|
|
|
On The Mechanisms Of Toxicity Of Chlorine Oxides Against Malarial Parasites - An Overview |
|---|
can be acidified as a convenient method to produce
chlorine dioxide (ClO2)
which is a
strong oxidant and a potent disinfectant. A protocol has
been developed whereby a solution of these compounds can
be taken orally. This procedure rapidly eliminates malaria
and other infectious agents in only one dose. Chlorine
dioxide (ClO2) is highly reactive with thiols (RSH)
, polyamines
, purines
, certain amino acids and iron, all of which are
necessary for the growth and survival of pathogenic
microbes. Properly dosed this new treatment is tolerable
orally with only transient side effects. More research
to better document efficacy in malaria and in other
infections is urgently called for.
is prepared. The remaining 20% is a mixture of the usual
excipients necessary in the manufacture and stabilization
of sodium chlorite (NaClO2) powder or flake. Such are mostly sodium chloride (NaCl) ~19%
, sodium hydroxide (NaOH) <1%
, and sodium chlorate (NaClO3) <1%
. The actual sodium chlorite (NaClO2) present is
therefore 22.4%. Using a medium caliber dropper (25 drops
per cc), the usual administered dose per treatment is 6 to
15 drops. In terms of milligrams of sodium chlorite (NaClO2), this
calculates out to 9mg per drop or 54mg to 135mg per treatment.
Effectiveness is enhanced, if prior to administration the
selected drops are premixed with 2.5 to 5 cc of table vinegar
or lime juice or 5-10% citric acid
and allowed to react for
3 minutes. The resultant solution is always mixed into a glass
of water or apple juice and taken orally. The carboxylic acids
neutralize the sodium hydroxide (NaOH)
and at the same time convert
a small portion of the chlorite (ClO2-)
to its conjugate acid known as chlorous acid (HClO2)
.
Under such conditions the
chlorous acid (HClO2) will oxidize other chlorite anions (ClO2-)
and gradually produce chlorine dioxide (ClO2).
Chlorine dioxide (ClO2)
appears in solution as a yellow tint which smells exactly like
elemental chlorine (Cl2)
.
The above described procedure can be repeated a few hours later if necessary.
Considerably lower dosing should be applied in children or
in emaciated individuals scaled down according to size or weight.
The diluted solution can be taken without food to enhance effectiveness
but this often causes nausea. Drinking extra water usually relieves this.
Nausea is less likely to occur if food is present in the stomach.
Starchy food is preferable to protein as protein quenches chlorine dioxide (ClO2)
.
Significant amounts of vitamin C (ascorbic acid)
must not be present at any point in the mixtures
or else this will quench the chlorine dioxide (ClO2)
and render it ineffective. For the same reason antioxidant
supplements should not be taken on the day of treatment.
Other side effects reported are transient vomiting, diarrhea,
headache, dizziness, lethargy or malaise.
and chlorine dioxide (ClO2)
are already widely used as disinfectants.
What is novel and exciting here is that Mr. Humble's technique
seems: 1) easy to use, 2) rapidly acting, 3) successful,
4) apparently lacking in toxicity, and 5) affordable.
If this treatment continues to prove effective, it could be
used to help rid the world of one of the most devasting of all
known plagues. Especially moving in me is the empathy I feel
for anyone with a debilitating febrile illness. I cannot forget
how horrible I feel whenever I have caught influenza. How much
more miserable it must be to suffer like that again and again
every 2 to 3 days as happens in malaria. Millions of people
suffer this way year round. 1 to 3 million die from malaria
every year mostly children. Thus motivated I sought to learn
all I could about the chemistry of the oxides of chlorine.
I wanted to understand their probable mechanisms of toxicity
towards the causative agents of malaria (Plasmodium species).
I wanted to check available literature pertaining to issues
of safety or risk in human use.
, zinc peroxide
, various quinones (e.g. benzoquinone
, rhodizonic acid)
, various glyoxals (e.g. glyoxal
, methyl glyoxal
, ozone
, ultraviolet light, hyperbaric oxygen
, benzoyl peroxide
, anodes, artemisinin
, methylene blue
, allicin
,
iodine
and
permanganate
. Some work has been done using dilute solutions
of sodium chlorite (NaClO2)
internally to treat fungal infections,
chronic fatigue, and cancer; however, little has been
published in that regard.
Low dose oxidant exposure to living red blood cells induces an increase
in 2,3-diphosphoglycerate
levels inside these cells. This attaches to hemoglobin (Hb) in such a way
that oxyhemoglobin (HbO2) more readily releases oxygen (O2)
to the tissues throughout the body.
Hyperbaric oxygenation (oxygen under pressure):
Taken internally, intermittently and in low doses many
oxidants have been found to be powerful immune stimulants.
Sodium chlorite (NaClO2)
acidified with lactic acid
as in the product "WF10" has similarly been shown to modulate immune activation.
Exposure of live blood to ultraviolet light also has immune
enhancing effects. These treatments work through a natural
physiologic trigger mechanism, which induces peripheral white
blood cells to express and to release cytokines. These
cytokines serve as a control system to down-regulate allergic
reactions and as an alarm system to increase cellular attack
against pathogens.
Activated cells of the immune system naturally produce strong
oxidants as part of the inflammatory process at sites
of infection or cancer to rid the body of these diseases.
Examples are:
superoxide (*OO-)
, hydrogen peroxide (H2O2)
, hydroxyl radical (HO*)
, singlet oxygen (O=O)
and ozone (O3)
. Another is peroxynitrate (-OONO)
the coupled product of superoxide (*OO-)
and nitric oxide (*NO)
radicals.
| -OO* + *NO -> -OONO |
|---|
Yet another is hypochlorous acid (HOCl)
the conjugate acid of sodium hypochlorite (NaClO)
. The immune system uses these oxidants
to attack various parasites.
are commonly used as bleaching agents, as swimming pool sanitizers,
and as disinfectants. At low concentrations chlorine dioxide (ClO2)
has been shown to kill many types of bacteria, viruses and
protozoa. Ozone (O3)
or chlorine dioxide (ClO2)
are often used
to disinfect public water supplies or to sanitize and deodorize
waste water. Sodium chlorite (NaClO2)
or chlorine dioxide (ClO2)
solutions are used in certain mouth washes to clear mouth odors
and oral bacteria. Chlorine dioxide (ClO2) sanitizes food preparation
facilities. Acidified sodium chlorite is FDA approved as a spray
in the meat packing industry to sanitized meat. This can also
be used to sanitize vegetables and other foods. Farmers use
this to cleanse the udders of cows to prevent mastitis, or
to rid eggs of pathogenic bacteria. Chlorine dioxide (ClO2)
can be used to disinfect endoscopes. Oxidants such as iodine
, various peroxides
, permanganate
and chlorine dioxide
can be applied topically to the skin to treat infections caused
by bacteria or fungi.
, artemether
, t-butyl hydroperoxide
, xanthone
, various quinones
(e.g. atovaquone
, lapachol
, beta-lapachone
, menadione
) and methylene blue
.
. Thiols as a class
behave as reductants (electron donors). As such they are
especially sensitive to oxidants (electron grabbers). 
and other sulfur compounds are
reactive with sodium chlorite (NaClO2)
and with chlorine dioxide (ClO2)
. These are the very agents present in Mr. Humble's
solution. Possible products of oxidation of thiols (RSH)
using various oxides of chlorine are: disulfides (RSSR)
, disulfide monoxides (RSSOR)
, sulfenic acids (RSOH)
, sulfinic acids (RSO2H)
and sulfonic acids (RSO3H)
. 
by oxidation, the parasite
rapidly dies. A list of thiols (RSH) upon which survival
of Plasmodium species heavily depend includes:
dihydrolipoic acid
, coenzyme A
and acyl carrier protein
, glutathione
, glutathione reductase,
glutathione-S-transferase, peroxiredoxin, thioredoxin,
glutaredoxin, plasmoredoxin, thioredoxin reductase,
falcipain and ornithine decarboxylase. 
to the more
active chlorous acid (HClO2)
or chlorine dioxide (ClO2)
right inside the parasite. Furthermore, Plasmodia consume 50 to 100
times more glucose than noninfected red blood cells most of
which is metabolized to lactic acid
another known activator of chlorite (ClO2-).
Next falcipain a hemoglobin digesting enzyme hydrolyzes
hemoglobin protein to release its nutritional amino acids.
A necessary byproduct of this digestion is the release of 4 heme molecules
from each hemoglobin molecule digested.
Free heme (also known as ferriprotoporphyrin IX) is redox
active and can react with ambient oxygen (O2)
, an abundance
of which is always present in red blood cells. This produces
superoxide radical (*OO-)
, hydrogen peroxide (H2O2)
and
other reactive oxidant toxic species (ROTS). These can
rapidly poison the parasite internally. To protect themselves
against this dangerous side-effect of eating blood protein,
Plasmodia must maintain a high reductant capacity
(an abundance of reduced thiols (RSH)
and NADPH
) to quench these ROTS.
This is their main mechanism of antioxidant defense.
Plasmodia must also rapidly and continuously eliminate heme
,
which is accomplished by two methods. Firstly, heme is
polymerized producing hemozoin. Secondly, heme is metabolized
in a detoxification process that requires reduced glutathione
(GSH)
. Therefore any method (especially exposure to oxidants)
which limits the availability of reduced glutathione (GSH)
will cause a toxic build up of heme and of ROTS inside the
parasite cells. Sodium chlorite (NaClO2) and chlorine dioxide (ClO2)
(the exact agents present in Mr. Humble's treatment) readily
oxidize glutathione (GSH). Therefore, a rapid killing of Plasmodia
upon taking acidified sodium chlorite orally should be
expected.
, chloroquine
, mefloquine
, quinacrine
, amodiaquine
, primaquine
and other quinoline-like antibiotics
all work by blocking the
heme
detoxifying system inside the trophozoites. Many
Plasmodial strains against which quinolines have repeatedly
been used have found ways to adapt to these drugs and to
acquire resistance. Research into the mechanisms of resistance
has found that often resistance is accomplished by a meere
upregulation of glutathione (GSH)
production and utilization.
Consequently oxidizing or otherwise depleting glutathione (GSH)
inside the parasite usually restores sensitivity to the
quinoline antibiotics. Therefore, protocols combining the use
of oxidants with quinolines are under developement and already
showing signs of success. In this context let us consider that
no amount of intraplasmodial glutathione (GSH) could ever
resist exposure to a suffient dose of chlorine dioxide (ClO2)
. Note that each molecule of chlorine dioxide (ClO2) can disable 1 to 5
molecules of glutathione (GSH) depending on the reaction mechanism.
|
2(GSH) + 2(ClO2) --> 1(GSSG) + 2(H+) + 2(ClO2-) or 10(GSH) + 2(ClO2) --> 5(GSSG) + 2(H+) + 2(Cl-) + 4(H2O) |
|---|
by virtue of its oxidative power. However, quinolines contain
secondary amino groups
or tertiary amino groups
which react with chlorine dioxide (ClO2)
in such a way that both could destroy each other.
Some possible strategies to resolve this incompatibility are
suggested below.
and many other drugs if they have an unoxidized sulfur atom,
a phenol group
, a secondary amine
or a tertiary amine.
Such are reactive with the chlorine dioxide (ClO2)
component.
.
| 2 [H] + (RSSR) -> 2(RSH) |
|---|
This system is known as the hexose monophophate shunt.
A key player in this system is the enzyme glucose-6-phosphate-
dehydrogenase (G6PDH).
This enzyme is an essential part of a complex process that
produces NADPH
the main provider of reductants to the reductases
(enzymes which convert oxidized sulfur compounds back into thiols (RSH)
).
Patients with a genetic defect of G6PDH,
known as glucose-6-phosphate-dehydrogenase deficiency disease,
are especially sensitive to oxidants and to prooxidant drugs.
However, this genetic disease has a benefit in that such
individuals are naturally resistant to malaria. They can still
catch malaria, but it is much less severe in them, since they
permanently lack the enzyme necessary to assist the parasite
in reactivating glutathione disulfide (GSSG)
and other oxidized thiols.
Chlorine dioxide (ClO2)
has been shown to oxidize and denature
G6PDH by reaction with the tyrosine
and the tryptophan
residues inside the enzyme.
Furthermore, G6PDH is sensitive to inhibition by sodium chlorate (NaClO3)
, another member of the chlorine oxide family of compounds.
Sodium chlorate (NaClO3) is a trace
ingredient present in Jim Humble's antimalarial solution.
Some sodium chlorate (NaClO3)
should also be produced in vivo by a slow reaction of chlorine
dioxide (ClO2) with water under alkaline conditions.
| 2(ClO2) + 2(OH-) -> (ClO2-) + (ClO3-) + H2O |
|---|
The Plasmodia may attempt to restore
any thiols (RSH)
lost to oxidation. However, this becomes more
difficult as G6PDH is inhibited by chlorine dioxide (ClO2)
or
by chlorate (ClO3-)
.
. Other mechanisms
of toxicity of the oxides of chlorine against Plasmodia
should also be considered. Oxides of chlorine are generally
rapidly reactive with ferrous iron (Fe++) converting it to
ferric (Fe+++). This explains why in cases of overdosed
exposures to oxides of chlorine such as sodium chlorite
(NaClO2)
there was a notable rise in methemoglobin levels.
Methemoglobin is a metabolically inactive form of hemoglobin
in which its ferrous iron (Fe++) cofactor has been oxidized
to ferric (Fe+++).
In living things including parasites iron
is a necessary cofactor for many enzymes. Thus it is
reasonable to expect that any damage to Plasmodia caused
by oxides of chlorine is compounded by conversion of ferrous
(Fe++) cofactors to ferric (Fe+++) or other alterations of
iron compounds. Superoxide dismutase (SOD) inside Plasmodial
cells also utilizes iron in its active center. Chlorine dioxide
also oxidizes manganese (Mn++).
, which are
deadly to parasites and to tumors. Chlorine dioxide (ClO2)
is known to be especially reactive against secondary amines
. This includes spermine
and spermidine
the two main
biologically important polyamines.
and polyamines does quadruple damage to the pathogen: 
and spermine
. 
are essential to many life processes. These molecules
have a double ring structure. The rings are heterocyclic
being composed of both carbon and nitrogen. The secondary amino nitrogen atoms
are vulnerable to reaction with chlorine dioxide (ClO2)
. Examples of important biologic purines are xanthine
, hypoxanthine
, inosine
, guanine
and
adenine
. Guanine and adenine are
essential components of DNA and RNA necessary for all genetic
functions and for all protein syntheses. Adenine is an
essential component of the cofactors NADH
, NADPH
, FAD
and ATP
, necessary for many metabolic functions including oxidation-
reduction and energy metabolism. Any purines lost because of
chlorine dioxide (ClO2)
exposure can be readily replaced by host cells.
Plasmodia and other apicomplexae are uniquely vulnerable to purine
deficiency as they lack the enzymes necessary to produce
purines for themselves. Instead these must be scavenged from
host cells and imported across the plasma membranes of the
parasite cells. Drugs are under development to inhibit purine
utilization by Plasmodia and are already showing signs of
success. Temporarily destroying some of the purines in the
blood as should occur upon brief exposure to chlorine dioxide (ClO2)
in vivo is probably an additional stress that Plasmodia cannot
tolerate.
is highly reactive with thiols (RSH)
, phenols
, secondary amines
and tertiary amines
. Therefore,
proteins composed of amino acids which present these
reactive groups are vulnerable to oxidation by this agent.
Proteins which present thiol groups as residue(s) of the
amino acid L-cysteine
are discussed above under TARGETING THIOLS.
L-tyrosine
presents a phenol group and is therefore
similarly vulnerable. L-tryptophan
, L-histidine
, L-proline
and 4-hydroy-L-proline
present secondary amino groups which are also
especially reactive with chlorine dioxide (ClO2)
. 
levels in frequent users. Sodium chlorite (NaClO2)
, as found in municipal water supplies after disinfection
by chorine dioxide (ClO2)
, has been studied and proven safe.
Animal studies using much higher oral or topical doses have
proven relatively safe. In a suicide attempt 10g of sodium
chlorite (NaClO2) taken orally caused refractory methemoglobinemia
and nearly fatal kidney failure. Inhalation or aerosol exposure to
chlorine dioxide (ClO2) gas is highly irritating and generally not
recommended. Special precautions must be employed
in cases of glucose-6-phosphate-dehydrogenase deficiency
disease, as these patients are especially sensitive to oxidants
of all kinds. Nevertheless, oral acidified sodium chlorite
solutions might even be found safe and effective in them,
but probably will need to be administered at lower doses.
dependent parasites should also be susceptible to acidified sodium chlorite.
For example Trypanosoma and Leishmania extensively utilize and
cannot survive without the cofactor known as trypanothione.
Each molecule of trypanothione presents 2 sulfur atoms and 5 secondary
amino groups all of which are vulnerable to oxidative destruction
from chlorine dioxide (ClO2)
.
Chlorine dioxide (ClO2) has been proven to be cidal to almost all known infectious agents in vitro using remarkably low concentrations. This includes parasites, fungi, bacteria and viruses. The experiences noted above imply that this compound is tolerable orally at effective concentrations. Therefore extensive research is warranted to determine if acidified sodium chlorite is effective in treating other infections. We may be on the verge of discovering the most potent and broad spectrum antimicrobial agent yet known. Special thanks go to Jim Humble for his willingness to share his discovery with the world.