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BioLogical

A BIOLOGICAL THERAPIES NEWSLETTER

Ebola and Marburg viruses


and Vitamin C
Current outbreak of Ebola in West Africa

E
bola outbreaks have occurred in Africa on previous Ebola after being in contact with an Ebola sufferer. Tracking his
occasions without significant outbreaks in Europe, Asia, contacts is now also paramount to help prevent an outbreak in
Americas or Australia. Transmission does not occur the USA an unlikely scenario, but containment is by far and
easily and is mainly through exchange of bodily fluids. Personal away the best method at this stage. Unfortunately the survival
hygiene/poor diet and compromised immunity associated with rate once patients have contracted this particular strain of Ebola
squalid living conditions almost certainly play major roles in is only around about 50%. Some patients have been treated
disease transmission. As with most diseases personal hygiene with the plasma of patients (passive immunity by the contained
habits which are adequate under normal circumstances antibodies) who have recovered from Ebola but this carries the
may be inadequate when challenged with a large dose of distinct possibility of transmitting other serious diseases such
Ebola so countries outside of Africa should not necessarily as Hepatitis and AIDS not all patients treated by this method
consider themselves immune from a possible outbreak. This have survived but this method has worked for several health
phenomenon has been recognised by the CDC and government care workers. Other methods for producing the appropriate
in the USA who have sent many health care workers and troops antibodies are currently under intense development but will be
trained to assist in helping to contain and treat such epidemics very costly and an early phase 1 clinical trial on a proposed
and to follow up contacts of those who have or had the Ebola vaccine has demonstrated safety. However it will still be another
disease. To date thousands of Ebola victims have died in this 12 months before a phase 2 trial is completed and of course
current outbreak in West Africa and there is now a recent report there is no guarantee at this stage that it will be sufficiently
of a US citizen returning from West Africa who is critically ill with successful or safe in a much larger African population.

Clinical background is there a


case for Vitamin C?
The question is being asked about using high dose Vitamin
There is a significant body of
work now about Vitamin C
C in patients who have contracted Ebola virus. It is a good
question, because there are runs on the board for using high and its effects on immunity
dose Vitamin C in other viral infections, such as Epstein-Barr
virus/glandular fever. By far the majority of these cases are
unpublished; however there is at least some published material
and especially viruses.
in these cases to use as a basis for clinical evidence i. There is
a significant body of work now about Vitamin C and its effects But are there any case reports published or unpublished about
on immunity and especially viruses. A review of drug therapies the use of Vitamin C in Ebola? At this stage apparently not. But
in Avian Influenza has highlighted the potential and typical does this mean that we should disregard the possibility? Since
use of Vitamin C in serious Influenza infections ii. In this review Vitamin C is known to be non-toxic, and that it has been used
Yuan states that effective inhibition of viral replication and successfully in patients with other viral infections, it might be
apparent symptom alleviation usually requires over 5mM of VC worth a try.
(plasma concentration) Also Yuan comments that oral Vitamin
C is inadequate because these levels cannot be obtained. In A lot is now known about how Ebola infects hosts, what cells it
cancer therapy intravenous Vitamin C protocols are now well infects and how the pathophysiology of infection develops into
established to achieve at least these levels and much higher the obvious clinical presentations iii. A lot is now known about
levels like 20-25mM and above are well represented in
clinical trials xi.
Correspondence to: Dr. Ian Dettman. PO Box 702,
Braeside VIC 3195 Australia. 61 3 9587 3948 biol@biol.com.au

2014 Biological Therapies, A division of Orthomolecular Medisearch Laboratories Pty Ltd.


5, 20-30 Malcolm Rd. Braeside, VIC, 3195. Australia www.biologicaltherapies.com biol@biol.com.au 61 3 9587 3948 1
BioLogical
the machinery of Ebola, how it works and how the host immune
responses are organised and deranged iv. Macrophages,
Use of Vitamin C in septic shock
dendritic cells, endothelial cells and hepatocytes are heavily and burns successful human
targeted by Ebola infection. Infected macrophages rapidly
spread the virus and release pathological amounts of a variety clinical trials
of inflammatory cytokines. Lymphocyte apoptosis is a feature
of this infection. Through a variety of mechanisms Ebola Human clinical trials exist where high dose intravenous Vitamin
manufactures decoys to absorb neutralising antibodies and also C has been used in septic shock patients and burns patients.
down-regulates the Interferon (IFN) replated response to viruses.
In many patients who die of the disease infected endothelial In a septic shock trial conducted by Fowler et al.v intravenous
cells undergo apoptosis leading to a rapid collapse of capillary Vitamin C (IVC) was used as follows: Twenty-four patients
integrity and frank haemorrhage, hence the significant with severe sepsis in the medical intensive care unit were
proportion of patients who die from shock and haemorrhagic randomized 1:1:1 to receive intravenous infusions every six
fever. Ebola blunts many aspects of the host immune response, hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24
discussed above, but at the same time dramatically increases h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5%
the inflammatory cascade resulting in fever, shock and death. dextrose/water, n = 8). The 200 mg/kg/24 h dose patients
Some infected patients are still able to mount an appropriate had the best response, having a significant decrease in their
response before the overwhelming pathological destruction sequential organ failure scores. 200 mg/kg/24 h works out at
sets in. These are the survivors. approx 15g IVC per day.

Some would suggest that this is nowhere near enough

many clinicians currently use Vitamin C. Another clinical trial using IVC in septic shock is
now recruiting, with the IVC dose to be 66mg/kg/hour of
high dose IV Vitamin C for a variety peripheral intravenous Vitamin C infusion for 24 hour duration,
maximum total of 200 grams. This is the typical dose used
of acute viral infections, IV Vitamin C is now being used in in burns units ix. In cancer clinical trials IVC is typically used
humans with sepsis, and there are significant similarities at doses from 11.5 g/kg. In a clinical trial on IVC in ovarian
cancer by Ma et al.xi they used a dose-escalating protocol,
between Ebola and sepsis presentations. Vitamin C given with final dose of either 75 or 100 g per infusion depending on
intravenously to Ebola patients would seem to be a wise step. peak plasma concentration of each individual. The target peak
plasma concentration of ascorbate was 350 to 400 mg/dl (20 to
23mM). In the original clinical burns trial conducted in Japan
Given this knowledge it is apparent that the excessive by Tanaka et al.viii IVC was used at a dose of 66 mg/kg/hour
inflammatory cascade and pathological derangements of Ebola for 24 hours. This works out at approx. 100g IVC per 24 hours
in disrupting microcirculation share some common pathways for a typical patient. The vitamin C dramatically reduced the
with other derangements of immune response, such as septic resuscitation fluid requirements in the treatment group.
shock and severe burns.

So what has this got to do with Vitamin C? There are now Some Mechanisms of Vitamin C
many animal studies on the use of high dose Vitamin C in
experimentally induced septic shock. And now there are also
in septic shock (microcirculation
SUCCESSFUL human clinical trials of high dose intravenous disruption, also occurs in
Vitamin C in septic shock v with more recruiting and on the
way vi. In particular intravenous Vitamin C is known to rapidly severe burns)
repair the microcirculation in septic shock and rapidly restore
the response to vasoconstrictors vii. High dose intravenous These key points below are taken directly from Wilson et al vii:
Vitamin C has also been shown clinically to stabilise Sepsis is associated with mal-distribution of blood flow
microcirculation and dramatically reduce fluid resuscitation within organs and loss of microvascular control of tissue
requirements in severe burns viii, ix. So much so that high dose oxygenation, as well as with arteriolar hypo-responsiveness to
intravenous Vitamin C is now used routinely in these patients vasoconstrictors and vasodilators
in many burns units x. Given the common factor of disruption Tissue hypoxia may precipitate organ failure. Indeed,
of the micro-circulation in septic shock, burns and Ebola it is microvascular dysfunction is a strong predictor of death and
reasonable to suggest that high dose Vitamin C could also one-third of severe sepsis patients die of organ failure even
impact the course of an Ebola infection. An optimistic clinical when shock is prevented
expectation is that the natural course of the disease could be Sepsis and tissue hypoxia are also associated with increased
slowed significantly, enough for the infected host to mount an production of reactive oxygen species (ROS) and peroxynitrite
appropriate immune defence against the infection. In other that deplete antioxidant molecules and cause oxidative stress
words we would hope that high dose Vitamin C could buy time ROS modulate redox-sensitive intracellular signalling pathways
and also deal directly with some of the nastier consequences that control the expression of genes critical to the initiation
of Ebola infection. If this were the case then a lot of lives and perpetuation of sepsis; these genes encode proteins
could be saved. that synthesize inflammatory cytokines, increase blood
coagulation, and alter endothelial cells regulation of blood
Lets review some uses of Vitamin C in sepsis and burns and pressure and capillary blood flow
compare the similarities between them and Ebola infection.

2009 Biological Therapies, A division of Orthomolecular Medisearch Laboratories Pty Ltd.


5, 20-30 Malcolm Rd. Braeside, VIC, 3195. Australia www.biologicaltherapies.com biol@biol.com.au 61 3 9587 3948 2
BioLogical
Ascorbate defends against ROS. In doing so it is oxidised to Once inside the body, the virus attacks macrophages and
Ascorbate Free Radical (AFR) and dehydroascorbate (DHAA). monocytes, relying upon host antibodies and complement
Ascorbate concentrations are subnormal in plasma and component 1 for efficient infection. The white blood cells
leukocytes, whereas plasma AFR concentration in plasma is respond by releasing large amounts of pro-inflammatory
elevated in critically ill patients cytokines that increase permeability of the vascular
Ascorbate deficiency may have serious consequences, endothelium, which facilitates easier entry into the viruss
since prior depletion of ascorbate decreases survival in mice secondary targets, endothelial cells. These cytokines also
injected with pathogenic bacteria recruit more macrophages to the area, maximizing the number
Septic insult increases the activity and expression levels of of cells that Ebola can use to spread throughout the body. In
NADPH oxidases (NOX) in vascular cells the meantime, hepatocytes are being destroyed by the virus,
Endothelial NADPH oxidases synthesize intracellular ensuring that these cell signals cannot be cleared from the
superoxide, which reacts to form other ROS bloodstream
Endothelial NADPH oxidase-derived ROS increase the Fatal Ebola infections are marked by unchecked viral
expression of inducible nitric oxide synthase (iNOS) in replication combined with an inadequate antiviral response.
microvascular endothelial cells exposed to septic insult. In order for this to occur, the early antiviral innate immune
Expression of iNOS leads to uncontrolled production of Nitric response must be delayed or inhibited
Oxide (NO) During infection, monocytes/macrophages in the lymphoid
NO and superoxide react to for peroxynitrites which further tissues are early and sustained targets of this deadly virus.
damage capillaries and stimulate further immune responses Since these cells usually elicit the response cascade in the
and excessive production of cytokines. acute phage of inflammation, their early infection helps Ebola
NADPH oxidase-derived superoxide avidly interacts with NOS- evade the immune system while subsequently spreading
derived nitric oxide to form peroxynitrite. Further, peroxynitrite throughout the host. In addition, infected macrophages
oxidizes the essential NOS cofactor Tetrahydrobiopterin (BH4). release increased amounts of nitric oxide (NO), a gaseous
BH4 control is essential for the local control of microcirculation hormone that normally functions in cell communication.
and response to vasoconstrictors. Loss of control of However, in high concentrations, NO depresses the
microcirculation leads to uncontrolled loss of fluid and shock mitochondrial membrane potential, causing apoptosis in
Ascorbate rapidly acts within endothelial cells to prevent nearby natural killer cells. Further clinical evidence exists for
induction of iNOS, bacterial endotoxin and inflammatory dramatically elevated NO levels in fatal cases xiv.
cytokines Macrophages and monocytes are releasing a cocktail
Ascorbate rapidly restores normal NO homoeostasis of pro-inflammatory cytokines that destroy the vascular
Infusion of ascorbate reverses arteriolar hypo-responsiveness endothelium, but also activate the coagulation cascade.
to vasoconstrictors (norepinephrine, angiotensin, vasopressin) There is an excessive and pathological cytokine release from
in patients who have inflammatory disease or have been macrophages. This puts your body in a paradoxical state
injected with lipo-polysaccharide (LPS/endotoxin) in which you can die of hypovolemic shock from massive
In humans the ascorbate needs to be given intravenously in haemorrhage, or from catastrophic thrombosis, the formation
high dose. The response is rapid. Intravenous ascorbate is of blood clots around the body
now being used in human clinical trials (sepsis) v,vi Ebola infection significantly inhibits Interferon (IFN) related
anti-viral activity

Histamine
Ebola - Similarities with Sepsis?
Low plasma ascorbate has been demonstrated in infection and
critically ill patients. Multiple organ failure and survival in critically While there are obvious differences between an Ebola
ill patients has been inversely related to plasma ascorbate infection and a typical sepsis patient, the two do share
concentration xii. Also, plasma histamine levels are inversely some common pathological events. In both can be seen a
associated with plasma ascorbate levels xiii. Elevated histamine diffuse overproduction of a range of cytokines which are both
levels are associated with capillary leakage and shock. damaging to the microcirculation and serve to increase the
damage by further immune system recruitment. In both we see
a derangement of Nitric Oxide. In both we see systemic organ
failure and the development of shock.
Ebola specific mechanisms
Vitamin C has been show in vitro, in animals and in humans
These key points below are taken directly from Infection to interfere with sepsis signalling. It has been shown to
Mechanism of Genus Ebolavirus MicrobeWiki iv dramatically reduce the cytokine production in uncontrolled
The span of time from onset of symptoms to death is usually sepsis signalling, to normalise and stabilise NO levels and
between 6 and 16 days. By the second week of the infection, to dramatically reduce fluid lost from the microvasculature in
the patient will either experience a full recovery or undergo severely burned patients.
systemic multi-organ failure. Mortality rates are generally high,
ranging from 50-90% depending on the specific strain. The So at this stage, given the similarities, and given the
cause of death is normally due to hypovolemic shock or organ effectiveness of high dose Vitamin C in septic patients, it is a
failure. While haemorrhages can be severe and have been the reasonable assertion to suggest that it is worth a go in Ebola
calling card of this virus, they are actually present in fewer than patients. Wilson xii makes the point that for effectiveness in
half of patients

2009 Biological Therapies, A division of Orthomolecular Medisearch Laboratories Pty Ltd.


5, 20-30 Malcolm Rd. Braeside, VIC, 3195. Australia www.biologicaltherapies.com biol@biol.com.au 61 3 9587 3948 3
BioLogical
sepsis, Vitamin C must be given intravenously. This is because
of limited uptake and distribution of Vitamin C when given
orally, as is also pointed out by Yuan ii. Given the severity
of the Ebola presentation it would be prudent to get a lot
of Vitamin C in as quickly as possible.
In the typical presentations of
patients with sepsis Vitamin C
In the treatment of glandular fever Vitamin C is typically is shown clearly to rapidly
administered intravenously in doses ranging from 7.5g to 50g i.
Mikirova et al i report a decrease in duration of Epstein-Barr
Virus (EBV) illness and a decrease in EBV antibodies when
restore microcirculatory
patients are administered IV Vitamin C. Anecdotal reports
(unpublished) suggest that IV Vitamin C in glandular fever homoeostasis. It is reasonable
can be dramatic. Similar reports exist for a range of common
mosquito borne viruses (Dengue, Ross River etc.) with rapid and
dramatic reductions in symptoms reported. to expect these sorts of effects
Many people have speculated as to how Vitamin C has these
effects. There is very little research published in this area
in Ebola infections. For a
outside sepsis type signalling. Vitamin C is known to have
immune modulatory effects, e.g. in a clinical study on 23 replication of the dramatic
patients with Furunculosis and depressed immunity Vitamin
C was shown to increase decreased neutrophil motility and
chemotaxis to normal levels xv. In research Vitamin C has been
effects seen in sepsis the
demonstrated to have a variety of immune effects, including the
stimulation of lymphoblastosis xvi and the stimulation of natural Vitamin C should be given
killer cells xvii. It is also demonstrated to have a significant anti-
histamine effect xiii and to inhibit excessive chemotaxis xviii as
occurs in Ebola infection and sepsis. Vitamin C has also been intravenously in high dose,
shown in a variety of studies to significantly improve Interferon
mediated responses to a variety of viral infections xix, xx, xxi. All
of these things are direct targets of Ebola infection and are all
at least in a dose seen to
deranged in infected patients.
be effective in a sepsis
Vitamin C appears at first glance to have some paradoxical
effects on various aspects of immunity; sometimes it stimulates,
sometimes it suppresses. A general review of some of the
clinical trial.
known immune modulatory, immune stimulating and immune
overactivity suppression effects of Vitamin C has been
published by Wintergerst and Hornig xxii.

In the typical presentations of patients with sepsis Vitamin C is Given that many clinicians currently use high dose IV Vitamin
shown clearly to rapidly restore microcirculatory homoeostasis vii. C for a variety of acute viral infections, that IV Vitamin C is now
It is reasonable to expect these sorts of effects in Ebola being used in humans with sepsis, and that there are significant
infections. For a replication of the dramatic effects seen in similarities between Ebola and sepsis presentations, Vitamin C
sepsis the Vitamin C should be given intravenously in high dose, given intravenously to Ebola patients would seem to be a wise
at least in a dose seen to be effective in a sepsis clinical trial v. step. At least it may buy some time for the patient to minimise
As already stated some would not consider this dose to be high microvascular disruption and to make a recovery via normal
enough. Vitamin C is not toxic so a conservative dose in a life immune defence which will also be supported and stimulated
threatening situation such as Ebola infection may not be wise. by Vitamin C.

Authors: Cliff Meakin* and Dr Ian Dettman*

* Cliff Meakin is a research employee at Biological Therapies


* Dr Ian Dettman is the Managing Director of Biological Therapies
Biological Therapies manufactures TGA registered parenteral
Vitamin C solutions.

2009 Biological Therapies, A division of Orthomolecular Medisearch Laboratories Pty Ltd.


5, 20-30 Malcolm Rd. Braeside, VIC, 3195. Australia www.biologicaltherapies.com biol@biol.com.au 61 3 9587 3948 4
BioLogical
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2009 Biological Therapies, A division of Orthomolecular Medisearch Laboratories Pty Ltd.


5, 20-30 Malcolm Rd. Braeside, VIC, 3195. Australia www.biologicaltherapies.com biol@biol.com.au 61 3 9587 3948 5

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