infected

oral vitamin C in combination with zinc provided the largest amount of antibody titers 42 days

linear relationship between days of vitamin C therapy and survival duration

other studies were unable to find any definitive improvement concerning therapy with vitamin C

Fowler et al. aimed to see if a high-dose vitamin C infusion would benefit patients affected by ARDS, but they were unable to conclude that vitamin C infusion, compared to a placebo, could decrease vascular inflammation and damage in ARDS

in a sample of 67 COVID-19-positive ICU patients, 82% of them displayed plasma vitamin C levels below 0.4 mg/dL

continuous vitamin C infusion at a rate of 60 mg/kg/day for four days decreased the need for mechanical ventilation and vasopressor use but had no significant effect on overall mortality

Carr et al. suggested that high-dose IV vitamin C is most effective when treating sepsis as septic patients receiving the normal daily recommendations through diet still showed decreased vitamin C levels

High-dose IV vitamin C treatment has also been shown by Kakodkar et al. to decrease syndecan-1, an endothelial glycocalyx that contributes to mortality in septic patients

combined with hydrocortisone and thiamine, septic patients treated with 1.5 g of IV vitamin C every six hours showed a distinct decrease in their SOFA scores and none of the patients treated developed organ failure

combined with hydrocortisone and thiamine, septic patients treated with 1.5 g of IV vitamin C every six hours showed a distinct decrease in their SOFA scores and none of the patients treated developed organ failure

reduced overall mortality

reduced overall mortality

propose the use for high-dose vitamin C to aid in the treatment of septic shock-induced hypotension

treatment of severe sepsis using a high dose (up to 200 mg/kg/day) of IV vitamin C was explored in phase I, a double-blind, randomized, placebo-controlled trial by Fowler et al. [75]. Their findings included a reduction in SOFA scores and decreased vascular injury compared to a placebo control group, all while showing minimal adverse side effects

Maintaining a daily intake of 75 and 100 mg for men and women, respectively, as recommended by the U.S. Institute of Medicine

bone marrow suppression

cardiomyopathy

irreversible retinal toxicity

hypoglycaemia

daily doses up to 400 mg of HCQ or 250 mg CQ for several years are considered to carry an acceptable risk for CQ-induced retinopathies, with the exception of individuals of short stature

chronic CQ or HCQ therapy be monitored through regular ophthalmic examinations (3–6 month intervals), full blood counts and blood glucose level checks

long-term HCQ exposure, skeletal muscle function and tendon reflexes should be monitored for weakness

both CQ and HCQ, specific caution is advised in patients suffering from impaired hepatic function (especially when associated with cirrhosis), porphyria, renal disease, epilepsy, psoriasis, glucose-6-phosphate dehydrogenase deficiency and known hypersensitivity to 4-aminoquinoline compounds

CQ and HCQ can effectively increase the efficacy of various anti-cancer drugs

CQ can prevent the entrapment of protonated chemotherapeutic drugs by buffering the extracellular tumour environment and intracellular acidic spaces

This study recommends an adjuvant HCQ dose of 600 mg, twice daily.

HCQ addition was shown to produce metabolic stress in the tumours

HCQ (400 mg/day)

important effects of CQ and HCQ on the tumour microenvironment

The main and most studied anti-cancer effect of CQ and HCQ is the inhibition of autophagy

the expression levels of TLR9 are higher in hepatocellular carcinoma, oesophageal, lung, breast, gastric and prostate cancer cells as compared with adjacent noncancerous cells, and high expression is often linked with poor prognosis

TLR9-mediated activation of the NF-κB signalling pathway and the associated enhanced expression of matrix metalloproteinase-2 (MMP-2), MMP-7 and cyclo-oxygenase 2 mRNA

HCQ can activate caspase-3 and modulate the Bcl-2/Bax ratio inducing apoptosis in CLL, B-cell CLL and glioblastoma cells

In triple-negative breast cancer, CQ was shown to eliminate cancer stem cells through reduction of the expression of Janus-activated kinase 2 and DNA methyl transferase 1 [106] or through induction of mitochondrial dysfunction, subsequently causing oxidative DNA damage and impaired repair of double-stranded DNA breaks

CQ or HCQ would be considered for use in combination with immunomodulation anti-cancer therapies

Therapies used in combination with CQ or HCQ include chemotherapeutic drugs, tyrosine kinase inhibitors, various monoclonal antibodies, hormone therapies and radiotherapy

Most studies hypothesise that CQ and HCQ could increase the efficacy of other anti-cancer drugs by blocking pro-survival autophagy.

daily doses between 400 and 1200 mg for HCQ are safe and well tolerated, but two studies identified 600-mg HCQ daily as the MTD

HCQ is often administered twice daily to limit plasma fluctuations and toxicity