Description
TECHNICAL FIELD
This invention relates to an aqueous metal bicarbonate
solution, a process of preparing the aqueous metal bicarbonate
solution and a method of preventing and treating certain
inflammatory diseases, degenerative diseases and viral diseases
in mammals.
Generally the certain inflammatory diseases, degenerative
diseases and viral diseases in mammals are those that require
extracellular or intracellular acidic conditions or
extracellular or intracellular proton concentrations at some
point in disease process or disease pathogenesis.
Typically the certain inflammatory diseases, degenerative
diseases and viral diseases in mammals are those that require
the activities of carbonic anhydrase enzymes and/or the
activities of acid (aspartic) protease enzymes and/or the
activities of endosomal or lysosomal acid-requiring-enzymes
and/or the activities of V-type ATPase proton pumps at some
point in disease process or disease pathogenesis. Typically the
certain inflammatory diseases, degenerative diseases and viral
diseases in mammals are represented by the diseases of arthritis
and influenza;
This invention relates to a method of using an aqueous metal
bicarbonate solution to decrease senescence and to increase
longevity in mammals. Generally senescence is decreased and
longevity is increased in mammals by improving the buffering
capacity of the extracellular and intracellular fluids of the
body. Generally senescence is decreased and longevity is
increased in mammals by the improved buffering capacity causing
a decrease in proton concentrations in the extracellular and
intracellular fluids of the body.
Typically senescence is decreased and longevity is increased in
mammals by improving the buffering capacity of the extracellular
and intracellular bicarbonate buffers. Typically senescence is
decreased and longevity is increased in mammals by the improved
extracellular and intracellular bicarbonate buffers causing a
decrease in proton concentrations.
BACKGROUND ART
Certain inflammatory diseases, degenerative diseases and viral
diseases are major causes of morbidity and mortality in mammals.
Typically these diseases are represented by the diseases of
arthritis and influenza.
Arthritis is any inflammatory condition of the joints,
characterised by pain and swelling. Osteoarthritis is the most
common form of arthritis in which one or many joins undergo
degenerative changes. Treatment includes rest of the involved
joints, heat, and antiinflammatory drugs. Intraarticular
injections of corticosteroids may give relief. Surgical
treatment is sometimes necessary and may reduce pain and greatly
improve the function of the joint. However these treatments,
apart from surgical treatment, only provide temporary relief and
some may have severe side reactions.
Influenza is a highly contagious infection of the respiratory
tract caused by a myxovirus and transmitted by airborne droplet
infection. It occurs in isolated cases, epidemics and pandemics
Treatment is symptomatic and usually involves bed rest,
antipyretics such as aspirin and drinking of fluids. New strains
of the virus emerge at regular intervals so it is difficult to
take preventative measures to avoid the infection There is a
need for a method to prevent and to treat certain inflammatory
diseases, degenerative diseases and viral diseases in mammals.
There is a need for a method to prevent and to treat arthritis
and influenza in mammals.
Senescence in mammals is characterised by progressive
oxidations of the structural and functional molecules that
constitute body cells and tissues. Oxidations of the structural
and functional molecules in body cells and tissues are increased
in rate by acidic conditions. Oxidations of structural and
functional molecules are increased in rate by the presence of
excess proton concentrations. There is a need for a method to
prevent and treat excess proton concentrations in body cells so
that oxidations of structural and functional molecules are
decreased in rate. There is a need for a method to decrease and
treat senescence in mammals.
OBJECTS OF INVENTION
It is an object of this invention to provide an aqueous metal
bicarbonate solution to prevent and to treat certain
inflammatory diseases, degenerative diseases and viral diseases
in mammals. It is a further object of this invention to provide
a process of preparing the aqueous metal bicarbonate solution.
It is also an object of this invention to provide methods for
the prevention and treatment of certain inflammatory diseases,
degenerative diseases and viral diseases in mammals using the
aqueous metal bicarbonate solution. Generally the certain
inflammatory diseases, degenerative diseases and viral diseases
in mammals are those that require extracellular or intracellular
acidic conditions or extracellular or intracellular proton
concentrations at some point in disease process or disease
pathogenesis. Typically the certain inflammatory diseases,
degenerative diseases and viral diseases in mammals are those
that require the activities of carbonic anhydrase enzymes and/or
the activities of acid (aspartic) protease enzymes and/or the
activities of endosomal or lysosommal acid-requiring-enzymes
and/or the activities of V-type ATPase proton pumps at some
point in disease process or disease pathogenesis. Typically the
certain inflammatory diseases, degenerative diseases and viral
diseases in mammals are represented by the diseases of arthritis
and influenza.
It is an object of this invention to provide an aqueous metal
bicarbonate solution to decrease senescence and to treat
senescence and to increase longevity in mammals. It is a further
object of this invention to provide a process of preparing the
aqueous metal bicarbonate solution. It is also an object of this
invention to provide methods for the decrease of senescence and
the treatment of senescence and the increase in longevity in
mammals using the aqueous metal bicarbonate solution. Generally
senescence is decreased and longevity is increased in mammals by
improving the buffering capacity of the extracellular and
intracellular fluids of the body. Generally senescence is
decreased and longevity is increased in mammals by the improved
buffering capacity causing a decrease in proton concentrations
in the extracellular and intracellular fluids of the body.
Typically senescence is decreased and longevity is increased in
mammals by improving the buffering capacity of the extracellular
and intracellular bicarbonate buffers. Typically senescence is
decreased and longevity is increased in mammals by the improved
extracellular and intracellular bicarbonate buffers causing a
decrease in proton concentrations.
DISCLOSURE OF INVENTION
According to a first embodiment of the present invention there
is provided an aqueous metal bicarbonate solution comprising a
stoichiometric concentration of bicarbonate anions and a
corresponding substantially stoichiometric concentration of
metal cations in association with the bicarbonate anions, the
metal bicarbonate being present in a therapeutically effective
amount and an acceptable carbon dioxide-containing-aqueous
diluent to maintain the metal bicarbonate in the aqueous
diluent. Typically the solution is acceptable for oral
administration.
In one embodiment there is provided a combination comprising
the solution of the first embodiment in combination with a
stabilising agent in an amount effective to maintain and
stabilise the bicarbonate anions in the neutral to mildly
alkaline solution. Generally the combination is kept in a sealed
or closed container at 0.8 to 5 atmospheres, more typically 1
atmosphere at 0-25° C., more typically 0.1-10° C. In one
particular embodiment the stabilising agent may be present in
the solution in an amount effective to maintain and stabilise
the bicarbonate anions in the neutral to mildly alkaline
solution. In another particular embodiment the stabilising agent
may consist of or comprise a gas above the solution in an amount
effective to maintain and stabilise the bicarbonate anions in
the neutral to mildly alkaline solution. In a further particular
embodiment the stabilising agent may be present in the solution
and also may consist of or comprise a gas above the solution,
the total amount of stabilising agent in the solution and in the
gas above the solution being in an amount effective to maintain
and stabilise the bicarbonate anions in the neutral to mildly
alkaline solution. The stabilising agent which consists of a gas
above the solution may be carbon dioxide. The stabilising agent
which comprises a gas above the solution may be carbon dioxide
in an an inert gas such as nitrogen, air, oxygen, argon and/or
helium, for example. The stabilising agent in the solution may
be carbon dioxide dissolved in the solution, hydrated carbon
dioxide, carbonic acid, and/or other suitable source of carbon
dioxide.
According to a second embodiment of the present invention there
is provided a process of preparing an aqueous metal bicarbonate
solution comprising a stoichiometric concentration of
bicarbonate anions and a corresponding substantially
stoichiometric concentration of metal cations in association
with the bicarbonate anions, which process comprises reacting a
concentration of a metal carbonate or metal carbonate hydroxide
or metal oxide or metal hydroxide with a concentration of
carbonic acid or hydrated carbon dioxide to produce the metal
bicarbonate aqueous solution, wherein said metal bicarbonate
being present in a therapeutically effective amount.
Typically the aqueous metal bicarbonate solution has a neutral
to mildly alkaline pH. Typically the pH is in the range 7 to 9.
Typically the temperature of the aqueous metal bicarbonate
solution is maintained at a level to maintain the metal
bicarbonate in the aqueous diluent.
According to a third embodiment of the present invention there
is provided an aqueous metal bicarbonate solution whenever
prepared by the process of the second embodiment.
According to a fourth embodiment of the present invention there
is provided a method of preventing and treating certain
inflammatory diseases and degenerative diseases in a mammal in
need of such prevention or treatment comprising administering to
said mammal an effective amount of an aqueous metal bicarbonate
solution of the first or third embodiment or a metal
bicarbonate.
Generally the certain inflammatory diseases and degenerative
diseases in a mammal are those that require extracellular or
intracellular acidic conditions or extracellular or
intracellular proton concentrations at some point in disease
process or disease pathogenesis.
Typically the certain inflammatory diseases and degenerative
diseases in a mammal are those that require the activities of
carbonic anhydrase enzymes and/or the activities of acid
(aspartic) protease enzymes and/or the activities of endosomal
or lysosomal acid-requiring-enzymes and/or the activities of
V-type ATPase proton pumps at some point in disease process or
disease pathogenesis.
Typically the certain inflammatory diseases or degenerative
diseases may present as arthritis. Typically the arthritis may
present as osteoarthritis.
According to a fifth embodiment of the present invention there
is provided a method of preventing and treating certain viral
diseases in a mammal in need of such prevention or treatment
comprising administering to said mammal an effective amount of
an aqueous metal bicarbonate solution of the first or third
embodiment or a metal bicarbonate.
Typically the certain viral diseases require intracellular
acidic conditions or intracellular proton concentrations for
either removal of viral protein coats or assembly of viral
protein coats. Typically the viral diseases may present as
influenza.
According to a sixth embodiment of the present invention there
is provided a method of decreasing and treating senescence and
of increasing longevity in a mammal comprising administering to
said mammal an effective amount of an aqueous metal bicarbonate
solution of the first or third embodiment or a metal
bicarbonate.
Typically senescence is decreased and longevity is increased by
maintaining or increasing normal extracellular and/or
intracellular alkaline conditions. Typically senescence is
decreased and longevity is increased by improving the buffering
capacity of the extracellular and intracellular fluids of the
body. Typically longevity is increased by maintaining or
increasing normal mitochondrial alkaline conditions. Typically
longevity is increased by decreasing extracellular and
intracellular acidic conditions or by decreasing extracellular
and intracellular proton concentrations.
Typically senescence is decreased and longevity is increased in
mammals by improving the buffering capacity of the extracellular
and intracellular bicarbonate buffers. Typically senescence is
decreased and longevity is increased in mammals by the improved
extracellular and intracellular bicarbonate buffers causing a
decrease in proton concentrations. Typically senescence is
decreased and longevity is increased by preventing or treating
certain inflammatory diseases, degenerative diseases and viral
diseases in mammals. Typically longevity is increased by
decreasing the morbidity and mortality associated with these
diseases.
According to a seventh embodiment of the present invention
there is provided a method of scavenging protons in a mammal
comprising administering to said mammal an effective amount of a
proton scavenger.
Typically the proton scavenger comprises a metal bicarbonate.
Typically the metal bicarbonate is in the form of the aqueous
metal bicarbonate solution of the first or third embodiment.
According to an eighth embodiment of the present invention
there is provided a method of decreasing proton concentrations
in a mammal by altering carbonic anhydrase enzyme reactions in
said mammal comprising administering to said mammal an effective
amount of an aqueous metal bicarbonate solution of the first or
third embodiment or a metal bicarbonate.
According to a ninth embodiment of the present invention there
is provided a method of decreasing inflammation and inflammatory
conditions in a mammal comprising administering to said mammal
an effective amount of an aqueous metal bicarbonate solution of
the first or third embodiment or a metal bicarbonate.
Generally inflammation and inflammatory conditions are
decreased by decreasing the extracellular and intracellular
acidic conditions that are required for inflammatory processes.
Generally inflammation and inflammatory conditions are decreased
by decreasing the extracellular and intracellular proton
concentrations that are required for inflammatory processes.
Typically inflammation is decreased by altering carbonic
anhydrase enzyme reactions and/or decreasing the activities of
acid (aspartic) protease enzymes and/or decreasing the
activities of endosomal or lysosomal acid-requiring-enzymes
and/or decreasing the activities of V-type ATPase proton pumps.
According to a tenth embodiment of the present invention there
is provided a method of increasing motor activity in a mammal
comprising administering to said mammal an effective amount of
an aqueous metal bicarbonate solution of the first or third
embodiment or a metal bicarbonate.
Typically motor activity is increased by decreasing
extracellular and intracellular acidic conditions or by
decreasing extracellular and intracellular proton
concentrations. Typically motor activity is increased by
improving the buffering capacity of extracellular and
intracellular fluids. Typically motor activity is increased by
improving the buffering capacity of the extracellular and
intracellular bicarbonate buffers. Typically motor activity is
increased by increasing extracellular and intracellular alkaline
conditions. Typically motor activity is increased by scavenging
protons produced by ATP hydrolysis, lactic acid production,
lipid metabolism and other metabolic processes.
According to an eleventh embodiment of the present invention
there is provided an aqueous neutral to mildly alkaline metal
bicarbonate solution, comprising metal bicarbonate dissolved in
the solution, said metal bicarbonate comprising bicarbonate
anions and metal cations, and a pH adjusting agent in the
solution in an amount whereby the solution is at a neutral to
mildly alkaline pH.
Typically a corresponding substantially stoichiometric
concentration of metal cations are in association with the
bicarbonate anions. Typically the solution is acceptable for
oral administration.
In one embodiment there is provided a combination comprising a
substantially stable aqueous neutral to mildly alkaline metal
bicarbonate solution, comprising metal bicarbonate dissolved in
the solution, said metal bicarbonate comprising bicarbonate
anions and metal cations, and a pH adjusting agent in the
solution in an amount whereby the solution is at a neutral to
mildly alkaline pH, in combination with a stabilising agent in
an amount effective to maintain and stabilise the bicarbonate
anions in the neutral to mildly alkaline solution. In another
embodiment there is provided a combination comprising a
substantially stable aqueous neutral to mildly alkaline metal
bicarbonate solution, comprising metal bicarbonate dissolved in
the solution, said metal bicarbonate comprising bicarbonate
anions and metal cations, in combination with a stabilising
agent in an amount effective to maintain and stabilise the
bicarbonate anions in the solution whereby the solution is at a
neutral to mildly alkaline pH.
The pH adjusting agent and the stabilising agent may be the
same or different. Generally the combination is kept in a sealed
or closed container at 0.8 to 5 atmospheres, more typically 1
atmosphere at 0-25° C., more typically 0.1-10° C.
In one particular embodiment the stabilising agent may be
present in the solution in an amount effective to maintain and
stabilise the bicarbonate anions in the neutral to mildly
alkaline solution. In another particular embodiment the
stabilising agent may consist of or comprise a gas above the
solution in an amount effective to maintain and stabilise the
bicarbonate anions in the neutral to mildly alkaline solution.
In a further particular embodiment the stabilising agent may be
present in the solution and may consist of or comprise a gas
above the solution, the total amount of stabilising agent in the
solution and in the gas above the solution being in an amount
effective to maintain and stabilise the bicarbonate anions in
the neutral to mildly alkaline solution. The stabilising agent
which consists of a gas above the solution may be carbon
dioxide. The stabilising agent which comprises a gas above the
solution may be carbon dioxide in an an inert gas such as
nitrogen, air, oxygen, argon and/or helium, for example. The
stabilising agent in the solution may be carbon dioxide
dissolved in the solution, hydrated carbon dioxide, carbonic
acid, and/or other suitable source of carbon dioxide.
According to a twelfth embodiment of the present invention
there is provided a solution for preventing and/or treating
certain inflammatory diseases and/or degenerative diseases
and/or certain viral diseases in a mammal, comprising the
aqueous neutral to mildly alkaline metal bicarbonate solution of
the eleventh embodiment whereby the metal bicarbonate is present
in an amount effective to prevent and/or treat said diseases.
According to a thirteenth embodiment of the present invention
there is provided a solution for decreasing and/or treating
senescence and/or increasing longevity in a mammal, comprising
the aqueous neutral to mildly alkaline metal bicarbonate
solution of the eleventh embodiment whereby the metal
bicarbonate is present in an amount effective to decrease and/or
treat senescence and/or increase longevity.
According to a fourteenth embodiment of the present invention
there is provided a solution for scavenging protons in a mammal,
comprising the aqueous neutral to mildly alkaline metal
bicarbonate solution of the eleventh embodiment whereby the
metal bicarbonate is present in an amount effective to scavenge
protons.
According to a fiftenth embodiment of the present invention
there is provided a solution for decreasing proton
concentrations in a mammal, comprising the aqueous neutral to
mildly alkaline metal bicarbonate solution of the eleventh
embodiment whereby the metal bicarbonate is present in an amount
effective to decrease proton concentrations.
According to a sixteenth embodiment of the present invention
there is provided a solution for decreasing inflammation and
inflammatory conditions in a mammal, comprising the aqueous
neutral to mildly alkaline metal bicarbonate solution of the
eleventh embodiment whereby the metal bicarbonate is present in
an amount effective to decrease inflammation and/or inflammatory
conditions.
According to a seventeenth embodiment of the present invention
there is provided a solution for increasing motor activity
and/or decrease fatigue in a mammal, comprising the aqueous
neutral to mildly alkaline metal bicarbonate solution of the
eleventh embodiment whereby the metal bicarbonate is present in
an amount effective to increase motor activity.
According to an eighteenth embodiment of the present invention
there is provided a process of preparing an aqueous neutral to
mildly alkaline metal bicarbonate solution comprising
bicarbonate anions and metal cations, which process comprises
reacting a compound selected from the group consisting of metal
carbonate, metal carbonate hydroxide, metal oxide, metal
hydroxide and any mixture thereof with an effective
concentration of a pH adjusting agent to produce the aqueous
neutral to mildly alkaline metal bicarbonate solution, wherein
the pH adjusting agent is present in an amount whereby the
solution is at a neutral to mildly alkaline pH.
Typically a corresponding substantially stoichiometric
concentration of metal cations are in association with the
bicarbonate anions. Generally the solution is stored in a sealed
or closed container at 0.8 to 5 atmospheres, more typically 1
atmosphere at 0-25° C., more typically 0.1-10° C. In one
embodiment the process further comprises combining the solution
with a stabilising agent in an amount effective to maintain and
stabilise the bicarbonate anions in the neutral to mildly
alkaline solution. In one particular embodiment the process
comprises conducting the process under gaseous atmosphere
comprising a stabilising agent in an amount effective to
maintain and stabilise the bicarbonate anions in the neutral to
mildly alkaline solution. The stabilising agent may be carbon
dioxide or comprise carbon dioxide in an inert gas such as
nitrogen, air, oxygen, argon and/or helium, for example.
Generally the combination is stored in a sealed or closed
container at 0.8 to 5 atmospheres, more typically 1 atmosphere
at 0-25° C., more typically 0.1-10° C. One particular embodiment
may comprise adding the stabilising agent to the solution in the
solution in an amount effective to maintain and stabilise the
bicarbonate anions in the neutral to mildly alkaline solution.
Another particular embodiment may comprise blanketing the
solution with a gas consisting of or comprising the stabilising
agent in an amount effective to maintain and stabilise the
bicarbonate anions in the neutral to mildly alkaline solution. A
further particular embodiment may comprise adding the
stabilising agent to the solution in the solution and blanketing
the solution with a gas consisting of or comprising the
stabilising agent, the total amount of stabilising agent in the
solution and in the gas above the solution being in an amount
effective to maintain and stabilise the bicarbonate anions in
the neutral to mildly alkaline solution. The stabilising agent
which consists of a gas above the solution may be carbon
dioxide. The stabilising agent which comprises a gas above the
solution may be carbon dioxide in an inert gas such as nitrogen,
air, oxygen, argon and/or helium, for example. The stabilising
agent in the solution may be carbon dioxide dissolved in the
solution, hydrated carbon dioxide, carbonic acid, and/or other
suitable source of carbon dioxide.
According to a nineteenth embodiment of the present invention
there is provided a aqueous neutral to mildly alkaline metal
bicarbonate solution whenever prepared by the process of the
eighteenth embodiment.
According to a twentieth embodiment of the present invention
there is provided a method of preventing and/or treating certain
inflammatory diseases and/or degenerative diseases in a mammal
in need of such prevention and/or treatment comprising
administering to said mammal an effective amount of an aqueous
neutral to mildly alkaline metal bicarbonate solution of the
eleventh or a metal bicarbonate.
Generally the certain inflammatory diseases and degenerative
diseases in a mammal are those that require extracellular or
intracellular acidic conditions or extracellular or
intracellular proton concentrations at some point in disease
process or disease pathogenesis.
Typically the certain inflammatory diseases and degenerative
diseases in a mammal are those that require the activities of
carbonic anhydrase enzymes and/or the activities of acid
(aspartic) protease enzymes and/or the activities of endosomal
or lysosomal acid-requiring-enzymes and/or the activities of
V-type ATPase proton pumps at some point in disease process or
disease pathogenesis.
Typically the certain inflammatory diseases or degenerative
diseases may present as arthritis. Typically the arthritis may
present as osteoarthritis.
According to a twenty-first embodiment of the present invention
there is provided a method of preventing and/or treating certain
viral diseases in a mammal in need of such prevention and/or
treatment comprising administering to said mammal an effective
amount of an aqueous neutral to mildly alkaline metal
bicarbonate solution of the eleventh embodiment or a metal
bicarbonate.
Typically the certain viral diseases require intracellular
acidic conditions or intracellular proton concentrations for
either removal of viral protein coats or assembly of viral
protein coats. Typically the viral diseases may present as
influenza.
According to a twenty-second embodiment of the present
invention there is provided a method of decreasing and/or
treating senescence and/or of increasing longevity in a mammal
comprising administering to said mammal an effective amount of
an aqueous neutral to mildly alkaline metal bicarbonate solution
of the eleventh embodiment or a metal bicarbonate.
Typically senescence is decreased and longevity is increased by
maintaining or increasing normal extracellular and/or
intracellular alkaline conditions. Typically senescence is
decreased and longevity is increased by improving the buffering
capacity of the extracellular and intracellular fluids of the
body. Typically longevity is increased by maintaining or
increasing normal mitochondrial alkaline conditions. Typically
longevity is increased by decreasing extracellular and
intracellular acidic conditions or by decreasing extracellular
and intracellular proton concentrations. Typically senescence is
decreased and longevity is increased in mammals by improving the
buffering capacity of the extracellular and intracellular
bicarbonate buffers. Typically senescence is decreased and
longevity is increased in mammals by the improved extracellular
and intracellular bicarbonate buffers causing a decrease in
proton concentrations.
Typically senescence is decreased and longevity is increased by
preventing or treating certain inflammatory diseases,
degenerative diseases and viral diseases in mammals. Typically
longevity is increased by decreasing the morbidity and mortality
associated with these diseases.
According to a twenty-third embodiment of the present invention
there is provided a method of scavenging protons in a mammal
comprising administering to said mammal an effective amount of a
proton scavenger.
Typically the proton scavenger comprises a metal bicarbonate.
Typically the metal bicarbonate is in the form of the aqueous
neutral to mildly alkaline metal bicarbonate solution of the
eleventh embodiment.
According to a twenty-fourth embodiment of the present
invention there is provided a method of decreasing proton
concentrations in a mammal by altering carbonic anhydrase enzyme
reactions in said mammal comprising administering to said mammal
an effective amount of an aqueous neutral to mildly alkaline
metal bicarbonate solution of the eleventh embodiment or a metal
bicarbonate.
According to a twenty-fifth embodiment of the present invention
there is provided a method of decreasing inflammation and/or
inflammatory conditions in a mammal comprising administering to
said mammal an effective amount of an aqueous neutral to mildly
alkaline metal bicarbonate solution of the eleventh embodiment
or a metal bicarbonate.
Generally inflammation and inflammatory conditions are
decreased by decreasing the extracellular and intracellular
acidic conditions that are required for inflammatory processes.
Generally inflammation and inflammatory conditions are decreased
by decreasing the extracellular and intracellular proton
concentrations that are required for inflammatory processes.
Typically inflammation is decreased by altering carbonic
anhydrase enzyme reactions and/or decreasing the activities of
acid (aspartic) protease enzymes and/or decreasing the
activities of endosomal or lysosomal acid-requiring-enzymes
and/or decreasing the activities of V-type ATPase proton pumps.
According to a twenty-sixth embodiment of the present invention
there is provided a method of increasing motor activity and/or
decreasing fatigue in a mammal comprising administering to said
mammal an effective amount of an aqueous neutral to mildly
alkaline metal bicarbonate solution of the eleventh embodiment
or a metal bicarbonate.
The methods of the invention typically involve orally
administering to the mammal, the mammal being typically human.
Further the methods of the invention typically involve orally
administering to a mammal in need of treatment for the specified
condition of the particular embodiment, the mammal being
typically human. Typically motor activity is increased by
decreasing extracellular and intracellular acidic conditions or
by decreasing extracellular and intracellular proton
concentrations. Typically motor activity is increased by
improving the buffering capacity of extracellular and
intracellular fluids. Typically motor activity is increased by
improving the buffering capacity of the extracellular and
intracellular bicarbonate buffers. Typically motor activity is
increased by increasing extracellular and intracellular alkaline
conditions. Typically motor activity is increased by scavenging
protons produced by ATP hydrolysis, lactic acid production,
lipid metabolism and other metabolic processes.
The term mammal as used herein includes vertebrate. Examples of
mammals and vertebrates to which the methods of the invention
apply include a bovine, human (male or female), ovine, equine,
caprine, Leporine, feline or canine mammal or vertebrate.
Specific examples of animals include sheep, cattle, horses,
rabbits, cats, goats, alpacas, cats, dogs, pigs, rabbits, fowls,
deer, buffaloes and other livestock and domestic animals.
Metal Bicarbonate Generally
Generally the pH of the aqueous metal bicarbonate solution is
neutral to mildly alkaline, typically mildly alkaline and more
typically in the range of 7 to 9 even more typically 8 to 8.6
and the temperature of the aqueous neutral to mildly alkaline
metal bicarbonate solution is maintained at such a level so as
to maintain the metal bicarbonate in the aqueous diluent. The
aqueous neutral to mildly alkaline metal bicarbonate solution
may be kept under an atmosphere comprising carbon dioxide of
from about 0.8 to 5 or 1 to 5 atmospheres, more typically 1 to 3
atmospheres and even more typically slightly above atmospheric
pressure such as the sorts of pressures that soft drinks are
currently under in cans or bottles, for example, so as to
maintain the metal bicarbonate in the aqueous diluent.
Generally the metal cation is an alkaline earth metal cation or
an alkali metal cation. Generally a metal cation is chosen which
is capable of acting as a bicarbonate transporter into mammalian
cells. More particularly the metal cation may be cations of
magnesium, sodium, potassium, calcium, lithium or any mixture
thereof. Where a mixture of alkaline earth metal cations or
alkali metal cations are used; (1) two different alkaline earth
metal cations or alkali metal cations or mixtures thereof, the
molar ratio of the first metal cation to the second may be in
the range 0.5:99.5 to 99.5:0.5, typically 75:25 to 25:75, more
typically 0.7:1 to 1:0.7; (2) three different alkaline earth
metal cations or alkali metal cations or mixtures thereof, the
molar ratio of the first metal cation to the second to the third
may be in the range 99.5:0.5:0.5 to 0.5:99.5:99.5, typically
75:25:25 to 25:75:75, more typically 0.5:1:1 to 1:0.5:0.5; (3)
four different alkaline earth metal cations or alkali metal
cations or mixtures thereof, the molar ratio of the first metal
cation to the second to the third to the fourth may be in the
range 99.5:0.5:0.5:0.5 to 0.5:99.5:99.5:99.5, typically
75:25:25:25 to 25:75:75:75, more typically 0.5:1:1:1 to
0.5:1:1:1. Generally the metal cation is magnesium or a mixture
of magnesium and sodium metal cations. Typically the aqueous
neutral to mildly alkaline metal bicarbonate solution has a high
metal cation concentration in association with bicarbonate
anions.
Typically the metal bicarbonate is used at a concentration of
10-100 mole % or weight % of its saturation solubility (which
will depend on the actual metal bicarbonate(s) used), more
typically 10-90%, 10-80%, 10-70%, 10-60%, 10-50%, 10-40%,
10-30%, 10-20%, more typically 15-95%, 15-85%, 15-75%, 15-65%,
15-55%, 15-45%, 15-35%, 15-25%, more typically 15-90%, 15-80%,
15-70%, 15-60%, 15-50%, 15-40%, 15-30%, 15-20%, more typically
10-95%, 10-85%, 10-75%, 10-65%, 10-55%, 10-45%, 10-35%, 10-25%,
more typically 20-90%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%,
20-30%, more typically 25-95%, 25-85%, 25-75%, 25-65%, 25-55%,
25-45%, 25-35%, more typically 25-90%, 25-80%, 25-70%, 25-60%,
25-50%, 25-40%, 25-30%, more typically 20-95%, 20-85%, 20-75%,
20-65%, 20-55%, 20-45%, 20-35%, more typically 30-90%, 30-80%,
30-70%, 30-60%, 30-50%, 30-40%, more typically 35-95%, 35-85%,
35-75%, 35-65%, 35-55%, 35-45%, more typically 35-90%, 35-80%,
35-70%, 35-60%, 35-50%, 35-40%, more typically 30-95%, 30-85%,
30-75%, 30-65%, 30-55%, 30-45%, more typically 40-90%, 40-80%,
40-70%, 40-60%, 40-50%, more typically 45-95%, 45-85%, 45-75%,
45-65%, 45-55%, more typically 45-90%, 45-80%, 45-70%, 45-60%,
45-50%, more typically 40-95%, 40-85%, 40-75%, 40-65%, 40-55%,
more typically 50-90%, 50-80%, 50-70%, 50-60%, more typically
55-95%, 55-85%, 55-75%, 55-65%, more typically 55-90%, 55-80%,
55-70%, 55-60%, more typically 50-95%, 50-85%, 50-75%, 50-65%,
more typically 60-90%, 60-80%, 60-70%, more typically 65-95%,
65-85%, 65-75%, more typically 65-90%, 65-80%, 65-70%, more
typically 60-95%, 60-85%, 60-75%, more typically 70-90%, 70-80%,
more typically 75-95%, 75-85%, more typically 75-90%, 75-80%,
more typically 70-95%, 70-85%, more typically 80-90%, more
typically 85-95%, more typically 85-90%, more typically 80-95%,
more typically 20-100%, 30-100%, 40-100%, 50-100%, 60-100%,
70-100%, 80-100% or 90-100%. Depending on the solubility of the
metal bicarbonate, the amount of metal cation may range from 20
mg to 1250 mg or 25 mg to 1250 mg per liter of aqueous neutral
to mildly alkaline metal bicarbonate solution, typically 20 mg
to 1000 mg or 50 mg to 1000 mg per liter of aqueous neutral to
mildly alkaline metal bicarbonate solution, more typically 20 mg
to 750 mg or 50 mg to 750 mg or 20 mg to 600 mg or 50 mg to 600
mg per liter of aqueous neutral to mildly alkaline metal
bicarbonate solution, even more typically 20 mg to 50 mg or 30
mg to 500 mg or 50 mg to 500 mg per liter of aqueous neutral to
mildly alkaline metal bicarbonate solution, even more typically
20 mg to 250 mg or 50 mg to 250 mg per liter of aqueous neutral
to mildly alkaline metal bicarbonate solution, most typically
100 mg to 500 mg or 100 mg to 400 mg or 100 mg to 300 mg or 100
mg to 250 mg per liter of aqueous neutral to mildly alkaline
metal bicarbonate solution, even most typically 20 mg to 200 mg
or 20 to 150 mg or 20 mg to 120 mg or 120 mg to 300 mg or 120 mg
to 200 mg. Typically when the metal cation is magnesium, the
amount of magnesium may range from 30 mg to 140 mg per liter of
aqueous neutral to mildly alkaline metal bicarbonate solution,
typically 30 mg to 130 mg, 30 mg to 120 mg, 30 mg to 110 mg, 30
mg to 100 mg, 30 mg to 90 mg, 30 mg to 80 mg, 30 mg to 70 mg, 30
mg to 60 mg, 30 mg to 50 mg, 30 mg to 40 mg, 50 mg to 120 mg, 60
mg to 120 mg, 70 mg to 120 mg, 80 mg to 120 mg, 90 mg to 120 mg
or 75 mg to 120 mg or 100 mg to 120 mg per liter of aqueous
neutral to mildly alkaline metal bicarbonate solution. Typically
when the metal cation is sodium and/or potassium, the amount of
sodium and/or potassium may range from greater than 30 mg to
1250 mg per liter of aqueous neutral to mildly alkaline metal
bicarbonate solution, typically 50 mg to 1000 mg or 50 mg to 750
mg or 50 mg to 500 mg or 75 mg to 1250 mg or 75 mg to 1000 mg or
75 mg to 500 mg or 100 mg to 1000 mg or 100 mg to 500 mg or 250
mg to 1000 mg or 250 mg to 500 mg per liter of aqueous neutral
to mildly alkaline metal bicarbonate solution. Typically when
the metal cation is calcium, the amount of calcium may range
from greater than 20 mg to 1250 mg per liter of aqueous neutral
to mildly alkaline metal bicarbonate solution, typically 20 mg
to 1000 mg or 20 mg to 750 mg or 20 mg to 500 mg or 20 mg to 250
mg or 20 mg to 200 mg or 20 mg to 150 mg or 20 mg to 100 mg per
liter of aqueous neutral to mildly alkaline metal bicarbonate
solution. Typically the amount of bicarbonate anion present will
be stoichiometric with the amount of metal cation in solution so
as to form the metal bicarbonate. Alternatively, the
concentration of the metal bicarbonate can be based on the
bicarbonate anion concentrations in which case the amount of
bicarbonate anion (which will depend on the saturation
solubility of tie actual metal bicarbonate anion(s) used). The
concentration of bicarbonate typically ranges from 120 mg or 150
mg to 3500 mg per liter of aqueous neutral to mildly alkaline
metal bicarbonate solution, typically 120 mg or 150 mg to 3000
mg or 200 mg to 3000 mg per liter of aqueous neutral to mildly
alkaline metal bicarbonate solution, more typically 250 mg to
2100 mg or 300 mg to 2000 mg or 200 mg to 1500 mg or 300 mg to
1500 mg or 400 mg to 1500 mg or 500 mg to 1500 mg or 600 mg to
1500 mg or 700 mg to 1500 mg or 800 mg to 1500 mg or 900 mg to
1500 mg or 1000 mg to 1500 mg or 200 mg to 1000 mg or 300 mg to
1000 mg or 400 mg to 1000 mg or 500 mg to 1000 mg or 600 mg to
1000 mg or 700 mg to 1000 mg or 800 mg to 1000 mg or 900 mg to
1000 mg or 1000 mg to 1500 mg or 1200 mg to 1500 mg per liter of
aqueous neutral to mildly alkaline metal bicarbonate solution,
even more typically 600 mg to 1000 mg or 500 mg to 1500 mg per
liter of aqueous neutral to mildly alkaline metal bicarbonate
solution, most typically 950 mg or 200 mg to 200 mg or 200 mg to
1750 mg or 200 mg to 1250 mg or 200 mg to 100 mg per liter of
aqueous neutral to mildly alkaline metal bicarbonate solution.
Typically at least 600 mg of bicarbonate anions per liter of
solution is present, more typically 600-1800 mg/l, 600-1500
mg/l, 600-1350 mg/l, 600-1200 mg,/l 600-1100 mg/l, 600-1000
mg/l, 600-950 mg/l, 600-900 mg/l, 600-850 mg/l, 600-800 mg/l,
600-750 mg/l , 600-700 mg/l or 600-650 mg/l. Typically a mildly
alkaline saturated magnesium bicarbonate solution is used or a
mildly alkaline solution comprising a mixture of sodium and/or
potassium and magnesium bicarbonate, more typically sodium and
magnesium bicarbonate. Typically the range for a mixture of
sodium and/or potassium and magnesium bicarbonate, more
typically sodium and magnesium bicarbonate varies from 20 mg to
1250 mg or 25 mg to 1250 mg per liter of aqueous neutral to
mildly alkaline metal bicarbonate solution, typically 20 mg to
1000 mg or 50 mg to 1000 mg per liter of aqueous neutral to
mildly alkaline metal bicarbonate solution, more typically 20 mg
to 750 mg or 50 mg to 750 mg or 20 mg to 600 mg or 50 mg to 600
mg per liter of aqueous neutral to mildly alkaline metal
bicarbonate solution, even more typically 20 mg to 500 mg or 30
mg to 500 mg or 50 mg to 500 mg per liter of aqueous neutral to
mildly alkaline metal bicarbonate solution, even more typically
20 mg to 250 mg or 50 mg to 250 mg or even more typically 20 mg
to 300 mg or 50 mg to 300 mg per liter of aqueous neutral to
mildly alkaline metal bicarbonate solution, most typically 75 mg
to 1000 mg or 75 mg to 500 mg or 100 mg to 1000 mg or 100 mg to
500 mg or 100 mg to 400 mg or 100 mg to 300 mg or 100 mg to 250
mg per liter of aqueous neutral to mildly alkaline metal
bicarbonate solution, even most typically 20 mg to 200 mg or 20
to 150 mg or 20 mg to 120 mg or 120 mg to 300 mg or 120 mg to
200 mg. Usually the ratio (weight to weight) of magnesium to
sodium is in the range 25:1 to 1:4, typically 1:1.125.
Generally the aqueous diluent is water or comprises water.
Generally the carbon dioxide-containing-aqueous diluent may be
carbonic acid in water, hydrated carbon dioxide in water, carbon
dioxide gas dissolved in water, carbonated soft drinks,
carbonated mineral water, soda water or other carbon
dioxide-containing-aqueous diluents. If carbon dioxide gas is
used, the carbon dioxide may be either bubbled into aqueous
solutions containing metal carbonate or metal carbonate
hydroxide or metal oxide or mixture thereof or the carbon
dioxide may be introduced in the form of a blanket over aqueous
solutions containing metal carbonate or metal carbonate
hydroxide or metal oxide or mixture thereof. Typically the
carbon dioxide-containing-aqueous diluent is pharmaceutically
acceptable. Typically carbonated mineral water, carbonic acid,
hydrated carbon dioxide in water or carbonated water is used.
The amounts of carbon dioxide-containing-aqueous diluent and
metal carbonate or metal carbonate hydroxide or metal oxide or
mixture thereof used are sufficient to obtain a clear solution
at a neutral to mildly alkaline pH, typically pH 7 to 9 or pH 7
to 8.6, more typically pH 7.5 to 8.8 or pH 7.5 to 8.5 or pH 7.8
to 8.6, pH 7.8 to 8.5, pH 7.8 to 8.4, pH 7.8 to 8.3, pH 7.8 to
8.2, pH 7.8 to 8.1, pH 7.8 to 8.0, pH 7.8 to 7.9, pH 7.9 to 8.6,
pH 7.9 to 8.5, pH 7.9 to 8.4, pH 7.9 to 8.3, pH 7.9 to 8.2, pH
7.9 to 8.1, pH 7.9 to 8.0, pH 8.0 to 8.6, pH 8.0 to 8.5, pH 8.0
to 8.4, pH 8.0 to 8.3, pH 8.0 to 8.2, pH 8.0 to 8.1, pH 8.1 to
8.6, pH 8.1 to 8.5, pH 8.1 to 8.4, pH 8.1 to 8.3, pH 8.1 to 8.2,
pH 8.2 to 8.6, pH 8.2 to 8.5, pH 8.2 to 8.4, pH 8.2 to 8.3, pH
8.3 to 8.6, pH 8.3 to 8.5, pH 8.3 to 8.4, pH 8.4 to 8.6, pH 8.4
to 8.5, pH 8.5 to 8.6, even more typically pH 8 to 8.5 or pH 8.2
to 8.6, most typically pH 8.3. Usually 10 to 60 mL, typically 25
to 55 mL, more typically 40 to 50 mL, most typically
approximately 45 mL of chilled carbonated mineral water per
liter of water is used. Usually the chilled carbonated mineral
water is at a temperature of 0 to 25° C., 0 to 20° C. 0.5 to 25°
C., 0.5 to 20° C., 0.5 to 15° C., 0.5 to 10° C., 0.5 to 9° C.,
0.5 to 8° C., 0.5 to 7° C., 1 to 20° C., 1 to 15° C., 1 to 10°
C., 1.5 to 20° C., 1.5 to 15° C., 1.5 to 10° C., 2 to 20° C., 2
to 15° C., 2 to 10° C., 3 to 20° C., 3 to 15° C., 4 to 20° C., 4
to 15° C., 4 to 10° C., 5 to 10° C., 5 to 15° C., 6 to 20° C., 6
to 15° C., 6 to 10° C., 7 to 20° C., 7 to 15° C., 7 to 10° C., 8
to 20° C., 8 to 15° C., 8 to 10° C., 9 to 20° C., 9 to 15° C., 9
to 10° C., 10 to 15° C., typically 0 to 15° C., more typically 0
to 10° C., even more typically 3° C. to 10° C., most typically
5° C. to 10° C. and even most typically 5° C. Alternatively the
metal carbonate or metal carbonate hydroxide or metal oxide or
mixture thereof can be added after the carbon dioxide has been
added.
Generally the metal bicarbonate in aqueous solution may be
derived from a metal carbonate or metal carbonate hydroxide or
metal oxide or metal bicarbonate or metal hydroxide or other
appropriate metal compound or any mixture thereof. Examples
include magnesium, sodium, potassium, calcium, lithium carbonate
or carbonate hydroxide or oxide or bicarbonate or a mixture of
any two or more thereof. For example magnesium carbonate
hydroxide pentahydrate, the calcite series or dolomite series of
minerals (Mg, Ca)CO3 or limestone or dolomite rocks
is used. Generally magnesium carbonate hydroxide pentahydrate or
a mixture of magnesium carbonate hydroxide pentahydrate and
sodium bicarbonate is used.
Generally the pH of the aqueous metal bicarbonate solution for
oral administration is neutral to mildly alkaline, typically in
the range pH 7 to 9 or pH 7 to 8.6, more typically pH7.5 to 8.8
or pH 7.5 to 8.5 or pH 7.8 to 8.6, pH 7.8 to 8.5, pH 7.8 to 8.4,
pH 7.8 to 8.3, pH 7.8 to 8.2, pH 7.8 to 8.1, pH 7.8 to 8.0, pH
7.8 to 7.9, pH 7.9 to 8.6, pH 7.9 to 8.5, pH 7.9 to 8.4, pH 7.9
to 8.3, pH 7.9 to 8.2, pH 7.9 to 8.1, pH 7.9 to 8.0, pH 8.0 to 8
6, pH 8.0 to 8.5, pH 8.0 to 8.4, pH 8.0 to 8.3, pH 8.0 to 8.2,
pH 8.0 to 8.1, pH 8.1 to 8.6, pH 8.1 to 8.5, pH 8.1 to 8.4, pH
8.1 to 8.3, pH 8.1 to 8.2, pH 8.2 to 8.6, pH 8.2 to 8.5, pH 8.2
to 8.4, pH 8.2 to 8.3, pH 8.3 to 8.6, pH 8.3 to 8.5, pH 8.3 to
8.4, pH 8.4 to 8.6, pH 8.4 to 8.5, pH 8.5 to 8.6, even more
typically pH 8 to 8.5 or pH 8.2 to 8.6, most typically pH 8.3.
Generally the pH of the aqueous metal bicarbonate solution for
parenteral administration is neutral to very mildly alkaline,
typically in the range pH 7 to 7.6. or pH 7.0 to 7.5, or pH 7.1
to 7.5, more typically pH 7.2 to 7.5 or pH 7.3 to 7.5 or pH 7.5
or pH 7.4 to 7.5. Generally the aqueous neutral to mildly
alkaline metal bicarbonate solution is prepared and stored at a
temperature ranging from 0 to 25° C., 0 to 20° C. 0.5 to 25° C.,
0.5 to 20° C., 0.5 to 15° C., 0.5 to 10° C., 0.5 to 9° C., 0.5
to 8° C., 0.5 to 7° C., 1 to 20° C., 1 to 15° C., 1 to 10° C.,
1.5 to 20° C., 1.5 to 15° C., 1.5 to 10° C., 2 to 20° C., 2 to
15° C., 2 to 10° C., 3 to 20° C., 3 to 15° C., 4 to 20° C., 4 to
15° C., 4 to 10° C., 5 to 10° C., 5 to 15° C., 6 to 20° C., 6 to
15° C., 6 to 10° C., 7 to 20° C., 7 to 15° C., 7 to 10° C., 8 to
20° C., 8 to 15° C., 8 to 10° C., 9 to 20° C., 9 to 15° C., 9 to
10° C., 10 to 15° C., typically 0 to 15° C., more typically 0 to
10° C., even more typically 3° C. to 10° C., most typically 5°
C. to 10° C. and even most typically 5° C.
Generally The pH adjusting agent is carbon dioxide gas,
carbonic acid in water, hydrated carbon dioxide in water, carbon
dioxide gas in water, carbonated soft drinks, carbonated mineral
water, soda water or other carbon dioxide-containing-aqueous
diluents or an alkali or any mixture thereof. Examples of
alkalis are water soluble drinkable alkalis such as sodium
hydroxide, sodium carbonate, potassium carbonate or potassium
hydroxide or any mixture thereof.
Typically additives may be added during the process of the
invention or to the aqueous neutral to mildly alkaline metal
bicarbonate solution. The additives may be 0 mg or 0.5 mg to
1000 mg sodium bicarbonate per liter of aqueous neutral to
mildly alkaline metal bicarbonate solution, typically 25 mg to
900 mg per liter of aqueous neutral to mildly alkaline metal
bicarbonate solution, typically 50 mg to 800 mg or 50 mg to 500
mg per liter of aqueous neutral to mildly alkaline metal
bicarbonate solution, more typically 100 mg to 700 mg per liter
of aqueous neutral to mildly alkaline metal bicarbonate
solution, even more typically 200 mg to 600 mg per liter of
aqueous neutral to mildly alkaline metal bicarbonate solution,
most typically 300 mg to 500 mg per liter of aqueous neutral to
mildly alkaline metal bicarbonate solution, even most typically
500 mg per liter of aqueous neutral to mildly alkaline metal
bicarbonate solution. The additives may also be chlorides and
appropriate salts of magnesium, sodium, potassium, calcium and
lithium, such as carbonates or hydroxides or sulfates, with or
without the addition of sodium bicarbonate. For example,
magnesium sulfate, magnesium chloride or other soluble salts of
magnesium. Further additives may include potassium bicarbonate,
calcium bicarbonate or lithium bicarbonate Generally calcium
bicarbonate is prepared by adding carbonic acid or carbonated
water or hydrated carbon dioxide or carbon dioxide gas to a
mixture of calcium carbonate in water. Generally lithium
bicarbonate is prepared by adding carbonic acid and/or
carbonated water and/or hydrated carbon dioxide and/or carbon
dioxide gas and/or solid carbon dioxide to a mixture of lithium
carbonate in water.
The aqueous neutral to mildly alkaline metal bicarbonate
solution may further include a stabilising agent. The
stabilising agent may also be a pH adjusting agent, Typically
the stabilising agent is a gaseous phase, for example carbon
dioxide gas, which maintains and/or stabilises the solution at a
pH of 7 to 9 and at a temperature of 0 to 55° C. more typically
0 to 25° C.
Generally once the solution is prepared, the solution may be
stored under a blanket of carbon dioxide gas or a mixture of
carbon dioxide gas and a nondeleterious inert gas, for example,
argon, helium, air, oxygen and/or nitrogen wherein the amount of
carbon dioxide present in the inert gas is sufficient to
maintain the solution at a pH of 7 to 9 and at a temperature of
0 to 25° C. and to prevent the metal bicarbonate from forming
insoluble compounds which can precipitate out of solution.
Typically the carbon dioxide gas above the solution prevents
loss of carbon dioxide from the solution. The amount of carbon
dioxide in the gaseous mixture provides partial pressure on the
liquid which is substantially equal to the partial pressure
which is produced from equilibrium of bicarbonate in the
solution at the mixing temperature.
Magnesium Bicarbonate Particularly
Typically the production of magnesium bicarbonate utilises the
dissolution of magnesium carbonate by carbonic acid or hydrated
carbon dioxide solutions. Ideally, the dissolution is produced
within a defined range of conditions--a defined range of pH
values, a defined range of temperature values and a defined
minimum time. For optimal biological and medical activities, and
for therapeutic safety, the concentrations of the component ions
are defined also.
Typically to prepare the aqueous neutral to mildly alkaline
metal bicarbonate solution, crushed or powdered metal carbonate,
or metal carbonate hydroxide or metal oxide, such as magnesium
carbonate MgCO3, or commercial magnesium carbonate
hydroxide pentahydrate (MgCO3)4.Mg(OH)2.5H2O,
or
other commercial magnesium carbonate hydroxides, or hydrated
magnesium oxides, or magnesium oxides heated with carbon
dioxide, or the calcite series or dolomite series of minerals
(Mg, Ca)CO3, or limestone or dolomite rocks is mixed
with water. A cloudy suspension is obtained. Sufficient carbonic
acid and/or hydrated carbon dioxide and/or carbon dioxide gas
and/or solid carbon dioxide is added to obtain a solution having
a pH 7 to 9 or pH 7 to 8.6, more typically pH 7.5 to 8.8 or pH
7.5 to 8.5 or pH 7.8 to 8.6, pH 7.8 to 8.5, pH 7.8 to 8.4, pH
7.8 to 8.3, pH 7.8 to 8.2, pH 7,8 to 8.1, pH 7.8 to 8.0, pH 7.8
to 7.9, pH 7.9 to 8.6, pH 7.9 to 8.5, pH 7.9 to 8.4, pH 7.9 to
8.3, pH 7.9 to 8.2, pH 7.9 to 8.1, pH 7.9 to 8.0, pH 8.0 to 8.6,
pH 8.0 to 8.5, pH 8.0 to 8.4, pH 8.0 to 8.3, pH 8.0 to 8.2, pH
8.0 to 8.1, pH 8.1 to 8.6, pH 8.1 to 8.5, pH 8.1 to 8.4, pH 8.1
to 8.3, pH 8.1 to 8.2, pH 8.2 to 8.6, pH 8.2 to 8.5, pH 8.2 to
8.4, pH 8.2 to 8.3, pH 8.3 to 8.6, pH 8.3 to 8.5, pH 8.3 to 8.4,
pH 8.4 to 8.6, pH 8.4 to 8.5, pH 8.5 to 8.6, even more typically
pH 8 to 8.6 or pH 8.2 to 8.6, most typically pH 8.3. The
solution is then typically placed in a closed or sealed
container at 0 to 20° C. or 0 to 15° C. with occasional mixing
until a clear solution develops. The amount of carbonic acid
and/or hydrated carbon dioxide and/or carbon dioxide gas bubbled
through the solution and dissolved therein and/or solid carbon
dioxide is sufficient to prevent precipitation of water
insoluble metal compounds (such as magnesium or calcium
carbonate). A clear solution is generally obtained in about 6
hours to 7 days, typically 12 hours to 5 days, more typically 24
hours to 5 days, most typically 24 hours to 3 days. Generally
the aqueous neutral to mildly alkaline metal bicarbonate
solution is prepared and stored at a temperature ranging from 0
to 55° C., 0 to 25° C., 0 to 20° C. 0.5 to 25° C., 0.5 to 20°
C., 0.5 to 15° C., 0.5 to 10° C., 0.5 to 9° C., 0.5 to 8° C.,
0.5 to 7° C., 1 to 20° C., 1 to 15° C., 1 to 10° C., 1.5 to 20°
C., 1.5 to 15° C., 1.5 to 10° C., 2 to 20° C., 2 to 15° C., 2 to
10° C., 3 to 20° C., 3 to 15° C., 4 to 20° C., 4 to 15° C., 4 to
10° C., 5 to 10° C., 5 to 15° C., 6 to 20° C., 6 to 15° C., 6 to
10° C., 7 to 20° C., 7 to 15° C., 7 to 10° C., 8 to 20° C., 8 to
15° C., 8 to 10° C., 9 to 20° C., 9 to 15° C., 9 to 10° C., 10
to 15° C., typically 0 to 15° C., more typically 0 to 10° C.,
even more typically 3° C. to 10° C., most typically 5° C. to 10°
C. and even most typically 5° C. Alternatively the crushed or
powdered metal carbonate, or metal carbonate hydroxide or metal
oxide or mixture thereof is added to an aqueous solution of the
carbonic acid and/or hydrated carbon dioxide and/or to an
aqueous solution through which carbon dioxide gas is bubbled
and/or solid carbon dioxide has been added. The amount of
carbonic acid and/or hydrated carbon dioxide and/or carbon
dioxide gas bubbled through the solution and dissolved therein
and/or solid carbon dioxide is sufficient to prevent
precipitation of water insoluble metal compounds (such as
magnesium or calcium carbonate).
Typically one liter of water is placed in a container and
sufficient carbonic acid and/or carbonated water and/or hydrated
carbon dioxide and/or carbon dioxide gas and/or solid carbon
dioxide is added to produce a pH value of approximately pH 5.2.
(In practice, approximately 40 to 45 mL of chilled (5.degree.
C.) carbonated mineral water is used depending on the initial pH
of the water). The container is sealed and the contents are
mixed. 485 mg magnesium carbonate hydroxide pentahydrate powder
(MgCO3)4.Mg(OH)2.5H2O,
molecular
weight 485 is added, The container is again sealed and the
contents are mixed.
The container is stored at a temperature of 0 to 10° C. and the
contents mixed regularly. Sufficient time is allowed for a clear
solution of magnesium bicarbonate to develop at a range of pH
8.0 to pH 8.6, preferably pH 8.3. This takes approximately 24 to
72 hours. Alternatively the carbonic acid and/or carbonated
water and/or hydrated carbon dioxide and/or carbon dioxide gas
and/or solid carbon dioxide is added to the magnesium carbonate
hydroxide pentahydrate powder in water. Alternatively one liter
of water is placed in a container and sufficient carbonic acid
and/or carbonated water and/or hydrated carbon dioxide and/or
solid carbon dioxide is added to produce a pH value less than pH
5 2. (In practice, approximately 30 mL to 40 mL of chilled water
is used depending on the initial pH of the water). The container
is sealed and the contents are mixed. 485 mg magnesium carbonate
hydroxide pentahydrate powder (MgCO3)4.Mg(OH)2.5H2O,
molecular
weight 485 is added. The container is again sealed and the
contents are mixed. The container is stored at a temperature of
0 to 10° C. and the contents mixed regularly. The pH of the
water is then adjusted with an alkali such as sodium hydroxide
or potassium hydroxide to a pH of 8 to 8.6, typically pH 8.3.
Alternatively the carbonic acid or carbonated water and/or
hydrated carbon dioxide and/or carbon dioxide gas and/or solid
carbon dioxide is added to the magnesium carbonate hydroxide
pentahydrate powder in water.
The above processes may optionally be conducted under an
atmosphere of carbon dioxide or a gas comprising carbon dioxide.
Generally once the solution is prepared, it may be stored under
a blanket of carbon dioxide gas to maintain the solution at a pH
of 7 to 9 and at a temperature of 0 to 25° C.
Usually one liter of the magnesium bicarbonate solution
prepared above contains approximately 120 mg of magnesium per
liter of aqueous neutral to mildly alkaline metal bicarbonate
solution and approximately 600 mg of bicarbonate. 500 mg sodium
bicarbonate (or potassium bicarbonate) is added to the magnesium
bicarbonate solution and mixed. The mixture is stored in a
sealed container in a refrigerator. The mixture contains
approximately 120 mg magnesium per liter of aqueous neutral to
mildly alkaline metal bicarbonate solution, 135 mg sodium per
liter of aqueous neutral to mildly alkaline metal bicarbonate
solution and 950 mg bicarbonate per liter of aqueous neutral to
mildly alkaline metal bicarbonate solution.
Generally the aqueous neutral to mildly alkaline metal
bicarbonate solution of the invention is administered or
consumed orally. Typically the solution is an orally drinkable
solution. Typically the solution is a therapeutic orally
drinkable solution. Alternatively a gelling agent may added to
the solution and the solution subjected to gelling conditions to
gel the solution and the resultant gel may be consumed orally.
For example, the aqueous neutral to mildly alkaline metal
bicarbonate solution may be prepared as a solution or an iced
confectionary, such as an ice block or iced dessert, which is
ingested orally. Alternatively the aqueous neutral to mildly
alkaline metal bicarbonate solution may be prepared in the form
of a tablet, lozenge or lolly which is ingested orally. For
example, the aqueous neutral to mildly alkaline metal
bicarbonate solution may be administered for metabolic acidosis
or renal failure. Optionally the solution may be sterilised.
Typically the aqueous neutral to mildly alkaline metal
bicarbonate solution is prepared as a solution which is ingested
on a regular basis hourly, daily, monthly or yearly. The amount
and frequency of aqueous neutral to mildly alkaline metal
bicarbonate solution administered/consumed in a day is generally
sufficient so as to maintain a steady bicarbonate level in the
bicarbonate concentration of a taker's body fluids. It is
preferable to avoid a rapid increase in the bicarbonate level in
the bicarbonate concentration of a taker's body fluids. The
amount of aqueous neutral to mildly alkaline metal bicarbonate
solution administered in a day ranges from 250 mL to 6 liters,
typically 250 mL to 5.5 liters, 250 mL to 5 liters, 250 mL to
4.5 liters, 250 mL to 4 liters, 250 mL to 3.5 liters, 250 mL to
3 liters, 500 mL to 6 liters, 500 mL to 5.5 liters, 500 mL to 5
liters, 500 mL to 4.5 liters, 500 mL to 4 liters, 500 mL to 3.5
liters, 500 mL to 3 liters, more typically 1 liter to 6 liters,
1 liter to 5.5 liters, 1 liter to 5 liters, 1 liter to 4,5
liters, 1 liter to 4 liters, 1 liter to 3.5 liters, even more
typically 1 liter to 3 liters, 1.5 liters to 6 liters, 1.5
liters to 5.5 liters, 1.5 liters to 5 liters, 1.5 liters to 4.5
liters, 1.5 liters to 4 liters, 1.5 liters to 3.5 liters, 1.8
liters to 3.3 liters, 1.8 to 2.8 liters, 1.8 to 2.5 liters, 1.8
to 2.3 liters, 1.8 to 2.0 liters, most typically 2 to 3 liters,
typically 2.3 to 2.8 liters, more typically 2.3 to 2.6 liters,
usually 2.1 to 3 liters. The aqueous neutral to mildly alkaline
metal bicarbonate solution may be administered on a full or
empty stomach, typically the aqueous neutral to mildly alkaline
metal bicarbonate solution is administered on an empty stomach.
Usually 1.5 to 3.5 liters, typically 1.8 to 3 liters, more
typically 1.5 to 2.4 liters, even more typically 1.8 to 2.1
liters and usually between 1.8 and 2.7 liters of aqueous neutral
to mildly alkaline metal bicarbonate solution is ingested,
administered or consumed on an empty stomach by a mammal
(typically a human) in equal or non equal volume amounts
(100-1000 mL, 200-800 mL, 250-750 mL, 275-700 mL, 300-650 mL,
350-600 mL, 400-550 mL, 450-500 mL, typically about 300-400 mL,
more typically about 375 mL volume amounts a number of times
(typically at set times) each day for the required number of
times per day to drink the desired daily amount of the
solution). For example if 1800 mL per day is to be consumed then
a user may drink six 300 mL amounts of the solution every 2 to
2.5 hours throughout the day. The oral consumption of the
solution three or more times at roughly equally spaced apart
intervals throughout the day is more desirable than consuming
the solution in one or two lots throughout the day. The idea of
taking the solution is to take it regularly throughout the day
so that a simulated continuous oral intake or a close to
continuous regular oral intake of the solution occurs. Thus
depending on the condition and the subject one suitable
administration/consumption regime could be nine by 200 mL
amounts of the solution, each 200 mL amount being orally
administered/consumed about every 1.5-1.75 hours to provide a
total daily intake of 1800 mL. Alternatively, once again
depending on the condition and the subject one suitable
administration/consumption regime could be nine by 300 mL
amounts of the solution, each 300 mL amount being orally
administered/consumed about every 1.5-1.75 hours to provide a
total daily intake of 2700 mL. Alternatively, once again
depending on the condition and the subject one suitable
administration/consumption regime could be nine by 350 mL
amounts of the solution, each 350 mL amount being orally
administered/consumed about every 1.5-1.75 hours to provide a
total daily intake of 3150 mL. Typically the solution is
administered/consumed 3 to 30, 3-25, 3-20, 3-15, 3-12, 3-10,
3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-30, 4-25, 4-20, 4-15, 4-12,
4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-30, 5-25, 5-20, 5-15, 5-12,
5-11, 5-10, 5-9, 5-8, 5-7, 5-6, 6-30, 6-25, 6-20, 6-15, 6-12,
6-11, 6-10, 6-9, 6-8, 6-7, 7-30, 7-25, 7-20, 7-15, 7-12, 7-11,
7-10, 7-9, 7-8, 8-30, 8-25, 8-20, 8-15, 8-12, 8-11, 8-10, 8-9
times per day at regular or irregular intervals or a mixture of
both regular and irregular intervals, throughout each day.
Typically the solution is administered/consumed every 0.3-10,
0.3-8, 0.3-7, 0.3-6, 0.3-5, 0.3-4.5, 0.3-4, 0.3-3.5, 0.3-3,
0.3-2.5, 0.3-2, 0.3-1.5, 0.3-1, 0.3-0.75, 0.3-0.5 hours/day when
the subject is awake. More typically the solution is
administered/consumed every 0.5-8, 0.5-7, 0.5-6, 0.5-5, 0.5-4.5,
0.5-4, 0.5-3.5, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1, 0.5-0.8,
0.5-0.75 hours/day when the subject is awake. Where possible the
solution is consumed/administered on an empty (e.g. before
eating). The solution may be administered according to these
latter dosages over short (for example 1 to 60 days, 10 to 40
days, 3 months to 6 months, 1 day to 6 months) or long (for
example 6 months to 10 years or more, 9 months to 18 months, 1
year to 3 years, 1 year to 5 years, 2 to 6 years) periods as
required. Usually the amount of aqueous neutral to mildly
alkaline metal bicarbonate solution administered to a mammal is
5 to 100 mL per Kg, more usual 10 to 50 mL per Kg, most usual 14
to 29 mL per Kg or 25 to 43 mL per Kg.
The solution may include other additives such as sweeteners,
preservatives, flavourings and other suitable additives.
Examples of suitable sweetners include sucrose, lactose,
glucose. aspartame or saccharine. Examples of suitable
flavouring agents include peppermint oil, oil of wintergreen,
cherry, orange or raspberry flavouring. Examples of suitable
preservatives include sodium benzoate, vitamin E,
alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben
or sodium bisulphite.
Typically the aqueous neutral to mildly alkaline metal
bicarbonate solution is orally administered/consumed on an empty
stomach. Usually consumption in this manner avoids the mixing of
bicarbonate anions with stomach acid which may result in the
loss of bicarbonate Usually the aqueous neutral to mildly
alkaline metal bicarbonate solution is consumed in small amounts
a number of times through a day typically at set times each day
to avoid a rapid increase in the bicarbonate concentration of
body fluids. Usually the amount of aqueous neutral to mildly
alkaline metal bicarbonate solution consumed at commencement is
500 mL per day and is increased by increments over a period of
one month to the maximum consumption. This start-up schedule
generally avoids any gastrointestinal side effects due to the
smooth muscle relaxation properties of magnesium.
The aqueous neutral to very mildly alkaline metal bicarbonate
solution of the invention may be administered intravenously
(e.g. by discrete injection, semi continuous injection or drip
feed or continuous injection or drip feed) or by other
parenteral routes. Another embodiment of the invention is
directed to a pharmaceutical composition comprising the solution
of the first or eleventh embodiments together with one or more
pharmaceutically acceptable carriers, diluents, adjuvants and/or
excipients. Typically the pharmaceutical composition is suitable
for oral or parenteral administration. Another embodiment of the
invention is directed to a veterinary composition comprising the
solution of the first or eleventh embodiments together with one
or more veterinarily acceptable carriers, diluents, adjuvants
and/or excipients. Typically the veterinary composition is
suitable for oral or parenteral administration. The amount and
frequency of aqueous neutral to mildly alkaline metal
bicarbonate solution administered/consumed in a day is generally
sufficient so as to maintain a steady bicarbonate level in the
bicarbonate concentration of a taker's body fluids. It is
preferable to avoid a rapid increase in the bicarbonate level in
the bicarbonate concentration of a taker's body fluids. For
parenteral administration, the solution is generally sterile.
Suitable mono-toxic parenterally acceptable diluents or solvents
include waters, Ringer's solution, isotonic salt solution,
1,3-butanediol, ethanol, propylene glycol or polyethylene
glycols in mixtures with water. Aqueous solutions or suspensions
may further comprise one or more buffering agents. Suitable
buffering agents include sodium borate, sodium acetate, sodium
citrate, or sodium tartrate, for example. Typically the solution
is administered on a regular basis throughout a day to a patient
requiring treatment. For example a patient may be parenterally
administered the solution by way of a continuous drip feed or
alternatively by way of a number of injections of the solution
throughout a day (e.g. every 0.5-8 hours, more typically every
1-4 hours). The treatment is generally continued as long as
required to alleviate the patient's symptoms to a satisfactory
level. For concentration of metal bicarbonate in the
compositions, frequency of administration and amount
administered see discussion under oral administration.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 are plots of the survival curves for a control group of
sheep and a treatment group of sheep;
FIG. 2 is a photograph showing osteoarthritis in the joints of
the fingers and thumb. Osteoarthritis before the consumption of
aqueous metal bicarbonate solution. Note the swelling and
`claw-like` hand resulting from joint flexion and joint
displacement. (The patient was pushing down with her hand `as
hard as possible` in an attempt to place her hand flat on the
underlying surface.); and
FIG. 3 is a photograph showing osteoarthritis in the joints of
the fingers and thumb. Osteoarthritis twelve months after
commencement of the consumption of aqueous metal bicarbonate
solution. Note that the fingers can be extended and the joints
are `straighter` than twelve months previously. The patient had
placed her hand flat on the underlying surface without exerting
any force.)
BEST MODE AND OTHER MODE(S) FOR CARRYING OUT THE INVENTION
Magnesium bicarbonate is a natural hydrated salt which exists
only in an aqueous solution. It may be formed in spring water by
an ion exchange process between the protons in carbonic acid
(formed from the hydration of carbon dioxide located in the
atmosphere, organic material, soils and rocks) and the magnesium
in the constituent minerals of rocks (particularly the
ferromagnesian minerals known as pyroxene and olivine that
constitute basalt rocks).
The ion exchange process can be represented by the following
equations
The term magnesium bicarbonate is used universally to describe
the mixture of magnesium cations and bicarbonate anions found in
spring waters and mineral waters. Most spring waters and mineral
waters have acidic pH values (about pH 6.0). If the pH value of
the water rises (due to contact with hydroxides), the magnesium
cations and bicarbonate anions "attract" each other (reversibly)
to form the true salt. The chemical formula of magnesium
bicarbonate may be written as Mg(HCO3)2,
or (more accurately) Mg(H2O)4(HCO3)2.
This latter formula takes into account the hexahydrated
magnesium cation Mg(H2O)6.2+.
In essence, magnesium bicarbonate exists in aqueous solution
probably as an hydrated salt of indeterminate hydration size due
to the hydrogen bonds between linked water dipoles centred
around the hydrated magnesium cation.
The chemical processes occurring in magnesium bicarbonate
solutions are complex and depend on the concentrations of
magnesium cations and other ions. The following reactions are
considered to occur:
There exists also a range of possible acid-base equilibria
involving HCO3-, H3O+,
CO32- and OH- ions and CO2
and H2CO3. Usually the pH adjusting agent
(and/or stabilising agent) maintains the acid-base equilibria.
Typically to prepare the aqueous neutral to mildly alkaline
metal bicarbonate solution, crushed or powdered metal carbonate,
or metal carbonate hydroxide or metal oxide, such as magnesium
carbonate MgCO3, or commercial magnesium carbonate
hydroxide pentahydrate (MgCO3)4.Mg(OH)2.5H2O,
or
other commercial magnesium carbonate hydroxides, or hydrated
magnesium oxides, or magnesium oxides heated with carbon
dioxide, or the calcite series or dolomite series of minerals
(Mg, Ca)CO3, or limestone or dolomite rocks is mixed
with water. A cloudy suspension is obtained. Sufficient carbonic
acid or hydrated carbon dioxide or carbon dioxide gas is added
to obtain a solution having a pH 7 to 9 or pH 7 to 8.6, more
typically pH 7.5 to 8.8 or pH 7.5 to 8.5 or pH 7.8 to 8.6, pH
7.8 to 8.5, pH 7.8 to 8.4, pH 7.8 to 8.3, pH 7.8 to 8.2, pH 7.8
to 8.1, pH 7.8 to 8.0, pH 7.8 to 7.9, pH 7.9 to 8.6, pH 7.9 to
8.5, pH 7.9 to 8.4, pH 7.9 to 8.3, pH 7.9 to 8.2, pH 7.9 to 8.1,
pH 7.9 to 8.0, pH 8.0 to 8.6, pH 8.0 to 8.5, pH 8.0 to 8.4, pH
8.0 to 8.3, pH 8.0 to 8.2, pH8.0 to 8.1, pH8.1 to8.6, pH8.1 to
8.5, pH8.1 to 8.4, pH 8.1 to 8.3, pH 8.1 to 8.2, pH 8.2 to 8.6,
pH 8.2 to 8.5, pH 8.2 to 8.4, pH 8.2 to 8.3, pH 8.3 to 8.6, pH
8.3 to 8.5, pH 8.3 to 8.4, pH 8.4 to 8.6, pH 8.4 to 8.5, pH 8.5
to 8,6, even more typically pH 8 to 8.5 or pH 8.2 to 8.6, most
typically pH 8.3. The solution is then typically placed in a
sealed container at 0 to 20° C. with occasional mixing until a
clear solution develops. A clear solution is generally obtained
in about 6 hours to 7 days, typically 12 hours to 5 days, more
typically 24 hours to 5 days, most typically 24 hours to 3 days.
Generally the aqueous neutral to mildly alkaline metal
bicarbonate solution is prepared and stored at a temperature
ranging from 0 to 25° C., 0 to 20° C. 0.5 to 25° C., 0.5 to 20°
C., 0.5 to 15° C., 0.5 to 10° C., 0.5 to 9° C., 0.5 to 8° C.,
0.5 to 7° C., 1 to 20° C., 1 to 15° C., 1 to 10° C., 1.5 to 20°
C., 1.5 to 15° C., 1.5 to 10° C., 2 to 20° C., 2 to 15° C., 2 to
10° C., 3 to 20° C., 3 to 15° C., 4 to 20° C., 4 to 15° C., 4 to
10° C., 5 to 10° C., 5 to 15° C., 6 to 20° C., 6 to 15° C., 6 to
10° C., 7 to 20° C., 7 to 15° C., 7 to 10° C., 8 to 20° C., 8 to
15° C., 8 to 10° C., 9 to 20° C., 9 to 15° C., 9 to 10° C., 10
to 15° C., typically 0 to 15° C., more typically 0 to 10° C.,
even more typically 3° C. to 10° C., most typically 5° C. to 10°
C. and even most typically 5° C.. Alternatively the crushed or
powdered metal carbonate, or metal carbonate hydroxide or metal
oxide or mixture thereof is added to an aqueous solution of the
carbonic acid or hydrated carbon dioxide or carbon dioxide gas.
Typically one liter of water is placed in a container and
sufficient carbonic acid or carbonated water or hydrated carbon
dioxide or carbon dioxide gas is added to produce a pH value of
approximately pH 5.2. (In practice, approximately 40 to 45 mL of
chilled (5° C.) carbonated mineral water is used depending on
the initial pH of the water). The container is sealed and the
contents are mixed. 485 mg magnesium carbonate hydroxide
pentahydrate powder (MgCO3)4.Mg(OH)2.5H2O,
molecular
weight 485 is added. The container is again sealed and the
contents are mixed. The container is stored at a temperature of
0 to 10° C. and the contents mixed regularly. Sufficient time is
allowed for a clear solution of magnesium bicarbonate to develop
at a range of pH 8.0 to pH 8.5, typically pH 8.3. This takes
approximately 24 to 72 hours. Alternatively the carbonic acid or
carbonated water or hydrated carbon dioxide or carbon dioxide
gas is added to the magnesium carbonate hydroxide pentahydrate
powder in water.
Alternatively one liter of water is placed in a container and
sufficient carbonic acid or carbonated water or hydrated carbon
dioxide gas is added to produce a pH value less than pH 5.2. (In
practice, approximately 30 mL to 40 mL of chilled water is used
depending on the initial pH of the water). The container is
sealed and the contents are mixed. 485 mg magnesium carbonate
hydroxide pentahydrate powder (MgCO3)4.Mg(OH)2.5H2O,
molecular
weight 485 is added. The container is again sealed and the
contents are mixed. The container is stored at a temperature of
0 to 10° C. and the contents mixed regularly. The pH of the
water is then adjusted with an alkali such as sodium hydroxide
or potassium hydroxide to a pH of 8 to 8.5, typically pH 8.3.
Alternatively the carbonic acid or carbonated water or hydrated
carbon dioxide or carbon dioxide gas is added to the magnesium
carbonate hydroxide pentahydrate powder in water.
Generally once the solution is prepared, the solution may be
stored in a closed container under a blanket of carbon dioxide
gas or a mixture of carbon dioxide gas and usually a
nondeleterious inert gas, for example, argon, helium and/or
nitrogen to maintain the solution at a pH of 7 to 9 and at a
temperature of 0 to 25° C. and at 0.8 to 5 atm. The carbon
dioxide gas blanket prevents loss of carbon dioxide from the
solution. The amount of carbon dioxide in the gaseous mixture
provides partial pressure on the liquid which is substantially
equal to the partial pressure of carbon dioxide from carbon
dioxide from the solution which is produced from equilibrium of
bicarbonate in the solution at the particular temperature. In
this way the solution is stabilised. If the solution were left
in an open container for any substantial length of time
precipitation of metal carbonate from the solution would occur
as a result of decomposition of the bicarbonate in the solution
as carbon dioxide is liberated from the solution. By using a
stabilising agent in and/or above the solution such
decomposition is substantially minimised or prevented.
Alternatively the solution may be stored in a closed or sealed
container (generally airtight) which is substantially filled
with the solution whereby there is substantially no gas in the
container or little gas compared to the amount of liquid in the
container.
The relevant chemical reactions may be represented by the
following equations:
Usually one liter of the magnesium bicarbonate solution
prepared above contains approximately 120 mg of magnesium per
liter of aqueous neutral to mildly alkaline metal bicarbonate
solution and approximately 600 mg of bicarbonate. 500 mg sodium
bicarbonate (or potassium bicarbonate) is added to the magnesium
bicarbonate solution and mixed. The mixture is stored in a
sealed container in a refrigerator. The mixture contains
approximately 120 mg magnesium per liter of aqueous neutral to
mildly alkaline metal bicarbonate solution, 135 mg sodium per
liter of aqueous neutral to mildly alkaline metal bicarbonate
solution and 950 mg bicarbonate per liter of aqueous neutral to
mildly alkaline metal bicarbonate solution.
In the body, normal intracellular pH value is pH 7.2. Under
acidic conditions, such as adenosine triphosphate (ATP)
hydrolysis, intracellular pH value may decrease to pH 6.5. In
practice, a pH value is chosen for bicarbonate solutions that
exceeds normal blood plasma pH value (pH>7.38).
A low temperature, between 0 and 10° C., typically 5 to 10° C.,
ensures that carbon dioxide stays dissolved in solution to
maximise carbon dioxide hydration. Above 15 to 20° C., the
solubility of carbon dioxide is low, the carbon dioxide leaves
the solution, and particles and sediments may occur in the
solution. Above 15 to 20° C., the solution may be cloudy in
appearance.
At high magnesium concentrations, a minimum time, at least 24
to 72 hours at 5° C., is required for completion of the kinetic
processes that produce a clear solution of magnesium
bicarbonate. (The kinetic processes include the hydration of
carbon dioxide, the dissolution of magnesium carbonate and the
dissolution of magnesium hydroxide.)
The concentration of magnesium cations (in association with
bicarbonate anions) is generally in the range 25 mg to 250 mg
per liter aqueous neutral to mildly alkaline metal bicarbonate
solution (depending on the pH value of the metal bicarbonate
solution). Usually the maximum magnesium concentration that can
be maintained in solution as magnesium bicarbonate may be
approximately 120 mg per liter aqueous neutral to mildly
alkaline metal bicarbonate solution at pH 8.3. As the pH value
decreases, the concentration of magnesium that can be maintained
in solution increases. Because magnesium chloride is soluble,
higher concentrations of magnesium can be maintained in solution
if chlorides (such as sodium chloride) are added to the aqueous
neutral to mildly alkaline metal bicarbonate solution.
The solubility product constant for magnesium carbonate is
reported to be approximately 3.5.times.10.sup.-8. The solubility
product constant for magnesium hydroxide is reported to be
approximately 1.1 x 10-11. Calculated from these
values, the maximum concentrations of magnesium cations that can
exist in solution as carbonates or hydroxides are approximately
20 mg per liter aqueous metal bicarbonate solution and 10 mg per
liter aqueous neutral to mildly alkaline metal bicarbonate
solution respectively.
Generally the aqueous neutral to mildly alkaline metal
bicarbonate solution of the invention is administered or
consumed orally. Typically the solution is an orally drinkable
solution. Typically the solution is a therapeutic orally
drinkable solution. For example, the aqueous neutral to mildly
alkaline metal bicarbonate solution may be prepared as a
solution or an iced confectionary, such as an ice block or iced
dessert, which is ingested orally. Alternatively the aqueous
neutral to mildly alkaline metal bicarbonate solution may be
prepared in the form of a tablet, lozenge or lolly which is
ingested orally. For example, the aqueous neutral to mildly
alkaline metal bicarbonate solution may be administered for
metabolic acidosis or renal failure. Optionally the solution may
be sterilised. Typically the aqueous neutral to mildly alkaline
metal bicarbonate solution is prepared as a solution which is
ingested hourly, daily, monthly or yearly. The amount of aqueous
neutral to mildly alkaline metal bicarbonate solution
administered in a day ranges from 250 mL to 6 liters, typically
250 mL to 5.5 liters, 250 mL to 5 liters, 250 mL to 4.5 liters,
250 mL to 4 liters, 250 mL to 3.5 liters, 250 mL to 3 liters,
500 mL to 6 liters, 500 mL to 5.5 liters, 500 mL to 5 liters,
500 mL to 4.5 liters, 500 mL to 4 liters, 500 mL to 3.5 liters,
500 mL to 3 liters, more typically 1 liter to 6 liters, 1 liter
to 5.5 liters, 1 liter to 5 liters, 1 liter to 4.5 liters, 1
liter to 4 liters, 1 liter to 3.5 liters, even more typically 1
liter to 3 liters, 1.5 liters to 6 liters, 1.5 liters to 5.5
liters, 1.5 liters to 5 liters, 1.5 liters to 4.5 liters, 1.5
liters to 4 liters, 1.5 liters to 3.5 liters, most typically 2
to 3 liters, usually 2.1 to 3 liters. The aqueous neutral to
mildly alkaline metal bicarbonate solution may be administered
on a full or empty stomach, typically the aqueous neutral to
mildly alkaline metal bicarbonate solution is administered on an
empty stomach. Usually 1.5 to 3 liters, more typically 1.5 to
2.4 liters, even more typically 1.8 to 2.1 liters and usually
between 1.8 and 2.7 liters of aqueous neutral to mildly alkaline
metal bicarbonate solution is ingested on an empty stomach in
approximately 300 mL volumes at set times each day. The solution
may be administered according to these latter dosages over short
(for example 1 to 10 days) or long (for example 6 months to 10
years or more) periods as required. Usually the amount of
aqueous neutral to mildly alkaline metal bicarbonate solution
administered to a mammal is 5 to 100 mL per Kg, more usual 10 to
50 mL per Kg, most usual 14 to 29 mL per Kg or 25 to 43 mL per
Kg.
Typically the aqueous neutral to mildly alkaline metal
bicarbonate solution is consumed on an empty stomach. Usually
consumption in this manner avoids the mixing of bicarbonate
anions with stomach acid which may result in the loss of
bicarbonate. Usually the aqueous neutral to mildly alkaline
metal bicarbonate solution is consumed in small amounts at set
times each day to avoid a rapid increase in the bicarbonate
concentration of body fluids. Usually the amount of aqueous
neutral to mildly alkaline metal bicarbonate solution consumed
at commencement is 500 mL per day and is increased by increments
over a period of one month to the maximum consumption. This
start-up schedule generally avoids any gastrointestinal side
effects due to the smooth muscle relaxation properties of
magnesium.
The advantages of the aqueous neutral to mildly alkaline metal
bicarbonate solution of the invention are that the magnesium
cations function as bicarbonate transporters into body cells.
Magnesium bicarbonate enters body cells and the bicarbonate
anions function to displace from equilibrium the dissociation
reaction of intracellular carbonic acid. Magnesium bicarbonate
enters body cells and the bicarbonate anions function as an
intracellular proton sink (or proton scavenger). These reactions
can be represented by the one equation
Magnesium bicarbonate enters body cells and the bicarbonate
anions function to displace from equilibrium the hydration
reaction of carbon dioxide which is catalysed by the enzyme
carbonic anhydrase. This reaction can be represented by the
equation
Usually appropriate salts of magnesium, sodium, potassium,
calcium and lithium should not exceed the concentrations of the
component elements recommended by health authorities. The
concentrations of component elements cannot exceed
concentrations restricted by the solubility product constants of
respective hydroxides and carbonates.
EXAMPLE 1
An Experiment to Decrease Intracellular Proton
Concentrations and to Increase Intracellular Bicarbonate
Concentrations in Mammalian Cells in vitro
Aqueous bicarbonate anions act as proton sinks in the presence
of excess proton concentrations in solution. This reaction can
be represented by the chemical equation
In the presence of sufficient concentrations of bicarbonate
anions, the reaction is essentially complete and proton
concentrations decrease. The pH value of the solution increases.
When plasma bicarbonate anions are present outside mammalian
body cells in sufficient concentrations, they are translocated
into the cytoplasm of the cells across the cell plasma
membranes. Indeed, bicarbonate anions equilibrate rapidly across
mammalian cell membranes. Bicarbonate translocation into cells
takes place via several processes. These processes include a
chloride-bicarbonate anion exchange and a sodium dependent
chloride-bicarbonate anion exchange and potassium co-transport
and magnesium co-transport.
An experiment was conducted to decrease intracellular proton
concentrations and to increase intracellular bicarbonate
concentrations in mammalian body cells in vitro. Throughout the
experiment, extracellular pH determinations were made using a pH
electrode and intracellular pH determinations were made using a
trapped fluorescein derivative. An increase in intracellular
proton concentrations (intracellular acidification) was achieved
by applying 10 mmol ammonium chloride (NH4Cl)
solution to a suspension of cells and then removing the NH4Cl.
An increase in intracellular bicarbonate concentrations was
achieved by applying an aqueous metal bicarbonate solution to a
suspension of cells. The aqueous metal bicarbonate solution
contained approximately Mg2+ 120 mg per liter, Na+
135 mg per liter and HCO3- 950 mg per
liter at pH 8.3. This aqueous metal bicarbonate solution was
equivalent to 15 mmol bicarbonate approximately. Blood was
collected in sodium heparin from a range of mammals and the
leucocytes removed. The leucocytes were washed and re-suspended
in isotonic saline. Intracellular pH determinations were made by
loading leucocytes for 15 minutes with (10 micromol in saline)
2,7-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF). Cells were
illuminated at 440 nm and 490 nm and fluorescence was measured
at 530 nm.
The experiment utilising sheep leucocytes is given stepwise
below:
Step 1. Increase in Intracellular Proton Concentrations
(cytoplasmic acidification)
A. Leucocytes suspended in normal saline after pretreatment
with fluorescein.
Extracellular pH 7,2
Intracellular pH 7.1
B. 10 mmol ammonium chloride (NH4Cl) solution pH 7.5
applied to suspension of leucocytes for 10 minutes.
C. Leucocytes washed and re-suspended in normal saline.
Extracellular pH 7.3
Intracellular pH 6.1
Result: Cells have increased intracellular proton
concentrations. Cytoplasm is acidified.
Step 2. Decrease in Intracellular Proton Concentrations
A. Acidified leucocytes (from Step 1.) divided into two groups;
Control group and Treatment group.
B. Treatment group of leucocytes exposed to aqueous metal
bicarbonate solution.
After 3 minutes:
Extracellular pH 7.5
Intracellular pH 7.0
C. Control group of leucocytes not exposed to aqueous metal
bicarbonate solution.
After 5 minutes:
Extracellular pH 7.2
Intracellular pH 6.6
Result: Cells treated with aqueous metal bicarbonate solution
rapidly decrease intracellular proton concentrations. Cytoplasm
shows rapid recovery from acidification relative to non-treated
cells.
Step 3. Increase in Intracellular Bicarbonate Concentrations
A. Leucocytes suspended in normal saline after pretreatment
with fluorescein.
Extracellular pH 7.2
Intracellular pH 7.1
B. Aqueous metal bicarbonate solution applied to suspension of
leucocytes for 20 minutes.
Extracellular pH 7.9
Intracellular pH 7.4
Result: Cells treated with aqueous metal bicarbonate solution
have increased intracellular bicarbonate concentrations which
are manifested by an increase in pH value of cytoplasm.
The experiment was repeated with leucocytes from mice, rats,
guinea pigs, cattle, horses, dogs, cats and humans. In all
cases, acidified cells treated with aqueous metal bicarbonate
solution had decreased intracellular proton concentrations. In
all cases, cells treated with aqueous metal bicarbonate solution
had increased intracellular bicarbonate concentrations which
were manifested by increased pH values of cytoplasm. The
experiment was repeated with aqueous metal bicarbonate solutions
that contained a range of concentrations of Mg2+, Na2+,
HCO3- and K+ and Ca2+
ions. Significant results were obtained for the following range
of concentrations:
______________________________________
Range
of concentrations to achieve
Ion significant results
______________________________________
Mg.sup.2+
20
to 120 mg/liter
Na.sup.+ 50 to 500 mg/liter
K.sup.+ 50 to 500 mg/liter
Ca.sup.2+ 20 to 150 mg/liter
HCO.sub.3 -- 250 to 2,100
mg/liter
(HCO.sub.3 --)
(4
mmol to 35 mmol)
______________________________________
Significant results were obtained for pH range pH 7.5 to 9.5.
(pH 9.5 was achieved by the addition of NaOH).
Aqueous metal bicarbonate solutions, containing a range of
cation and bicarbonate anion concentrations, decrease
intracellular proton concentrations and increase intracellular
bicarbonate concentrations in mammalian cells in vitro.
EXAMPLE 2
An experiment to Demonstrate Bicarbonate Anion Translocation
from Aqueous Metal Bicarbonate Solution into the Mammalian
Body against a Bicarbonate Anion Concentration Gradient
Mammalian plasma contains bicarbonate anions at a concentration
about 25 mmol (HCO3- 1,500 mg per liter).
When ingested, aqueous metal bicarbonate solution produces
biochemical, physiological and medical effects at bicarbonate
anion concentrations about 16 mmol (HCO3-
950 mg per liter). Aqueous metal bicarbonate solution, at
bicarbonate anion concentration about 16 mmol, contains two
thirds the bicarbonate anion concentration of plasma, so
bicarbonate anions must be translocated into the mammalian body
against a bicarbonate anion concentration gradient.
Mammalian plasma contains cations at concentrations around Mg2+
24 mg per liter, Na+ 3,300 mg per liter, K+
175 mg per liter and Ca2+ 100 mg per liter. Aqueous
metal bicarbonate solution commonly contains cations at
concentrations around Mg2+ 120 mg per liter, Na+
135 mg per liter, K+ 100 mg per liter and Ca2+
20 mg per liter. Aqueous metal bicarbonate solution commonly
contains 5 times the magnesium cation concentration of plasma.
Other cations are present commonly in aqueous metal bicarbonate
solution in concentrations lower than plasma.
The concentrations of cations and anions in plasma can be
compared with concentrations of cations and anions in aqueous
metal bicarbonate solution by examination of the following
table:
______________________________________
Concentrations of cations and anions
Aqueous
metal
Ion Plasma bicarbonate solution
______________________________________
Cl-- 3,600 mg/liter
0
mg/liter
Na.sup.+ 3,300 mg/liter 135
mg/liter
HCO.sub.3 -- 1,500 mg/liter 950
mg/liter
K.sup.+ 175 mg/liter
100 mg/liter
Ca.sup.2+ 100
mg/liter 20 mg/liter
Mg.sup.2+ 24 mg/liter
120 mg/liter
______________________________________
It is suggested that sodium cations and chloride anions leave
plasma along their respective concentration gradients and
magnesium and bicarbonate ions enter plasma along a magnesium
cation concentration gradient. Magnesium functions as a
bicarbonate transporter. In addition, it is suggested that
bicarbonate anions enter plasma by chloride-bicarbonate exchange
processes along a chloride anion concentration gradient
(chloride `our`, bicarbonate `in`).
In mammals, any large increases in plasma bicarbonate
concentrations can be decreased normally by a number of
biochemical and physiological homeostatic control processes.
These processes occur in time frames that range from minutes to
hours and longer. One of the main control processes that occurs
as a result of increased plasma bicarbonate concentration is an
alteration in bicarbonate chemistry in the kidneys. This is
manifested by a decrease in proton concentration in urine and by
a pH value of urine that is less acidic. In the presence of
increased plasma bicarbonate, kidney tubule cells decrease their
excretion of protons. Kidney control of bicarbonate
concentration is not instantaneous and occurs within a time
frame of several hours to several days. Unless a mammal has
physiological or clinical acidosis, it is difficult to detect
small increases in plasma bicarbonate concentration. Any
increases in plasma bicarbonate concentration are taken up by
body cells, Indeed, plasma bicarbonate equilibrates with
intracellular bicarbonate rapidly. In a normal mammal, a
measurable increase in plasma bicarbonate concentration occurs
only during an artificially induced alkalosis and is detectable
either when the consumption of bicarbonate anions (as NaHCO3)
greatly exceeds the concentration of bicarbonate in normal
plasma or when bicarbonate anions (as NaHCO3) are
administered intravenously.
An experiment was conducted to determine if bicarbonate anions
in aqueous metal bicarbonate solutions are translocated against
a bicarbonate concentration gradient into the body. Bicarbonate
translocation against a concentration gradient could occur
either via energy (ATP) dependent processes or via anion
(chloride-bicarbonate) exchange or via co-transport with cations
along cation concentration gradients. There are also complex
thermodynamic processes involving intracellular and
extracellular concentrations of bicarbonate anions, hydroxide
anions, protons and carbon dioxide that may assist in the
overall translocation of bicarbonate anions, These processes
often involve the production of bicarbonate anions by carbonic
anhydrase enzymes. In the experiment, entry of bicarbonate
anions into the body was assessed by determinations of proton
concentration in urine; that is, the pH value of urine.
Ten people had urine pH value assessed once per week for 3
months. Urine pH values were assessed once per week for a
further 3 months after commencement of consumption of aqueous
metal bicarbonate solution. The aqueous metal bicarbonate
solution contained approximately Mg2+ 120 mg per
liter, Na+ 135 mg per liter and HCO3-
950 mg per liter. The major component of the solution was
magnesium bicarbonate Mg(HCO3)2 720 mg per
liter approximately. Results are given below:
______________________________________
Mean pH value of urine
(Early morning sample)
______________________________________
Prior to consumption of aqueous
pH
5.9
metal bicarbonate solution:
After commencement of consumption
pH 6.7
of aqueous metal bicarbonate
solution:
______________________________________
The consumption of aqueous metal bicarbonate solution decreases
proton excretion by the kidneys. The pH value of urine
increases.
These results demonstrate that bicarbonate anions from aqueous
metal bicarbonate solution are translocated against a
bicarbonate anion concentration gradient into the body. This may
occur either via co-sport with cations along a cation
concentration gradient or via chloride-bicarbonate exchange
processes along a chloride anion concentration gradient
(chloride `out`, bicarbonate `in`). In the case of aqueous metal
bicarbonate solution, the only cation concentration gradient
possible is that involving magnesium cation concentrations.
The consumption of aqueous metal bicarbonate solution leads to
an increase in bicarbonate anion concentration in the body which
is manifested by a decrease in proton concentration in urine; an
increase in pH value of urine.
EXAMPLE 3
An Experiment to Improve the Buffering Capacities of the
Extracellular and Intracellular Bicarbonate Buffers and to
Decrease Senescence and to Increase Longevity in a
Representative Mammal
Mammalian body cells produce continuously concentrations of
carbon dioxide. Upon hydration, carbon dioxide increases proton
concentrations in the cytoplasm of body cells. The pH values of
the cytoplasm of body cells are lowered. The production of
protons in cytoplasm by the hydration of carbon dioxide can be
represented by the following chemical equations:
The protons produced in the cytoplasm of body cells by the
hydration of carbon dioxide, and other intracellular reactions,
are buffered normally by intracellular bicarbonate buffers. The
bicarbonate anions in intracellular buffers derive manly from
the extracellular bicarbonate of blood plasma. The bicarbonate
anions in blood plasma originate from erythrocytes as products
of erythrocyte carbonic anhydrase enzyme reactions.
When plasma bicarbonate anions are present outside mammalian
body cells in sufficient concentrations, they are translocated
into the cytoplasm of the cells across the cell plasma
membranes. Indeed, plasma bicarbonate equilibrates with
cytoplasmic bicarbonate rapidly. Bicarbonate translocation into
cells takes place via several processes. These processes include
a chloride-bicarbonate anion exchange and a sodium dependent
chloride-bicarbonate anion exchange and potassium co-transport
and magnesium co-transport. There are also complex thermodynamic
processes involving intracellular and extracellular
concentrations of bicarbonate anions, hydroxide ions, protons
and carbon dioxide that may assist in the overall translocation
of bicarbonate anions. These processes often involve the
production of bicarbonate anions by carbonic anhydrase enzymes.
Concentrations of bicarbonate anions that are translocated into
mammalian body cells improve the buffering capacity of the
cytoplasm of the cells. Concentrations of bicarbonate anions and
concentrations of carbon dioxide form a buffer system described
by the Henderson-Hasselbalch equation:
pH = pK + log ([HCO3sup.- ]/[H2 CO3])
(Where pK is the pK of hydrated carbon dioxide H2CO3
and has an approximate numerical value of 6.35).
For a classical (closed system) buffer to be effective, the
ratio of the conjugate base to the acid (in the above case [HCO3-
]/[H2CO3 ]) must be between 0.1 and 10.
This ratio applies also to buffers in biological (open) systems.
In mammalian body cells, the continuous and open production of
carbon dioxide means that continuous supplies of bicarbonate
anions are required to maintain effective and optimal buffering
capacities. Under conditions of excess proton concentrations,
from carbon dioxide production and ATP hydrolysis and other
metabolic processes, the supply of bicarbonate fails and the
effective and optimal buffering capacities of mammalian body
cells falter.
The vitality of mammalian body cells is linked critically to
the buffering capacities of the extracellular fluids and the
cytoplasm of the cells. Processes of cellular degeneration occur
when buffering capacities falter in the presence of excess
proton concentrations. Cellular degenerations are manifested in
the mammalian body by degenerative diseases and senescence.
Examples of degenerative diseases in mammals that are linked
casually to extracellular and intracellular proton
concentrations include osteoporosis, osteoarthritis, the
diseases associated with chronic inflammation, the diseases
associated with lysosomal enzyme activities, the diseases
associated with oxidations of cell nucleic acids, cell protein
amino acids and cell membrane lipids, and the diseases
associated with aberrations of mitochondrial respiration.
An experiment was conducted to improve the buffering capacities
of the extracellular and intracellular bicarbonate buffers and
to consequently decrease senescence and increase longevity in a
representative mammal. One hundred and ten Merino ewe lambs were
divided randomly at weaning into a control group and a treatment
group. The groups were of equal size and were maintained under
similar conditions except for the pH values and aqueous metal
bicarbonate concentrations of drinking water supplies. Sheep
were selected as the representative mammal because their life
span and body weight are more representative of typical mammals
tan laboratory rodents, their life span is not excessively long,
their body size permits multiple blood and tissue sample
collections, they are easy to handle and their husbandry is
suited to experimental conditions. The control group was
maintained, for the full life span of the sheep, in small
experimental paddocks with slightly acidic (less than pH 6.5)
drinking water supplies that contained bicarbonate
concentrations less than 30 mg per liter. The treatment group
was maintained, for the full life span of the sheep, in small
experimental paddocks with slightly alkaline (pH 7.8 to 9.0)
drinking water supplies that contained bicarbonate
concentrations between 300 mg per liter and 800 mg per liter.
The drinking water supplies for the treatment group were loaded
with the appropriate concentrations of bicarbonate anions by the
addition of crushed and powdered magnesite MgCO3 to
the water. The magnesite frequently contained calcite CaCO3
and dolomite (Ca,Mg)CO3. The magnesite was dissolved
in the drinking water either with the assistance of commercial
supplies of carbon dioxide gas or carbonic acid or with local
supplies of hydrated carbon dioxide. This dissolution process
can be represented by the following chemical equation
The treatment group of sheep consumed slightly alkaline (pH 7.8
to 9.0) drinking water that contained bicarbonate concentrations
between 300 mg per liter and 800 mg per liter. At this pH value,
and this bicarbonate concentration, bicarbonate was mostly in
the form of magnesium bicarbonate Mg (HCO3)2:
In addition, some sediments of carbonate (Ca,Mg)CO3
were present in the drinking water during summer months:
The mean pH values and the mean magnesium, calcium and
bicarbonate concentrations in the drinking water supplies are
given below (the concentrations of cations and bicarbonate
anions were not stoichiometric in the drinking
water--particularly the drinking water of the control
group--because of the presence of some concentrations of
sulphate, chloride and sodium ions):
______________________________________
Means of parameters in drinking water
Control
Group
Treatment
Group
______________________________________
pH
6.1 8.4
Mg.sup.2+ mg/liter 13 110
Ca.sup.2+ mg/liter 20 30
HCO.sub.3 -- mg/liter 25 660
______________________________________
In the lates stages of pregnancy, there is a tendency for
pregnant mammals to become hypoglycaemic and hyperketonaemic.
Hyperketonaemia subjects the pregnant mammal to an acid load
(increase in proton concentrations) This acid load may result in
clinical acidosis. Like all mammals, pregnant ewes tend to be
hypoglycaemic and hypoketonaemic late in pregnancy. In ewes
affected clinically with acidosis, bicarbonate concentrations
range between 14 to 20 mmol per liter plasma.
Over several years, plasma bicarbonate concentrations were
determined for the control group and the treatment group one
week prior to lambing. Determination of plasma bicarbonate
concentrations prior to lambing is a direct measure of
extracellular and intracellular bicarbonate buffering capacity.
In ewes with effective extracellular and intracellular
bicarbonate buffers, bicarbonate concentrations are maintained
in a range between 24 to 27 mmol per liter plasma. Plasma
bicarbonate concentrations are given below:
______________________________________
Mean plasma bicarbonate concentrations one
week prior to lambing (mmol
per liter)
Age (years)
Control Group
Treatment
Group
______________________________________
4
24.9 26.1
6 22.8 25.9
8 22.2 26.4
10 21.9 25.8
______________________________________
The treatment group had larger plasma bicarbonate
concentrations than the control group. The consumption of
aqueous metal bicarbonate solution, principally magnesium
bicarbonate solution, improves the buffering capacities of
extracellular and intracellular bicarbonate buffers in mammals.
In mammalians demography, there are two measurements utilised
commonly in the experimental study of degenerative diseases and
senescence. The first measurement is called fifty percent
survival. Fifty percent survival describes the chronological age
at which half an original population has died. The second
measurement is called maximum life span. Maximum life span
describes the age of the longest lived survivors of a
population. The fifty percent survival measurement is considered
to reflect susceptibility to accidents and infectious and
degenerative diseases in mammals. The maximum life span
measurement is considered to reflect the innate processes of
senescence in mammals. The fifty percent survival measurement
and the maximum life span measurement for the control group and
the treatment group are given below:
______________________________________
Fifty percent survival
Control
group 8 years
Treatment group 11
years
Maximum life span
Control
group 13 years
Treatment group 17
years
______________________________________
The treatment group had a larger fifty percent survival
measurement and a larger maximum life span measurement than the
control group.
The death of each member of a population of mammals can be
plotted graphicaly. The continuous function representing
mortality in a population is known as a survival curve. Survival
curves for the control group and treatment group are represented
in FIG. 1. The survival curves show that more mature sheep were
alive in the treatment group than the control group at any time.
This occurred with the consumption of normal physiological
volumes of water (as aqueous metal bicarbonate solution).
The consumption of aqueous metal bicarbonate solution, extends
the maximum life span of mammals by at least twenty percent and
increases the number of mature mammals alive at any time.
Senescence in mammals is characterised by progressive
oxidations of the structural and function molecules that
constitute body cells and tissues. These oxidations occur
particularly in nucleic acids, protein amino acids and cell
membrane lipids.
Because protons often participate in biological redox
reactions, oxidations of many structural and functional
molecules in body cells and tissues are increased in rate by the
presence of excess proton concentrations. Oxidations of
structural and functional molecules are increased in rate by
acidic conditions.
In general, oxidations of molecules are linked to proton
concentrations described by a formulation of the Gibbs energy
equation
EpH = Em + 2.3 RT/F
log([oxidised]/[reduced])
where EpH is a measure of oxidising power at a
particular pH value and E.sub.m is the mid-point potential. In
practice, EpH is decreased by between -30 mV and -60
mV for each decrease in proton concentration by a factor of 10.
That is, oxidising power is decreased by between -30 mV and -60
mV for each increase in pH value by 1 pH unit.
Oxidations of nucleic acids and protein amino acids lead to
nucleic acid and protein degradation respectively. These
degradations lead to senescence in mammals. Nucleic acid
degradation is manifested by either cell death or cell
transformation to the cancerous state. Protein degradation is
manifested by increased urea concentrations in the body which
can be detected in the plasma.
Determination of plasma urea concentrations in elderly mammals
is a direct measure of amino acid oxidation, protein degradation
and overall nitrogen (anabolic/catabolic) balance. Determination
of plasma urea concentrations in elderly mammals is a direct
measure of cellular degenerations and senescence.
Over several years, plasma urea concentrations were determined
for the control group and the treatment group. Plasma urea
concentrations are given below:
______________________________________
Mean plasma urea concentrations in elderly
sheep (mmol per liter)
Age (years) Control
Group Treatment Group
______________________________________
8
11 5
10
13 3
12
13 7
______________________________________
The treatment group had smaller plasma urea concentrations than
the control group.
The consumption of aqueous metal bicarbonate solution,
principally magnesium bicarbonate solution, decreases amino acid
oxidations, decreases protein degradation and improves overall
nitrogen (anabolic/catabolic) balance in mammals. The
consumption of aqueous metal bicarbonate solution, principally
magnesium bicarbonate solution, delays cellular degenerations
and senescence in mammals.
Autopsies were performed on sheep, when conditions permitted,
within 24 hours of death. Macroscopic signs of significant
degenerative diseases and other diseases were recorded.
Significant pathology is given below:
______________________________________
Prevalence of pathology at autopsy (%)
Macroscopic
Significant
Pathology Control Group Treatment
Group
(*most significant) (42
autopsies) (38 autopsies)
______________________________________
Lungs
24% 21%
*Heart 29% 11%
Liver 43% 21%
Kidney 24% 16%
Other Genito-urinary 17% 16%
Lymph nodes 40% 37%
Intestinal tract 10% 8%
*Joints 43% 5%
*Bone 24% 3%
Teeth 71% 40%
*Skin-wool 48% 21%
Cancer 12% 3%
______________________________________
The treatment group had a lower overall prevalence of pathology
than the control group.
In general, pathology in the treatment group was delayed (sheep
were older at autopsy) and progression was less advanced.
The consumption of aqueous metal bicarbonate solution,
principally magnesium bicarbonate solution, decreases the
prevalence of joint pathology (arthritis) and bone pathology
(osteoporosis) and cardiac pathology and skin pathology most
significantly and decreases the overall prevalence of the
pathology of most organs.
EXAMPLE 4
An Experiment to Distinguish Between the Consumption of
Magnesium Bicarbonate and the Consumption of Magnesium Cations
per se in Increasing Longevity in a Mammal
An experiment was conducted to assess if the consumption of
magnesium bicarbonate increased longevity in a mammal compared
to the consumption of magnesium cations per se. A short-lived
mammalian species was chosen. Short-lived mammals possess high
levels of proton leak across inner mitochondrial membranes, high
levels of carbonic anhydrase enzyme activities (for acid
production) and high levels of spontaneous cancer development
and spontaneous death. Any increase in longevity in a
short-lived species is indicative of an improvement in
fundamental cell biochemistry. Two hundred outbred (Swiss)
female mice were divided randomly at weaning into two groups of
100 mice and were maintained under identical management and
environmental conditions.
One group of mice was supplied with drinking water that
consisted of aqueous metal bicarbonate solution with a pH value
between pH 8.1 and pH 8.5. The aqueous metal bicarbonate
solution contained approximately Mg2+ 120 mg per
liter, Na+ 135 mg per liter and HCO3-
950 mg per liter. The major component of the solution was
magnesium bicarbonate Mg(HCO3)2 720 mg per
liter approximately. The second group of mice was supplied with
drinking water that contained magnesium sulphate (Epsom salts) 1
gram per liter with a pH value between pH 6.5 and pH 7.0. This
drinking water contained approximately Mg2+ 120 mg
per liter. Bicarbonate anions were absent.
Both groups of mice were fed commercial laboratory food that
contained 1 gram of magnesium per kilogram of food. Both groups
of mice were fed on alternate days with no food available on the
other days. Group-specific drinking water (as described above)
was available at all times. Feeding on alternate days decreased
the possible loss of bicarbonate anions by stomach acid and food
ingesta.
Results of the experiment are given below:
______________________________________
Fifty Percent Survival
Group consuming
magnesium bicarbonate
790
days
Group consuming magnesium
sulphate 736 days
Maximum Life Span
Group consuming
magnesium bicarbonate
1152
days
Group consuming magnesium
sulphate 1040 days
______________________________________
The group of mice consuming aqueous metal bicarbonate solution
had longevity increased by ten percent compared to the group of
mice consuming magnesium cations per se.
The consumption of aqueous metal bicarbonate solution,
principally magnesium bicarbonate solution, extends the maximum
life span of mammals by ten percent more than the consumption of
magnesium cations per se.
EXAMPLE 5
An Experiment to Decrease the Clinical Signs of
Osteoarthritis
Osteoarthritis is a disease of degeneration. There is
degradation and inflammation of the joints of the body.
Osteoarthritis is defamed as a disease process involving a
disturbance of the normal balance of degradation and repair in
the articular cartilage and subchondral bone of joints. This
disturbance of balance causes areas of morphological damage and
results in clinical problems such as pain and disability.
Osteoarthritis is manifested as a slowly progressive
degeneration of the joints of the hands and large weight-bearing
joints (hips and knees). It is common in post menopausal women.
Osteoarthritis is characterised by pain, enlargement of joints
and limitation of joint movements. The linings of osteoarthritic
joints show a moderate to marked degree of inflammation. The
principle pathological changes associated with osteoarthritis
are destruction of joint cartilage and neoformations of bone at
joint margins (osteophytes). In osteoarthritis, destruction of
joint cartilage is caused by acid protease enzymes (and other
enzymes) derived often from the lysosomes of cartilage cells
(chondrocytes), inflammatory cells and other cells.
Acid protease enzymes possess optimal activity in an acidic
environment; that is, an environment with high proton
concentrations Proton concentrations involved in the
pathogenesis of osteoarthritis derive from the hydration of
carbon dioxide catalysed by intracellular carbonic anhydrase
enzymes. The production of protons by carbonic anhydrase enzymes
can be represented by the equation
Protons formed by carbonic anhydrase enzymes are concentrated
by intracellular V-type proton pumps and stored in the endosomes
and lysosomes of body cells.
Functional endosomes and lysosomes maintain internal
concentrations of protons which give them internal pH values
between pH 3.0 and pH 6.0. Many degenerative diseases, including
osteoarthritis, involve intracellular and extracellular release
of lysosomal enzymes. In osteoarthritis, chemical fluxes through
the reactions catalysed by lysosomal enzymes result in the
breakdown of cartilage and bone.
An experiment was conducted to assess if the clinical signs of
osteoarthritis could be decreased by the consumption of aqueous
metal bicarbonate solution. The clinical signs of osteoarthritis
include pain, swelling, inflammation, skin discoloration, joint
deformities and decrease in joint function. An increase in
extracellular and intracellular bicarbonate anion concentrations
would decrease the production of protons from reactions
catalysed by carbonic anhydrase enzymes, decrease the pumping of
protons by V-type proton pumps, decrease the activities of acid
protease enzymes and decrease other activities of lysosomes. The
clinical signs of osteoarthritis would be alleviated. A group of
ten people were chosen who had been diagnosed with having
osteoarthritis. Each person in the group had been suffering from
(clinical) osteoarthritis for between 2 and 5 years. Five of the
group were post menopausal women who had clinical signs of
osteoarthritis in the joints of their hands. The osteoarthritic
joints included the distal and proximal interphalangeal joints
of the fingers and the carpometacarpal joint of the thumbs. In
all 5 cases, loss of joint function was moderate to severe.
In all 5 cases, the women suffered pain, swelling of the
fingers and loss of joint movement. Mucous cysts were associated
with distal joint osteoarthritis. Lateral deformities occurred
in some proximal joints with severe loss of joint function.
Women with affected thumbs had considerable loss of function and
considerable pain. Many hands were "claw-like" in appearance
(FIG. 2). The remainder of the group had osteoarthritis in the
hips and knees. These people suffered pain and moderate loss of
joint functions.
The people consumed aqueous metal bicarbonate solution with a
pH value between pH 8.1 and 8.5. The aqueous metal bicarbonate
solution contained approximately Mg2+ 120 mg per
liter, Na- 135 mg per liter and HCO3-
950 mg per liter. The major component of the solution was
magnesium bicarbonate Mg(HCO3)2 720 mg per
liter approximately
Consumption of the aqueous metal bicarbonate solution was
commenced at half a liter per day and increased by increments
over a period of one month to between 2 to 3 liters per day.
Consumption occurred on an empty stomach to avoid the loss of
bicarbonate by stomach acid (HCI). Consumption occurred in small
amounts (300 ml) at set times each day to avoid rapid increases
in bicarbonate concentrations of body fluids and to avoid over
hydration.
The results of the experiment were unequivocal. Within 3 to 6
months, all participants in the experiment demonstrated
substantial decreases in the clinical signs of osteoarthritis.
In all cases, there were remissions in the clinical signs of
osteoarthritis which were quantifiable by standard tests of
movement, flexibility and strength. The participants showed
considerable increases in joint functions and decreases in acute
and chronic joint swellings. The "stabbing" pain of
osteoarthritis was alleviated. Some participants had remissions
of inflammation and arthritis to the stage where many chronic
swellings were no longer observable and joint mobilities and
functions were restored (FIG. 3).
People in the experiment consumed aqueous metal bicarbonate
solution continuously for at least 2 years. During this period,
there was evidence of progressive improvement in healing
processes. Mucous cysts associated with distal joint
osteoarthritis were no longer visible.
Remissions in the clinical signs of osteoarthritis were
maintained only with the continual consumption of aqueous metal
bicarbonate solution. Once the consumption of aqueous metal
bicarbonate solution was halted, clinical signs of pain and
swelling began to reappear within 10 days. Clinical signs again
went into remission upon continuation of consumption of aqueous
metal bicarbonate solution.
The consumption of aqueous metal bicarbonate solution,
principally magnesium bicarbonate solution, results in
remissions in the clinical signs of osteoarthritis.
EXAMPLE 6
An Experiment to Maintain and Improve Motor Activity in
Mammals. An Experiment to Decrease Fatigue and Lethargy and
Improve Motor Activity. An Experiment to Decrease the Fatigue
and Lethargy of Chronic Disease and Improve Motor Activity
Mammals convert food energy into chemical energy that can be
used by body cells to maintain essential cell processes and cell
functions. The main chemical energy in mammalian body cells is
the chemical ATP (adenosine triphosphate). ATP is synthesised
mainly in the mitochondria of body cells. Mitochondrial ATP
production is linked intimately to the respiration rates of
mitochondria. The respiration rates of mitochondria are
dependent on many factors including the proton concentrations
(pH values) of the cytoplasm of body cells. If the intracellular
bicarbonate buffer of mammalian body cells is not maintained.
and is not functional, proton concentrations increase in the
cytoplasm and the pH value of the cytoplasm decreases. When
proton concentrations increase in the cytoplasm sufficiently (pH
value decreases sufficiently) the respiration rates of
mitochondria are diminished. When the respiration rates of
mitochondria are diminished, the production of ATP is
diminished. When the production of ATP is diminished, ATP
concentrations in the cell decrease and the main chemical energy
source for mammalian body cells becomes depleted. Under these
conditions, body cells cannot maintain essential cell processes
and cell functions. The body becomes fatigued and lethargic.
In addition to the hydration of carbon dioxide per se, one of
the sources of increased proton concentrations in the cytoplasm
of body cells is the hydrolysis of ATP. The hydrolysis of ATP
can be represented by the chemical equation
ATP + H2O <====> ADP + Pi + H+
Increased proton concentrations from the hydrolysis of ATP
occur particularly in the cytoplasm of muscle cells during
muscular (motor) activity. This is referred to often as an
increase in `lactic acid` (the lactic acid is, in fact, lactate
derived from glycolysis and the `acid` is the protons derived
from ATP hydrolysis).
An experiment was conducted to assess if motor activity could
be maintained and improved in mammals by improving the buffering
capacity of the extracellular and intracellular bicarbonate
buffers.
Two hundred inbred (Balb c) female mice were divided randomly
at weaning into two groups of 100 mice and maintained under
identical conditions for 3 years. Control groups of mice were
given drinking water that was deionised and slightly acidic (pH
5.0). Treatment groups of mice were given drinking water that
consisted of aqueous metal bicarbonate solution with a pH value
between pH 8.1 and 8.5. The aqueous metal bicarbonate solution
contained approximately Mg2+ 120 mg per liter, Na-
135 mg per liter and HCO3- 950 mg per
liter. The major component of the solution was magnesium
bicarbonate Mg(HCO3)2. 720 mg per liter
approximately.
Motor activity in mice was assessed at regular intervals for a
12 month period between 1 year and 2 years of age. Results of
the experiment are given below:
______________________________________
Mean motor activity in mice
Control
Group
Treatment
Group
______________________________________
Mean number of mice per hour
26
95
climbing to lid of cage
Mean number of mice per hour 48
82
engaged in exploratory activity
Mean time to exhaustion during 5
minutes 9 minutes
enforced motor activity
______________________________________
The treatment group had improved motor activity relative to the
control group.
The consumption of aqueous metal bicarbonate solution,
principally magnesium bicarbonate solution, maintains and
improves motor activity in mammals.
Mitochondria are described as `efficient` if they maintain
sufficient production of ATP for maintenance of essential cell
processes and cell functions. Efficient mitochondria are the
mitochondria of young mammals.
In mammals, there are declines in the efficiencies of
mitochondria which are correlated to chronological age. The
capacities of cells to maintain their particular energy
requirements are diminished progressively with chronological
age. Cells that are unable to meet their particular energy
requirements undergo senescence, become non-functional and
decline progressively towards cell death. This is manifested by
body senescence and ageing.
Mitochondria are described as `inefficient` if they cannot
maintain the necessary production of ATP for maintenance of
essential cell processes and cell functions. Mitochondrial
inefficiency arises from oxidative damage to mitochondrial
nucleic acids, mitochondrial enzymes and mitochondrial membrane
proteins and lipids, Inefficient mitochondria gradually and
progressively dominate in body cells through middle age to old
age. Middle aged and elderly mammals are fatigued and lethargic
relative to the young. Normal body cells attempt to produce
buffers that maintain a cytoplasmic pH value of about pH 7.2. In
vitro, if mitochondria are placed for a period in a medium
either with an improved buffer at pH 7.2 or with a pH value
buffered slightly higher than pH 7.2, there occurs an increase
in mitochondrial respiration rate and an increase in the
production of ATP.
An experiment was conducted to assess if fatigue and lethargy
could be decreased and motor activity improved by improving the
buffering capacity of the cytoplasmic bicarbonate buffer in a
group of middle aged and elderly people.
Improving the buffering capacity of the cytoplasmic bicarbonate
buffer would increase mitochondrial respiration rate and
increase the production of ATP. Mitochondria would become more
`efficient`. More chemical energy would be available for
maintenance of essential cell processes and cell functions.
Fatigue and lethargy would decrease and motor activity would
improve.
A group of nineteen people were chosen, with a mean age of 61
years, who had a history of fatigue and lethargy. In the context
of this experiment, fatigue and lethargy were determined as
subjective feelings of general exhaustion which were manifested
by mild to moderate lack of function. The people consumed
aqueous metal bicarbonate solution with a pH value between pH
8.1 and 8.5. The aqueous metal bicarbonate solution contained
approximately Mg2+ 120 mg per liter, Na+
135 mg per liter and HCO3- 950 mg per
liter. The major component of the solution was magnesium
bicarbonate Mg(HCO3)2 720 mg per liter
approximately.
Consumption of the aqueous metal bicarbonate solution was
commenced at half a liter per day and increased by increments
over a period of one month to between 2 to 3 liters per day.
Consumption occurred on an empty stomach to avoid the loss of
bicarbonate by stomach acid (HCl). Consumption occurred in small
amounts (300 ml) at set times each day to avoid rapid increases
in bicarbonate concentrations of body fluids and to avoid over
hydration.
The results of the experiment were unequivocal. Within 3
months, all participants in the experiment demonstrated
substantial decreases in fatigue and lethargy. All participants
described a feeling of well-being (mild euphoria). All
participants demonstrated an increased capacity for mild
physical activity; an improvement in motor activity. Function
was restored.
The consumption of aqueous metal bicarbonate solution,
principally magnesium bicarbonate solution, decreases fatigue
and lethargy and improves motor activity in middle aged and
elderly people.
Chronic disease (including degenerative disease) is manifested
often by chronic fatigue and lethargy and chronic pain. This is
true particularly for chronic inflammatory diseases and
autoimmune diseases.
The fatigue, lethargy and pain of chronic disease are
correlated often to the high proton concentrations involved in
the pathogenesis of chronic disease. In addition to the
hydration of carbon dioxide per se, proton concentrations
involved in the pathogenesis of chronic disease derive from the
hydration of carbon dioxide catalysed by intracellular carbonic
anhydrase enzymes. The production of protons by carbonic
anhydrase enzymes can be represented by the equation
Protons formed by carbonic anhydrase enzymes are concentrated
often by V-type proton pumps and stored in endosomes and
lysosomes in the cell. The breakdown of endosomes and lysosomes
creates concentrations of protons in the cell cytoplasm. This
lowers the pH value of the cytoplasm and decreases the
production of ATP in mitochondria. Cells become energy
deficient. Cells are unable to maintain essential cell processes
and cell functions. the body becomes fatigued and lethargic.
Functional endosomes and lysosomes maintain internal
concentrations of protons which give them internal pH values
between pH 3.0 and pH 6.0. Many of the chronic and degenerative
diseases of the body involve intracellular lysosomal activities
and intracellular and extracellular release of lysosomal
enzymes. Chemical fluxes through the reactions catalysed by
lysosomal enzymes result in the breakdown of cells and tissues.
Many lysosomal enzymes require low pH values for optimal
activity. Some of these enzymes are known as acid protease
enzymes.
Lysosomes located in cells known as macrophages, and in some
other cells, are involved in antigen processing and antigen
presentation. Antigen processing and presentation leads to cell
to cell interactions within the immune system which triggers
release of a set of chemicals called cytokines. Cytokine
concentrations in the body are correlated often to many of the
clinical signs of inflammation and disease. These clinical signs
include heat, swelling, pain, fatigue and lethargy.
An experiment was conducted to assess if fatigue and lethargy
could be decreased and motor activity improved by improving the
buffering capacity of the cytoplasmic bicarbonate buffer in a
group of people diagnosed and suffering with chronic disease.
Improving the buffering capacity of the cytoplasmic bicarbonic
buffer would decrease the hydration of carbon dioxide per se,
would decrease the production of protons from reactions
catalysed by carbonic anhydrase enzymes, decrease the pumping of
protons by V-type proton pumps, decrease the activities of acid
protease enzymes, decrease the activities of lysosomes, decrease
antigen processing and presentation, and increase the production
of ATP. Fatigue and lethargy would decrease and motor activity
would improve. Some of the clinical signs of chronic disease
would be alleviated.
A group of twenty three people were chosen who had been
diagnosed with having chronic disease. Each person had been
suffering from chronic disease for between 3 and 8 years.
The diseases consisted of chronic viral diseases, chronic
inflammatory diseases and autoimmune diseases and included
rheumatoid arthritis and dermatitis. All people had a history of
fatigue and lethargy. In the context of this experiment, fatigue
and lethargy were determined as subjective feelings of general
exhaustion which were manifested by moderate to severe lack of
function. The people consumed aqueous metal bicarbonate solution
with a pH value between pH 8.1 and 8.5. The aqueous metal
bicarbonate solution contained approximately Mg2+ 120
mg per liter, Na- 135 mg per liter, K+ 100
mg per liter and HCO3- 1,100 mg per liter.
The major component of the solution was magnesium bicarbonate
Mg(HCO3)2 720 mg per liter approximately.
Potassium bicarbonate 250 mg per liter was a component of the
aqueous metal bicarbonate solution to improve the co-transport
of bicarbonate anions into body cells. Consumption of the
aqueous metal bicarbonate solution was commenced at half a liter
per day and increased by increments over a period of one month
to between 2 to 3 liters per day. Consumption occurred on an
empty stomach to avoid the loss of bicarbonate by stomach acid
(HCl). Consumption occurred in small amounts (300 ml) at set
times each day to avoid rapid increases in bicarbonate
concentrations of body fluids and to avoid over hydration. The
results of the experiment were delayed but unequivocal. Within 3
to 9 months, all participants in the experiment demonstrated
substantial decreases in fatigue and lethargy. All participants
demonstrated an increased capacity for mild physical activity;
an improvement in motor activity. Function was improved. Those
participants with chronic rheumatoid disease (rheumatoid
arthritis) demonstrated some decreases in inflammation and some
decreases in pain. Those participants with chronic skin disease
(dermatitis) demonstrated decreases in inflammation. Those
participants with tissue calcification demonstrated decreases in
calcium deposits.
The consumption of aqueous metal bicarbonate solution,
principally magnesium bicarbonate solution, decreases fatigue
and lethargy and improves motor activity in people suffering
with chronic disease.
The consumption of aqueous metal bicarbonate solution,
principally magnesium bicarbonate solution, decreases clinical
signs of inflamation and pain and calcification in people
suffering with chronic disease.
EXAMPLE 7
An Experiment to Prevent and to Treat the Clinical Signs of
Diseases Caused by Viruses that Require Proton Concentrations
for Infectivity
Many viruses become infective by utilising high intracellular
proton concentrations in host cells. Proton concentrations
involved in the infectivity of viruses, and the pathogenesis of
viral diseases, derive from the hydration of carbon dioxide
catalysed by intracellular carbonic anhydrase enzymes. The
production of protons by carbonic anhydrase enzymes can be
represented by the equation
Protons formed by carbonic anhydrase enzymes are concentrated
by intracellular V-type proton pumps and stored in the endosomes
and lysosomes of body cells. Functional endosomes and lysosomes
maintain internal concentrations of protons which give them
internal pH values between pH 3.0 and pH 6.0.
Virus infectivity often requires the activities of acid
protease enzymes. Acid protease enzymes are enzymes that
function optimally at acidic pH levels. Acid protease enzymes
are located in endosomes and lysosomes of body cells.
Influenza viruses require acid protease enzyme activities for
their replication and infectivity. The acid proteases of
lysosomes and endosomes in body cells act to liberate the
nucleic acid (RNA) of the influenza virus from the outer viral
membrane.
Many viruses contain their own acid-dependent enzymes which
utilise proton concentrations in host cells. For example, the
acid proteases of lentiviruses are required for virus protein
assembly and viral infectivity.
An experiment was instigated with the aim of preventing and
treating the clinical signs of diseases caused by viruses that
require proton concentrations for infectivity. Natural
infections with influenza viruses and flu-like respiratory
viruses were taken as the model infections. Influenza is an
acute febrile infectious respiratory disease manifested by
inflammation of the bronchial mucosa. It is complicated often by
bacterial pneumonia. Clinical signs of influenza include
initially fever, malaise, headache and muscle pain followed by
coughing, sneezing and respiratory tract effusions. Flu-like
respiratory viruses cause respiratory diseases manifested
generally by clinical signs of less intensity than influenza.
Twenty people were chosen and divided into two equal groups.
The control group did not consume aqueous metal bicarbonate
solution. The treatment group consumed aqueous metal bicarbonate
solution with a pH value between 8.1 and 8.5. The aqueous metal
bicarbonate solution contained approximately Mg2+ 120
mg per liter, Na+ 135 mg per liter and HCO3-
950 mg per liter. The major component of the solution was
magnesium bicarbonate Mg(HCO3)2 720 mg per
liter approximately. Consumption of the aqueous metal
bicarbonate solution was commenced at half a liter per day and
increased by increments over a period of one month to between 2
to 3 liters per day. Consumption occurred on an empty stomach to
avoid the loss of bicarbonate by stomach acid (HCl). Consumption
occurred in small amounts (300 ml) at set times each day to
avoid rapid increases in bicarbonate concentrations of body
fluids and to avoid over hydration.
Aqueous metal bicarbonate solution was consumed by people in
the treatment group for 2 years.
People in both groups worked either in child care centres or in
homes for the elderly and were exposed to influenza and other
respiratory infections over a 2 year period. Clinical signs of
influenza and flu-like virus infections were observed and
recorded over the 2 years, Results are given below:
______________________________________
Record of influenza and flu-like virus
infections over a 2 year period
Control
Group
Treatment
Group
______________________________________
Influenza
Number of infections 8 2
Duration of symptoms 5 to 10 days
2 to 3 days
Severity of symptoms (0 to 4) 4 1
to 2
Flu-like viruses
Number of infections
15 3
Duration of symptoms 3 to 7 days
2 to 3 days
Severity of symptoms (0 to 4) 2
to 4 1 to 2
______________________________________
People consuming aqueous metal bicarbonate solution had a lower
prevalence of the clinical signs of influenza and flu-like virus
infections than people not consuming aqueous metal bicarbonate
solution. People consuming aqueous metal bicarbonate solution
had less severe symptoms and shorter duration of symptoms than
people not consuming aqueous metal bicarbonate solution.
The consumption of aqueous metal bicarbonate solution,
principally magnesim bicarbonate solution, decreases the
prevalence of the clinical signs of diseases caused by viruses
that require proton concentrations for infectivity.
The consumption of aqueous metal bicarbonate solution,
principally magnesium bicarbonate solution, decreases the
severity and the duration of the clinical signs of diseases
caused by viruses that require proton concentrations for
infectivity.
EXAMPLE 8
Suitable Formulation and Range of Parameters and Range of
Administration Volumes for the Aqueous Metal Bicarbonate
Solution
A suitable formulation for the aqueous metal bicarbonate
solution contains Mg(HCO3)2 720 mg per
liter approximately (Mg2+ 120 mg per liter and HCO3-
600 mg per liter approximately). The formulation usually
contains also NaHCO3 485 mg per liter approximately
(Na- 135 mg per liter and HCO3-
350 mg per liter approximately). The pH of the formulation is pH
8.3. The formulation is stored either at 5° C. to 10° C. at 1
atmosphere in a sealed container or at higher temperatures at
higher pressures. The formulation is administered or consumed by
a mammalian (typically human) user in 300 ml doses approximately
6 to 10 times per day usually on an empty stomach at
approximately equal time intervals throughout the day. Usually
the total amount of formulation usually administered is 1.8 to 3
liters per day.
The parameters of a suitable formulation for the aqueous metal
bicarbonate solution may be conveniently represented as follows:
______________________________________
Typical parameter range
Specific
parameters
______________________________________
Mg(HCO.sub.3).sub.2 150 mg/liter to
saturation
Mg(HCO.sub.3).sub.2
720 mg/liter
solubility per liter (Mg.sup.2+
120 mg/liter and
HCO.sub.3 -- 600 mg/liter)
NaHCO.sub.3 0 to 1,000 mg/liter
NaHCO.sub.3 485 mg/liter
(Na.sup.+ 135 mg/liter and
HCO.sub.3 -- 350 mg/liter
pH 8.0 to 8.5 pH 8.3
0.degree. C. to 10.degree. C. at
1 atmosphere 5.degree. C. to 10.degree.
C.
at
1 atmosphere
300 ml dose approximately 1 to 15
300 ml dose approximately
times per day 6 to 10 times per
day
______________________________________
There exists a range of combinations and concentrations of
metal cations that may be included in the suitable formulation
of the aqueous metal bicarbonate solution. There exists a range
of anions (other than bicarbonate) that may be included in
stoichiometric amounts with metal cations in the suitable
formulation of the aqueous metal bicarbonate solution. There
exists a range of concentrations of bicarbonate anions that may
be included in stoichiometric amounts with metal cations in the
suitable formulation of the aqueous metal bicarbonate solution.
A typical range of parameters that may be combined and included
in the suitable formulation of the aqueous metal bicarbonate
solution may be conveniently represented as follows:
______________________________________
Final Concentration in Solution
Typical
parameter range
Specific
parameters
______________________________________
Mg.sup.2+ 50 to 500 mg/liter
120
to 300 mg/liter
Na.sup.+ 50 to 1,000
mg/liter 120 to 300 mg/liter
K.sup.+ 50 to 500 mg/liter 120 to
300 mg/liter
Ca.sup.2+ 50 to 500 mg/liter 120
to 300 mg/liter
HCO.sub.3 -- 200 to 3,000
mg/liter 600 to 2,000 mg/liter
Anions other than
Stoichiometric
with metal cation concentrations
HCO.sub.3 --(eg. Cl--,
SO.sub.4.sup.2 --)
______________________________________
There exists a range of pH values for the suitable formulation
of aqueous metal bicarbonate solution (that includes cation and
anion parameter ranges above). The pH values may be conveniently
represented as follows:
______________________________________
Typical pH range
Specific
pH range
______________________________________
pH 7.5 to 8.8 pH 8.0 to 8.5
______________________________________
Above pH 8.5, the solution tends to become cloudy due to the
formulation of metal carbonates (CO32-).
There exists a range of physical parameters for the suitable
formulation of aqueous metal bicarbonate solution (that includes
cation and anion parameter ranges above). The physical
parameters may be conveniently represented as follows:
______________________________________
Typical parameter range
Specific
parameter range
______________________________________
0° C. to 30° C.
5°
C. to 10° C.
1 to 3 atmospheres 1 atmosphere
______________________________________
Above 10° C., carbon dioxide leaves solution and the solution
tends to become cloudy (with time) due to the formation of metal
carbonates (CO32-). This may be controlled
by increasing the pressure on the solution.
There exists a range of volumes of administration for the
suitable formulation of metal bicarbonate solution (that
includes cation and anion parameter ranges above), The volume of
aqueous metal bicarbonate solution administered depends on the
purpose for the administration.
The administered volumes of aqueous metal bicarbonate solution
may be conveniently represented as follows:
______________________________________
Purpose for administration of
Typical
volume range
aqueous metal bicarbonate
solution administered to 70 kg human
______________________________________
Increased longevity and delay
1
to 2 liters per day (normal
in senescence physiological
volume requirement
for water intake)
Prevention of degenerative
diseases 1 to 2 liters per day (normal
physiological
volume requirement
for water intake)
Treatment of osteoarthritis 1.8
to 3.0 liters per day
Treatment of chronic disease 1.8
to 3.0 liters per day
Maintain and improve motor
activity 1.8 to 3.0 liters per day
Decrease fatigue and lethargy 1.8
to 3.0 liters per day
Prevention and treatment of
influenza 1.8 to 3.0 liters per day
and
other acid-dependent viral
diseases
______________________________________
Aqueous metal bicarbonate solution is administered typically in
300 ml doses approximately 6 to 10 times per day at equal time
intervals throughout the day.
Typically, the solution is allowed to stand prior to
consumption until the solution reaches 15° C. to 20° C. (cool
room temperature).
A suitable formulation for the aqueous metal bicarbonate
solution contains Mg(HCO3)2 720 mg per
liter at pH 8.3. The formulation usually contains also NaHCO3
485 mg per liter. The aqueous metal bicarbonate solution may
contain a range of cations and anions within a pH range pH 7.5
to 8.8. The aqueous metal bicarbonate solution is administered
in volumes ranging from 1 to 3 liters per day.
EXAMPLE 9
Osteoarthritis is a slowly progressive degeneration of the
joints of the hands and large weight-bearing joints (hips and
knees). Osteoarthritis is common in post menopausal women.
Osteoarthritis is characterised by pain, enlargement of joints
and limitation of joint movements. The linings of osteoarthritic
joints show a moderate to marked degree of inflammation. The
principle pathological changes associated with osteoarthritis
are destruction of joint cartilage and neoformations of bone at
joint margins (osteophytes). In osteoarthritis, destruction of
joint cartilage is caused by acid protease enzymes (and other
enzymes) derived often from the lysosomes of cartilage cells
(chondrocytes), inflammatory cells and other cells.
For an experimental trial, a group of post menopausal women
were chosen who had clinical signs of osteoarthritis in the
joints of their hands. The osteoarthritic joints included the
distal and proximal interphalangeal joints of the fingers and
the carpometacarpal joint of the thumbs. In all cases, loss of
joint function was moderate to severe.
In all cases, the women suffered pain, swelling of the fingers
and loss of joint movement. Mucous cysts were associated with
distal joint osteoarthritis. Lateral deformities occurred in
some proximal joints with severe loss of joint function. Women
with affected thumbs had considerable loss of function and
considerable pain. Many hands were "claw-like" in appearance.
Women consumed magnesium bicarbonate solution, with added sodium
bicarbonate. The women consumed between 2 to 3 liters of
bicarbonate solution per day. In this solution, the magnesium
concentration was approximately 120 mg per liter, sodium
concentration was approximately 135 mg per liter and bicarbonate
concentration was approximately 950 mg per liter. Consumption
was commenced at half a liter per day and increased by
increments over a period of one month to 2 to 3 liters per day.
Consumption occurred on an empty stomach to avoid the loss of
bicarbonate by stomach acid. Consumption occurred in small
amounts (300 mL) at set times each day to avoid rapid increases
in bicarbonate concentrations of body fluids.
In all cases, there were remissions in the clinical signs of
osteoarthritis which were quantifiable by standard tests of
movement, flexibility and strength. The participants showed
considerable increases in joint functions and decreases in acute
and chronic joint swellings. The "stabbing" pain of
osteoarthritis was alleviated. Some participants had remissions
of inflammation and arthritis to the stage where many chronic
swellings were no longer observable and joint nobilities and
functions were restored. However, these improvements were
maintained only with the continued consumption of bicarbonate
anions. Once the consumption of bicarbonate anions ceased,
clinical signs of inflammation began to reappear often within a
week.
The participants commented on an absence of lethargy and the
presence of a feeling of well-being. Magnesium bicarbonate
alleviated the pain and swelling associated with osteoarthritis.
None of the participants demonstrated any clinical signs of
influenza or other respiratory. viral infections over the two
year period of the trial. This occurred despite several of the
participants working in situations where exposure to viral
infections was high (nursing homes and child care centres).
EXAMPLE 10
Influenza is an acute febrile infectious respiratory disease
manifested by inflammation of the bronchial mucosa. Influenza is
complicated often by bacterial pneumonia which may be fatal.
For an experimental trial, a group of men and women were chosen
who worked in situations where exposure to the influenza virus
was likely to occur (nursing homes and child care centres). Each
person in the experimental group consumed magnesium bicarbonate
solution, with added sodi bicarbonate. Each person consumed
between 2 to 3 liters of bicarbonate solution per day. In this
solution, the magnesium concentration was approximately 120 mg
per liter, sodium concentration was approximately 135 mg per
liter and bicarbonate concentration was approximately 950 mg per
liter.
Consumption was commenced at half a liter per day and increased
by increments over a period of one month to 2 to 3 liters per
day. Consumption occurred on an empty stomach to avoid the loss
of bicarbonate by stomach acid. Consumption occurred in small
amounts (300 mL) at set times each day to avoid rapid increases
in bicarbonate concentrations of body fluids.
Over the two year period of the experimental trial, no person
in the experimental group showed any clinical signs of
influenza.
EXAMPLE 11
A suitable formulation for the aqueous metal bicarbonate
solution contains 720 mg Mg(HCO3)2 per
liter (120 mg Mg2+ per liter and 600 mg HCO3
per liter approximately) and 485 mg NaHCO3 per liter
(135 mg Na+ per liter and 350 mg HCO3-
per liter approximately). The pH of this formulation is pH 8.3.
This formulation is stored at 5 to 10.degree. C. at 1 atmosphere
or it can be stored at higher temperatures at higher pressures.
This formulation is administered in 300 mL doses approximately 6
to 10 times per day. That is the amount of formulation usually
administered per day is 1.8 to 3 liters per day.
The parameters of the formulation may be conveniently
represented as follows:
______________________________________
Typical Parameter Range
Specific
Parameters
______________________________________
100 mg - saturation solubility
720
mg Mg(HCO.sub.3).sub.2 per liter (120 mg
Mg(HCO.sub.3).sub.2 per liter
Mg.sup.2+ and 600 mg HCO.sub.3 -- per
liter)
0-1000 mg NaHCO.sub.3 per liter
485 mg NaHCO.sub.3 per liter (135 mg
Na.sup.+
and 350 mg HCO.sub.3 -- per liter)
pH 8-8.6, typically 8-8.5 pH 8.3
0-10.degree. C. @ 1 atmosphere
5-10.degree. C. @ 1 atmosphere
300 mL dose approximately 1 to
300 mL dose approximately 6 to 10
20
times per day times per day
______________________________________
EXAMPLE 12
Mitochondria are inefficient if they cannot maintain the
necessary production of ATP for maintenance of essential cell
processes and cell functions. This inefficiency is due often to
functional damage to the mitochondrial inner membrane and other
mitochondrial molecules. Inefficient mitochondria are not able
to maintain normal carbon, electron and proton fluxes.
However, in middle age, carbon and electron fluxes may be
maintained by the synthesis of fatty acids in the cytoplasm of
body cells. In body cells of the middle aged, fatty acids can be
regarded as carbon and electron sinks necessary for the
maintenance of essential fluxes; that is, for the maintenance of
essential life processes. The synthesis of fatty acids utilises
ATP. However, the fluxes for production of ATP in mitochondria
are decreased in middle age. There is a consequent `energy`
deficit. The middle aged are flat and lethargic relative to the
young, though they can be regarded as fat by necessity; the
necessity of staying alive. In addition to utilisation of cell
ATP, the synthesis of fatty acids in body cells adds to the
carbon dioxide load of the cells and adds to concentrations of
intracellular protons. This occurs because the series of
chemical reactions that synthesise fatty acids results in a net
utilisation of bicarbonate anions and a net production of carbon
dioxide and protons. For example, each molecule of the fatty
acid palmitate that is synthesised by cells utilises seven
molecules of ATP and seven bicarbonate anions and produces seven
molecules of carbon dioxide and seven protons. Of course, fatty
acids are oxidised continuously from fat stores in the body
which produces even more carbon dioxide. When excess calories
are consumed at any chronological age (and converted to fatty
acids) the overall carbon dioxide load is considerable. Caloric
restricted rodents avoid this extra carbon dioxide load and, as
a consequence. they live longer lives with delays in the onset
of degenerative diseases.
A trial involving people consuming bicarbonate anions in water
was conducted. These people were middle aged and overweight and
complained of tiredness and lethargy. No control group was
maintained for the duration of the trial (people in an initial
control group were unable to consume the volumes of soft water
required). People involved in the trial were given a series of
lectures on the biochemistry of mitochondrial processes. They
were requested to decrease their food (calorie) intake
considerably and to avoid dietary fats. Excessive aerobic
exercise was not recommended due to the consequent increase in
hunger it produces, the large increase in carbon dioxide
concentrations that occur with increased aerobic muscle activity
and the damage excess activity does to inefficient mitochondria.
Indeed, active muscle cells contain mitochondria with most
nucleic acid damage relative to other body cells.
The trial consisted of each person consuming between two to
three liters per day of a mixture of magnesium bicarbonate and
sodium bicarbonate in water. Bicarbonate concentration was
established at a maximum of one gram per liter. (This
concentration of bicarbonate is well within the concentrations
in several water sources utilised for human consumption in
Europe. In these waters however, the bicarbonate is in the form
of calcium and sodium bicarbonate and pH values often are not
very alkaline.) Consumption was commenced at half a liter per
day and increased by increments over a period of one month to
the maximum consumption. This start-up schedule avoided any
gastrointestinal side effects due to the smooth muscle
relaxation properties of magnesium. Capillary dilation in the
face was apparent in several people (which was interpreted by
those affected as rosy, healthy cheeks). The capillary dilation
may have been due to magnesium or may have been due to a
decrease in activity of renin which is an acid protease enzyme
from the kidney that is central to the control of blood
pressure. (Renin exerts its effects ultimately by constriction
of small blood vessels.)
Each participant in the trial was advised to consume the
bicarbonate solution `on an empty stomach`. Consumption in this
manner avoided the mixing of bicarbonate anions with stomach
acid which would have resulted in the loss of bicarbonate.
Advice was given also to consume the solution in small amounts
at set times each day. Consumption in this manner avoided a
rapid increase in the bicarbonate concentrations of body fluids.
The results were unequivocal. Body weight was lost at about one
half of a kilogram per week after the initial start-up period
was completed. Other beneficial effects (more important than
weight loss to the participants in the trial) included the
absence of lethargy, the presence of a feeling of well-being
(mild euphoria) and the increased capacity for mild physical
activity. The participants all commented that their `energy
levels` had improved and that their outlook on life had
consequently become more positive.
EXAMPLE 13
A heart muscle cell contains mitochondria that occupy one
quarter of the cell volume. It is natural to expect the heart to
be rich in mitochondria when one considers the workload of the
heart and its subsequent requirement for `energy`. The
consumption of magnesium bicarbonate may assist in maintaining
efficient mitochondria in heart muscle cells. In the presence of
bicarbonate anions, mitochondrial efficiency in heart muscle
cells is maintained by processes which include decreases in
proton leaks across inner mitochondrial membranes, establishment
of proton circuits independent of proton leaks and maintenance
of alkaline pH values in mitochondrial matrixes. In the presence
of bicarbonate anions, mitochondrial damage and mitochondrial
failure are decreased. Efficient mitochondria in heart muscle
cells maintain ATP production so that the heart remains
functional as a vital organ.
There are further beneficial effects to the cardiovascular
system resulting from the consumption of magnesium bicarbonate.
First, decreased fatty acid synthesis in body cells results in
lowered body weight with subsequent reduction in high blood
pressure to a normal value. Indeed, these effects were observed
in people participating in the trial reported in Example 5.
Second, lysosomal enzyme damage to ischaemic heart muscle may be
prevented or decreased.
There is unequivocal evidence of correlation that heart
disease, senescence, degenerative diseases and death are caused
by inefficient mitochondria. Though inefficient mitochondria may
not be the only cause of these conditions. There is sufficient
evidence however that senescence and general degeneration in all
species studied, from fungi to humans, are correlated to the
damage to the complex molecules of the mitochondria. For
example, the mitochondria of aged people carry nucleic acid and
protein defects not observed in the mitochondria of young
people. This is true particularly of the mitochondria in muscle,
heart and brain cells. Accordingly, it has been proposed that
several chronic diseases common in old age may be related to
mitochondrial failure, including heart disease, late-onset
diabetes and Parkinson's and Alzheimer's diseases. That is, the
gradual loss of efficiency of cell mitochondria results in a
diminution of the functional capacity of body cells with
pathological consequences.
A progressive decline in organ function is characteristic of
old age. Some of the changes that occur as people grow older
are:
1. The ability to focus the eyes decreases and response time to
stimuli becomes slower.
2. Cancers in epithelial tissues (skin, lung, colon, mammary
gland) become more common.
3. Heart disease and widely disseminated atherosclerosis occur.
4 Osteoporosis and bone and joint pathology occur.
5 Thermoregulation becomes impaired.
6. There is a decline in the ability of body organs such as the
reproductive organs, lungs, glandular tissues and kidneys to
maintain their specialised life processes.
7. There is a reduced capacity for surviving haemorrhage.
8. There is an increase in autoimmune diseases and chronic
inflammatory diseases,
Relative to their life span of around three years, mice develop
heart disease, kidney disease, arthritis and cancer at similar
stages in life to humans. In other words, both senescence and
the similar degenerative diseases of mice and humans are
correlated to the chronological age of each species but carmot
be linked causally to chronological age per se. It has been
observed in many experiments that rodents fed caloric restricted
diets suffer less from the above diseases than control animals.
It has been observed also that careful necropsies on
diet-restricted rodents often do not reveal any gross or
microscopic pathology.
Mitochondrial proton leak is a contributing cause of
mitochondrial inefficiency and hence a source of senescence and
degenerative diseases in short-lived rodents. Mitochondrial
proton leak may be a source of senescence and degenerative
diseases in humans. Because the proton leak in humans is only a
fraction of the leak in rodents, humans develop senescence and
degenerative diseases at a later chronological age than rodents.
It may be possible to prevent inefficient processes in
mitochondria in order to extend longevity and to delay
degenerative diseases. Exogenous sources of appropriate
bicarbonate anions can be absorbed by body cells to maintain
intracellular alkaline pH values and that alkaline pH values
maintain mitochondrial respiration rates and maintain effective
proton concentration gradients across inner mitochondrial
membranes.
Intracellular alkaline pH values appear necessary for optimum
activities of many enzymes in body cells. These enzymes include
polymerases, phosphofructokinase and carbonic anhydrase. Enzymes
permit life processes to be perpetuated. Therefore, maintenance
of enzyme activities by maintenance of intracellular alkaline pH
values may assist in the perpetuation of longevity.
The long-term provision of appropriate bicarbonate anions to
body cells maintains efficient mitochondrial function, maintains
the DNA polymerase activity of mitochondria and therefore
maintains the integrity of mitochondrial DNA. This latter effect
results in accurate syntheses of the complex functional
molecules that are involved in electron fluxes in mitochondria.
Of course, bicarbonate anions will decrease the proton load per
se in body cells with a subsequent decrease in proton damage to
other cell molecules and a decrease in the tendency of oxidation
reactions to occur. Decreased oxidations result in decreased DNA
mutations and decreased amino acid oxidations. Degenerative
diseases are delayed.
Industrial Applicability
An aqueous metal bicarbonate solution of the invention can be
readily utilised in medicine to prevent and to treat certain
inflammatory diseases, degenerative diseases and viral diseases
in mammals.
US Patent # 6,328,997
Aqueous Metal Bicarbonate Solution and
Method of Use
Russell J. Beckett
Abstract -- An aqueous neutral to mildly alkaline metal
bicarbonate solution is disclosed. The solution comprises metal
bicarbonate dissolved in the solution, the metal bicarbonate
comprising bicarbonate anions and metal cations. In addition
there is a pH adjusting agent in the solution in an amount
whereby the solution is at a neutral to mildly alkaline pH. Also
disclosed is a process of preparing an aqueous neutral to mildly
alkaline metal bicarbonate solution comprising bicarbonate
anions and metal cations. The process comprises reacting a
compound selected from the group consisting of metal carbonate,
metal carbonate hydroxide, metal oxide, metal hydroxide and any
mixture thereof with an effective concentration of a pH
adjusting agent to produce the aqueous neutral to mildly
alkaline metal bicarbonate solution, wherein the pH adjusting
agent is present in an amount whereby the solution is at a
neutral to mildly alkaline pH. Further disclosed are a method of
preventing and/or treating certain inflammatory diseases and/or
degenerative diseases in a mammal, a method of preventing and/or
treating certain viral diseases in a mammal, a method of
decreasing and/or treating senescence and/or of increasing
longevity in a mammal, a method of scavenging protons in a
mammal, a method of decreasing proton concentrations in a mammal
by altering carbonic anhydrase enzyme reactions in said mammal,
a method of decreasing inflammation and/or inflammatory
conditions in a mammal and a method of increasing motor activity
and/or decreasing fatigue in a mammal.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This is a continuation of Application No. 09/041,787 filed on
Mar. 13, 1998 now U.S. Pat. No. 6,048,553.
Description
TECHNICAL FIELD
This invention relates to an aqueous metal bicarbonate
solution, a process of preparing the aqueous metal bicarbonate
solution and a method of preventing and treating certain
inflammatory diseases, degenerative diseases and viral diseases
in mammals. Generally the certain inflammatory diseases,
degenerative diseases and viral diseases in mammals are those
that require extracellular or intracellular acidic conditions or
extracellular or intracellular proton concentrations at some
point in disease process or disease pathogenesis.
Typically the certain inflammatory diseases, degenerative
diseases and viral diseases in mammals are those that require
the activities of carbonic anhydrase enzymes and/or the
activities of acid (aspartic) protease enzymes and/or the
activities of endosomal or lysosomal acid-requiring-enzymes
and/or the activities of V-type ATPase proton pumps at some
point in disease process or disease pathogenesis. Typically the
certain inflammatory diseases, degenerative diseases and viral
diseases in mammals are represented by the diseases of arthritis
and influenza.
This invention relates to a method of using an aqueous metal
bicarbonate solution to decrease senescence and to increase
longevity in mammals. Generally senescence is decreased and
longevity is increased in mammals by improving the buffering
capacity of the extracellular and intracellular fluids of the
body. Generally senescence is decreased and longevity is
increased in mammals by the improved buffering capacity causing
a decrease in proton concentrations in the extracellular and
intracellular fluids of the body. Typically senescence is
decreased and longevity is increased in mammals by improving the
buffering capacity of the extracellular and intracellular
bicarbonate buffers. Typically senescence is decreased and
longevity is increased in mammals by the improved extracellular
and intracellular bicarbonate buffers causing a decrease in
proton concentrations.
BACKGROUND ART
Certain inflammatory diseases, degenerative diseases and viral
diseases are major causes of morbidity and mortality in mammals.
Typically these diseases are represented by the diseases of
arthritis and influenza.
Arthritis is any inflammatory condition of the joints,
characterised by pain and swelling. Osteoarthritis is the most
common form of arthritis in which one or many joints undergo
degenerative changes. Treatment includes rest of the involved
joints, heat, and antiinflammatory drugs. Intraarticular
injections of corticosteroids may give relief. Surgical
treatment is sometimes necessary and may reduce pain and greatly
improve the function of the joint. However these treatments,
apart from surgical treatment, only provide temporary relief and
some may have severe side reactions.
Influenza is a highly contagious infection of the respiratory
tract caused by a myxovirus and transmitted by airborne droplet
infection. It occurs in isolated cases, epidemics and pandemics.
Treatment is symptomatic and usually involves bed rest,
antipyretics such as aspirin and drinking of fluids. New strains
of the virus emerge at regular intervals so it is difficult to
take preventative measures to avoid the infection. There is a
need for a method to prevent and to treat certain inflammatory
diseases, degenerative diseases and viral diseases in mammals.
There is a need for a method to prevent and to treat arthritis
and influenza in mammals.
Senescence in mammals is characterised by progressive
oxidations of the structural and functional molecules that
constitute body cells and tissues. Oxidations of the structural
and functional molecules in body cells and tissues are increased
in rate by acidic conditions. Oxidations of structural and
functional molecules are increased in rate by the presence of
excess proton concentrations. There is a need for a method to
prevent and treat excess proton concentrations in body cells so
that oxidations of structural and functional molecules are
decreased in rate. There is a need for a method to decrease and
treat senescence in mammals.
OBJECTS OF INVENTION
It is an object of this invention to provide an aqueous metal
bicarbonate solution to prevent and to treat certain
inflammatory diseases, degenerative diseases and viral diseases
in mammals. It is a further object of this invention to provide
a process of preparing the aqueous metal bicarbonate solution.
It is also an object of this invention to provide methods for
the prevention and treatment of certain inflammatory diseases,
degenerative diseases and viral diseases in mammals using the
aqueous metal bicarbonate solution. Generally the certain
inflammatory diseases, degenerative diseases and viral diseases
in mammals are those that require extracellular or intracellular
acidic conditions or extracellular or intracellular proton
concentrations at some point in disease process or disease
pathogenesis. Typically the certain inflammatory diseases,
degenerative diseases and viral diseases in mammals are those
that require the activities of carbonic anhydrase enzymes and/or
the activities of acid (aspartic) protease enzymes and/or the
activities of endosomal or lysosomal acid-requiring-enzymes
and/or the activities of V-type ATPase proton pumps at some
point in disease process or disease pathogenesis. Typically the
certain inflammatory diseases, degenerative diseases and viral
diseases in mammals are represented by the diseases of arthritis
and influenza.
It is an object of this invention to provide an aqueous metal
bicarbonate solution to decrease senescence and to treat
senescence and to increase longevity in mammals. It is a further
object of this invention to provide a process of preparing the
aqueous metal bicarbonate solution. It is also an object of this
invention to provide methods for the decrease of senescence and
the treatment of senescence and the increase in longevity in
mammals using the aqueous metal bicarbonate solution. Generally
senescence is decreased and longevity is increased in mammals by
improving the buffering capacity of the extracellular and
intracellular fluids of the body. Generally senescence is
decreased and longevity is increased in mammals by the improved
buffering capacity causing a decrease in proton concentrations
in the extracellular and intracellular fluids of the body.
Typically senescence is decreased and longevity is increased in
mammals by improving the buffering capacity of the extracellular
and intracellular bicarbonate buffers. Typically senescence is
decreased and longevity is increased in mammals by the improved
extracellular and intracellular bicarbonate buffers causing a
decrease in proton concentrations.
DISCLOSURE OF INVENTION
According to a first embodiment of the present invention there
is provided an aqueous metal bicarbonate solution comprising a
stoichiometric concentration of bicarbonate anions and a
corresponding substantially stoichiometric concentration of
metal cations in association with the bicarbonate anions, the
metal bicarbonate being present in a therapeutically effective
amount and an acceptable carbon dioxide-containing-aqueous
diluent to maintain the metal bicarbonate in the aqueous
diluent.
Typically the solution is acceptable for oral administration.
In one embodiment there is provided a combination comprising
the solution of the first embodiment in combination with a
stabilising agent in an amount effective to maintain and
stabilise the bicarbonate anions in the neutral to mildly
alkaline solution. Generally the combination is kept in a sealed
or closed container at 0.8 to 5 atmospheres, more typically 1
atmosphere at 0-25° C., more typically 0.1-10° C. In one
particular embodiment the stabilising agent may be present in
the solution in an amount effective to maintain and stabilise
the bicarbonate anions in the neutral to mildly alkaline
solution. In another particular embodiment the stabilising agent
may consist of or comprise a gas above the solution in an amount
effective to maintain and stabilise the bicarbonate anions in
the neutral to mildly alkaline solution. In a further particular
embodiment the stabilising agent may be present in the solution
and also may consist of or comprise a gas above the solution,
the total amount of stabilising agent in the solution and in the
gas above the solution being in an amount effective to maintain
and stabilise the bicarbonate anions in the neutral to mildly
alkaline solution. The stabilising agent which consists of a gas
above the solution may be carbon dioxide. The stabilising agent
which comprises a gas above the solution may be carbon dioxide
in an an inert gas such as nitrogen, air, oxygen, argon and/or
helium, for example. The stabilising agent in the solution may
be carbon dioxide dissolved in the solution, hydrated carbon
dioxide, carbonic acid, and/or other suitable source of carbon
dioxide.
According to a second embodiment of the present invention there
is provided a process of preparing an aqueous metal bicarbonate
solution comprising a stoichiometric concentration of
bicarbonate anions and a corresponding substantially
stoichiometric concentration of metal cations in association
with the bicarbonate anions, which process comprises reacting a
concentration of a metal carbonate or metal carbonate hydroxide
or metal oxide or metal hydroxide with a concentration of
carbonic acid or hydrated carbon dioxide to produce the metal
bicarbonate aqueous solution, wherein said metal bicarbonate
being present in a therapeutically effective amount.
Typically the aqueous metal bicarbonate solution has a neutral
to mildly alkaline pH. Typically the pH is in the range 7 to 9.
Typically the temperature of the aqueous metal bicarbonate
solution is maintained at a level to maintain the metal
bicarbonate in the aqueous diluent.
According to a third embodiment of the present invention there
is provided an aqueous metal bicarbonate solution whenever
prepared by the process of the second embodiment.
According to a fourth embodiment of the present invention there
is provided a method of preventing and treating certain
inflammatory diseases and degenerative diseases in a mammal in
need of such prevention or treatment comprising administering to
said mammal an effective amount of an aqueous metal bicarbonate
solution of the first or third embodiment or a metal
bicarbonate.
Generally the certain inflammatory diseases and degenerative
diseases in a mammal are those that require extracellular or
intracellular acidic conditions or extracellular or
intracellular proton concentrations at some point in disease
process or disease pathogenesis.
Typically the certain inflammatory diseases and degenerative
diseases in a mammal are those that require the activities of
carbonic anhydrase enzymes and/or the activities of acid
(aspartic) protease enzymes and/or the activities of endosomal
or lysosomal acid-requiring-enzymes and/or the activities of
V-type ATPase proton pumps at some point in disease process or
disease pathogenesis.
Typically the certain inflammatory diseases or degenerative
diseases may present as arthritis. Typically the arthritis may
present as osteoarthritis.
According to a fifth embodiment of the present invention there
is provided a method of preventing and treating certain viral
diseases in a mammal in need of such prevention or treatment
comprising administering to said mammal an effective amount of
an aqueous metal bicarbonate solution of the first or third
embodiment or a metal bicarbonate.
Typically the certain viral diseases require intracellular
acidic conditions or intracellular proton concentrations for
either removal of viral protein coats or assembly of viral
protein coats. Typically the viral diseases may present as
influenza.
According to a sixth embodiment of the present invention there
is provided a method of decreasing and treating senescence and
of increasing longevity in a mammal comprising administering to
said mammal an effective amount of an aqueous metal bicarbonate
solution of the first or third embodiment or a metal
bicarbonate.
Typically senescence is decreased and longevity is increased by
maintaining or increasing normal extracellular and/or
intracellular alkaline conditions. Typically senescence is
decreased and longevity is increased by improving the buffering
capacity of the extracellular and intracellular fluids of the
body. Typically longevity is increased by maintaining or
increasing normal mitochondrial alkaline conditions. Typically
longevity is increased by decreasing extracellular and
intracellular acidic conditions or by decreasing extracellular
and intracellular proton concentrations.
Typically senescence is decreased and longevity is increased in
mammals by improving the buffering capacity of the extracellular
and intracellular bicarbonate buffers Typically senescence is
decreased and longevity is increased in mammals by the improved
extracellular and intracellular bicarbonate buffers causing a
decrease in proton concentrations. Typically senescence is
decreased and longevity is increased by preventing or treating
certain inflammatory diseases, degenerative diseases and viral
diseases in mammals. Typically longevity is increased by
decreasing the morbidity and mortality associated with these
diseases.
According to a seventh embodiment of the present invention
there is provided a method of scavenging protons in a mammal
comprising administering to said mammal an effective amount of a
proton scavenger.
Typically the proton scavenger comprises a metal bicarbonate.
Typically the metal bicarbonate is in the form of the aqueous
metal bicarbonate solution of the first or third embodiment.
According to an eighth embodiment of the present invention
there is provided a method of decreasing proton concentrations
in a mammal by altering carbonic anhydrase enzyme reactions in
said mammal comprising administering to said mammal an effective
amount of an aqueous metal bicarbonate solution of the first or
third embodiment or a metal bicarbonate.
According to a ninth embodiment of the present invention there
is provided a method of decreasing inflammation and inflammatory
conditions in a mammal comprising administering to said mammal
an effective amount of an aqueous metal bicarbonate solution of
the first or third embodiment or a metal bicarbonate.
Generally inflammation and inflammatory conditions are
decreased by decreasing the extracellular and intracellular
acidic conditions that are required for inflammatory processes.
Generally inflammation and inflammatory conditions are decreased
by decreasing the extracellular and intracellular proton
concentrations that are required for inflammatory processes.
Typically inflammation is decreased by altering carbonic
anhydrase enzyme reactions and/or decreasing the activities of
acid (aspartic) protease enzymes and/or decreasing the
activities of endosomal or lysosomal acid-requiring-enzymes
and/or decreasing the activities of V-type ATPase proton pumps.
According to a tenth embodiment of the present invention there
is provided a method of increasing motor activity in a mammal
comprising administering to said mammal an effective amount of
an aqueous metal bicarbonate solution of the first or third
embodiment or a metal bicarbonate.
Typically motor activity is increased by decreasing
extracellular and intracellular acidic conditions or by
decreasing extracellular and intracellular proton
concentrations. Typically motor activity is increased by
improving the buffering capacity of extracellular and
intracellular fluids. Typically motor activity is increased by
improving the buffering capacity of the extracellular and
intracellular bicarbonate buffers. Typically motor activity is
increased by increasing extracellular and intracellular alkaline
conditions. Typically motor activity is increased by scavenging
protons produced by ATP hydrolysis, lactic acid production,
lipid metabolism and other metabolic processes.
According to an eleventh embodiment of the present invention
there is provided an aqueous neutral to mildly alkaline metal
bicarbonate solution, comprising metal bicarbonate dissolved in
the solution, said metal bicarbonate comprising bicarbonate
anions and metal cations, and a pH adjusting agent in the
solution in an amount whereby the solution is at a neutral to
mildly alkaline pH.
Typically a corresponding substantially stoichiometric
concentration of metal cations are in association with the
bicarbonate anions. Typically the solution is acceptable for
oral administration.
In one embodiment there is provided a combination comprising a
substantially stable aqueous neutral to mildly alkaline metal
bicarbonate solution, comprising metal bicarbonate dissolved in
the solution, said metal bicarbonate comprising bicarbonate
anions and metal cations, and a pH adjusting agent in the
solution in an amount whereby the solution is at a neutral to
mildly alkaline pH, in combination with a stabilising agent in
an amount effective to maintain and stabilise the bicarbonate
anions in the neutral to mildly alkaline solution. In another
embodiment there is provided a combination comprising a
substantially stable aqueous neutral to mildly alkaline metal
bicarbonate solution, comprising metal bicarbonate dissolved in
the solution, said metal bicarbonate comprising bicarbonate
anions and metal cations, in combination with a stabilising
agent in an amount effective to maintain and stabilise the
bicarbonate anions in the solution whereby the solution is at a
neutral to mildly alkaline pH.
The pH adjusting agent and the stabilising agent may be the
same or different. Generally the combination is kept in a sealed
or closed container at 0.8 to 5 atmospheres, more typically 1
atmosphere at 0-25° C., more typically 0.1-10° C.
In one particular embodiment the stabilising agent may be
present in the solution in an amount effective to maintain and
stabilise the bicarbonate anions in the neutral to mildly
alkaline solution. In another particular embodiment the
stabilising agent may consist of or comprise a gas above the
solution in an amount effective to maintain and stabilise the
bicarbonate anions in the neutral to mildly alkaline solution.
In a further particular embodiment the stabilising agent may be
present in the solution and may consist of or comprise a gas
above the solution, the total amount of stabilising agent in the
solution and in the gas above the solution being in an amount
effective to maintain and stabilise the bicarbonate anions in
the neutral to mildly alkaline solution. The stabilising agent
which consists of a gas above the solution may be carbon
dioxide. The stabilising agent which comprises a gas above the
solution may be carbon dioxide in an an inert gas such as
nitrogen, air, oxygen, argon and/or helium, for example. The
stabilising agent in the solution may be carbon dioxide
dissolved in the solution, hydrated carbon dioxide, carbonic
acid, and/or other suitable source of carbon dioxide.
According to a twelfth embodiment of the present invention
there is provided a solution for preventing and/or treating
certain inflammatory diseases and/or degenerative diseases
and/or certain viral diseases in a mammal, comprising the
aqueous neutral to mildly alkaline metal bicarbonate solution of
the eleventh embodiment whereby the metal bicarbonate is present
in an amount effective to prevent and/or treat said diseases.
According to a thirteenth embodiment of the present invention
there is provided a solution for decreasing and/or treating
senescence and/or increasing longevity in a mammal, comprising
the aqueous neutral to mildly alkaline metal bicarbonate
solution of the eleventh embodiment whereby the metal
bicarbonate is present in an amount effective to decrease and/or
treat senescence and/or increase longevity.
According to a fourteenth embodiment of the present invention
there is provided a solution for scavenging protons in a mammal,
comprising the aqueous neutral to mildly alkaline metal
bicarbonate solution of the eleventh embodiment whereby the
metal bicarbonate is present in an amount effective to scavenge
protons.
According to a fifteenth embodiment of the present invention
there is provided a solution for decreasing proton
concentrations in a mammal, comprising the aqueous neutral to
mildly alkaline metal bicarbonate solution of the eleventh
embodiment whereby the metal bicarbonate is present in an amount
effective to decrease proton concentrations.
According to a sixteenth embodiment of the present invention
there is provided a solution for decreasing inflammation and
inflammatory conditions in a mammal, comprising the aqueous
neutral to mildly alkaline metal bicarbonate solution of the
eleventh embodiment whereby the metal bicarbonate is present in
an amount effective to decrease inflammation and/or inflammatory
conditions.
According to a seventeenth embodiment of the present invention
there is provided a solution for increasing motor activity
and/or decrease fatigue in a mammal, comprising the aqueous
neutral to mildly alkaline metal bicarbonate solution of the
eleventh embodiment whereby the metal bicarbonate is present in
an amount effective to increase motor activity.
According to an eighteenth embodiment of the present invention
there is provided a process of preparing an aqueous neutral to
mildly alkaline metal bicarbonate solution comprising
bicarbonate anions and metal cations, which process comprises
reacting a compound selected from the group consisting of metal
carbonate, metal carbonate hydroxide, metal oxide, metal
hydroxide and any mixture thereof with an effective
concentration of a pH adjusting agent to produce the aqueous
neutral to mildly alkaline metal bicarbonate solution, wherein
the pH adjusting agent is present in an amount whereby the
solution is at a neutral to mildly alkaline pH.
Typically a corresponding substantially stoichiometric
concentration of metal cations are in association with the
bicarbonate anions. Generally the solution is stored in a sealed
or closed container at 0.8 to 5 atmospheres, more typically 1
atmosphere at 0-25° C., more typically 0.1-10° C. In one
embodiment the process further comprises combining the solution
with a stabilising agent in an amount effective to maintain and
stabilise the bicarbonate anions in the neutral to mildly
alkaline solution. In one particular embodiment the process
comprises conducting the process under gaseous atmosphere
comprising a stabilising agent in an amount effective to
maintain and stabilise the bicarbonate anions in the neutral to
mildly alkaline solution. The stabilising agent may be carbon
dioxide or comprise carbon dioxide in an inert gas such as
nitrogen, air, oxygen, argon and/or helium, for example.
Generally the combination is stored in a sealed or closed
container at 0.8 to 5 atmospheres, more typically 1 atmosphere
at 0-25° C., more typically 0.1-10° C. One particular embodiment
may comprise adding the stabilising agent to the solution in the
solution in an amount effective to maintain and stabilise the
bicarbonate anions in the neutral to mildly alkaline solution.
Another particular embodiment may comprise blanketing the
solution with a gas consisting of or comprising the stabilising
agent in an amount effective to maintain and stabilise the
bicarbonate anions in the neutral to mildly alkaline solution. A
further particular embodiment may comprise adding the
stabilising agent to the solution in the solution and blanketing
the solution with a gas consisting of or comprising the
stabilising agent, the total amount of stabilising agent in the
solution and in the gas above the solution being in an amount
effective to maintain and stabilise the bicarbonate anions in
the neutral to mildly alkaline solution. The stabilising agent
which consists of a gas above the solution may be carbon
dioxide. The stabilising agent which comprises a gas above the
solution may be carbon dioxide in an inert gas such as nitrogen,
air, oxygen, argon and/or helium, for example. The stabilising
agent in the solution may be carbon dioxide dissolved in the
solution, hydrated carbon dioxide, carbonic acid, and/or other
suitable source of carbon dioxide.
According to a nineteenth embodiment of the present invention
there is provided a aqueous neutral to mildly alkaline metal
bicarbonate solution whenever prepared by the process of the
eighteenth embodiment.
According to a twentieth embodiment of the present invention
there is provided a method of preventing and/or treating certain
inflammatory diseases and/or degenerative diseases in a mammal
in need of such prevention and/or treatment comprising
administering to said mammal an effective amount of an aqueous
neutral to mildly alkaline metal bicarbonate solution of the
eleventh or a metal bicarbonate.
Generally the certain inflammatory diseases and degenerative
diseases in a mammal are those that require extracellular or
intracellular acidic conditions or extracellular or
intracellular proton concentrations at some point in disease
process or disease pathogenesis.
Typically the certain inflammatory diseases and degenerative
diseases in a mammal are those that require the activities of
carbonic anhydrase enzymes and/or the activities of acid
(aspartic) protease enzymes and/or the activities of endosomal
or lysosomal acid-requiring-enzymes and/or the activities of
V-type ATPase proton pumps at some point in disease process or
disease pathogenesis.
Typically the certain inflammatory diseases or degenerative
diseases may present as arthritis. Typically the arthritis may
present as osteoarthritis.
According to a twenty-first embodiment of the present invention
there is provided a method of preventing and/or treating certain
viral diseases in a mammal in need of such prevention and/or
treatment comprising administering to said mammal an effective
amount of an aqueous neutral to mildly alkaline metal
bicarbonate solution of the eleventh embodiment or a metal
bicarbonate.
Typically the certain viral diseases require intracellular
acidic conditions or intracellular proton concentrations for
either removal of viral protein coats or assembly of viral
protein coats. Typically the viral diseases may present as
influenza.
According to a twenty-second embodiment of the present
invention there is provided a method of decreasing and/or
treating senescence and/or of increasing longevity in a mammal
comprising administering to said mammal an effective amount of
an aqueous neutral to mildly alkaline metal bicarbonate solution
of the eleventh embodiment or a metal bicarbonate.
Typically senescence is decreased and longevity is increased by
maintaining or increasing normal extracellular and/or
intracellular alkaline conditions. Typically senescence is
decreased and longevity is increased by improving the buffering
capacity of the extracellular and intracellular fluids of the
body. Typically longevity is increased by maintaining or
increasing normal mitochondrial alkaline conditions. Typically
longevity is increased by decreasing extracellular and
intracellular acidic conditions or by decreasing extracellular
and intracellular proton concentrations. Typically senescence is
decreased and longevity is increased in mammals by improving the
buffering capacity of the extracellular and intracellular
bicarbonate buffers. Typically senescence is decreased and
longevity is increased in mammals by the improved extracellular
and intracellular bicarbonate buffers causing a decrease in
proton concentrations.
Typically senescence is decreased and longevity is increased by
preventing or treating certain inflammatory diseases,
degenerative diseases and viral diseases in mammals. Typically
longevity is increased by decreasing the morbidity and mortality
associated with these diseases.
According to a twenty-third embodiment of the present invention
there is provided a method of scavenging protons in a mammal
comprising administering to said mammal an effective amount of a
proton scavenger.
Typically the proton scavenger comprises a metal bicarbonate.
Typically the metal bicarbonate is in the form of the aqueous
neutral to mildly alkaline metal bicarbonate solution of the
eleventh embodiment.
According to a twenty-fourth embodiment of the present
invention there is provided a method of decreasing proton
concentrations in a mammal by altering carbonic anhydrase enzyme
reactions in said mammal comprising administering to said mammal
an effective amount of an aqueous neutral to mildly alkaline
metal bicarbonate solution of the eleventh embodiment or a metal
bicarbonate.
According to a twenty-fifth embodiment of the present invention
there is provided a method of decreasing inflammation and/or
inflammatory conditions in a mammal comprising administering to
said mammal an effective amount of an aqueous neutral to mildly
alkaline metal bicarbonate solution of the eleventh embodiment
or a metal bicarbonate.
Generally inflammation and inflammatory conditions are
decreased by decreasing the extracellular and intracellular
acidic conditions that are required for inflammatory processes.
Generally inflammation and inflammatory conditions are decreased
by decreasing the extracellular and intracellular proton
concentrations that are required for inflammatory processes.
Typically inflammation is decreased by altering carbonic
anhydrase enzyme reactions and/or decreasing the activities of
acid (aspartic) protease enzymes and/or decreasing the
activities of endosomal or lysosomal acid-requiring-enzymes
and/or decreasing the activities of V-type ATPase proton pumps.
According to a twenty-sixth embodiment of the present invention
there is provided a method of increasing motor activity and/or
decreasing fatigue in a mammal comprising administering to said
mammal an effective amount of an aqueous neutral to mildly
alkaline metal bicarbonate solution of the eleventh embodiment
or a metal bicarbonate.
The methods of the invention typically involve orally
administering to the mammal, the mammal being typically human.
Further the methods of the invention typically involve orally
administering to a mammal in need of treatment for the specified
condition of the particular embodiment, the mammal being
typically human. Typically motor activity is increased by
decreasing extracellular and intracellular acidic conditions or
by decreasing extracellular and intracellular proton
concentrations. Typically motor activity is increased by
improving the buffering capacity of extracellular and
intracellular fluids. Typically motor activity is increased by
improving the buffering capacity of the extracellular and
intracellular bicarbonate buffers. Typically motor activity is
increased by increasing extracellular and intracellular alkaline
conditions. Typically motor activity is increased by scavenging
protons produced by ATP hydrolysis, lactic acid production,
lipid metabolism and other metabolic processes.
The term mammal as used herein includes vertebrate. Examples of
mammals and vertebrates to which the methods of the invention
apply include a bovine, human (male or female), ovine, equine,
caprine, Leporine, feline or canine mammal or vertebrate.
Specific examples of animals include sheep, cattle, horses,
rabbits, cats, goats, alpacas, cats, dogs, pigs, rabbits, fowls,
deer, buffaloes and other livestock and domestic animals.
Metal Bicarbonate Generally
Generally the pH of the aqueous metal bicarbonate solution is
neutral to mildly alkaline, typically mildly alkaline and more
typically in the range of 7 to 9 even more typically 8 to 8.6
and the temperature of the aqueous neutral to mildly alkaline
metal bicarbonate solution is maintained at such a level so as
to maintain the metal bicarbonate in the aqueous diluent. The
aqueous neutral to mildly alkaline metal bicarbonate solution
may be kept under an atmosphere comprising carbon dioxide of
from about 0.8 to 5 or 1 to 5 atmospheres, more typically 1 to 3
atmospheres and even more typically slightly above atmospheric
pressure such as the sorts of pressures that soft drinks are
currently under in cans or bottles, for example, so as to
maintain the metal bicarbonate in the aqueous diluent.
Generally the metal cation is an alkaline earth metal cation or
an alkali metal cation. Generally a metal cation is chosen which
is capable of acting as a bicarbonate transporter into mammalian
cells. More particularly the metal cation may be cations of
magnesium, sodium, potassium, calcium, lithium or any mixture
thereof. Where a mixture of alkaline earth metal cations or
alkali metal cations are used: (1) two different alkaline earth
metal cations or alkali metal cations or mixtures thereof, the
molar ratio of the first metal cation to the second may be in
the range 0.5:99.5 to 99.5:0.5, typically 75:25 to 25:75, more
typically 0.7:1 to 1:0.7; (2) three different alkaline earth
metal cations or alkali metal cations or mixtures thereof, the
molar ratio of the first metal cation to the second to the third
may be in the range 99.5:0.5:0.5 to 0.5:99.5:99.5, typically
75:25:25 to 25:75:75, more typically 0.5:1:1 to 1:0.5:0.5; (3)
four different alkaline earth metal cations or alkali metal
cations or mixtures thereof, the molar ratio of the first metal
cation to the second to the third to the fourth may be in the
range 99.5:0.5:0.5:0.5 to 0.5:99.5:99.5:99.5, typically
75:25:25:25 to 25:75:75:75, more typically 0.5:1:1:1 to
0.5:1:1:1. Generally the metal cation is magnesium or a mixture
of magnesium and sodium metal cations. Typically the aqueous
neutral to mildly alkaline metal bicarbonate solution has a high
metal cation concentration in association with bicarbonate
anions.
Typically the metal bicarbonate is used at a concentration of
10-100 mole % or weight % of its saturation solubility (which
will depend on the actual metal bicarbonate(s) used), more
typically 10-90%, 10-80%, 10-70%, 10-60%, 10-50%, 10-40%,
10-30%, 10-20%, more typically 15-95%, 15-85%, 15-75%, 15-65%,
15-55%, 15-45%, 15-35%, 15-25%, more typically 15-90%, 15-80%,
15-70%, 15-60%, 15-50%, 15-40%, 15-30%, 15-20%, more typically
10-95%, 10-85%, 10-75%, 10-65%, 10-55%, 10-45%, 10-35%, 10-25%,
more typically 20-90%, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%,
20-30%, more typically 25-95%, 25-85%, 25-75%, 25-65%, 25-55%,
25-45%, 25-35%, more typically 25-90%, 25-80%, 25-70%, 25-60%,
25-50%, 25-40%, 25-30%, more typically 20-95%, 20-85%, 20-75%,
20-65%, 20-55%, 20-45%, 20-35%, more typically 30-90%, 30-80%,
30-70%, 30-60%, 30-50%, 30-40%, more typically 35-95%, 35-85%,
35-75%, 35-65%, 35-55%, 35-45%, more typically 35-90%, 35-80%,
35-70%, 35-60%, 35-50%, 35-40%, more typically 30-95%, 30-85%,
30-75%, 30-65%, 30-55%, 30-45%, more typically 40-90%, 40-80%,
40-70%, 40-60%, 40-50%, more typically 45-95%, 45-85%, 45-75%,
45-65%, 45-55%, more typically 45-90%, 45-80%, 45-70%, 45-60%,
45-50%, more typically 40 -95%, 40-85%, 40-75%, 40-65%, 40-55%,
more typically 50-90%, 50-80%, 50-70%, 50 -60%, more typically
55-95%, 55-85%, 55-75%, 55-65%, more typically 55-90%, 55-80%,
55-70%, 55-60%, more typically 50-95%, 50-85%, 50-75%, 50-65%,
more typically 60-90%, 60-80%, 60-70%, more typically 65-95%,
65-85%, 65-75%, more typically 65-90%, 65-80%, 65-70%, more
typically 60-95%, 60-85%, 60-75%, more typically 70-90%, 70-80%,
more typically 75-95%, 75-85%, more typically 75-90%, 75-80%,
more typically 70-95%, 70-85%, more typically 80-90%, more
typically 85-95%, more typically 85-90%, more typically 80-95%,
more typically 20-100%, 30-100%, 40 -100%, 50-100%, 60-100%,
70-100%, 80-100% or 90-100%. Depending on the solubility of the
metal bicarbonate, the amount of metal cation may range from 20
mg to 1250 mg or 25 mg to 1250 mg per litre of aqueous neutral
to mildly alkaline metal bicarbonate solution, typically 20 mg
to 1000 mg or 50 mg to 1000 mg per litre of aqueous neutral to
mildly alkaline metal bicarbonate solution, more typically 20 mg
to 750 mg or 50 mg to 750 mg or 20 mg to 600 mg or 50 mg to 60
mg per litre of aqueous neutral to mildly alkaline metal
bicarbonate solution, even more typically 20 mg to 500 mg or 30
mg to 500 mg or 50 mg to 500 mg per litre of aqueous neutral to
mildly alkaline metal bicarbonate solution, even more typically
20 mg to 250 mg or 50 mg to 250 mg per litre of aqueous neutral
to mildly alkaline metal bicarbonate solution, most typically
100 mg to 500 mg or 100 mg to 400 mg or 100 mg to 300 mg or 100
mg to 250 mg per litre of aqueous neutral to mildly alkaline
metal bicarbonate solution, even most typically 20 mg to 200 mg
or 20 to 150 mg or 20 mg to 120 mg or 120 mg to 300 mg or 120 mg
to 200 mg. Typically when the metal cation is magnesium, the
amount of magnesium may range from 30 mg to 140 mg per litre of
aqueous neutral to mildly alkaline metal bicarbonate solution,
typically 30 mg to 130 mg, 30 mg to 120 mg, 30 mg to 110 mg, 30
mg to 100 mg, 30 mg to 90 mg, 30 mg to 80 mg, 30 mg to 70 mg, 30
mg to 60 mg, 30 mg to 50 mg, 30 mg to 40 mg, 50 mg to 120 mg, 60
mg to 120 mg, 70 mg to 120 mg, 80mg to 120 mg, 90 mg to 120 mg
or 75 mg to 120 mg or 100 mg to 120mg per litre of aqueous
neutral to mildly alkaline metal bicarbonate solution. Typically
when the metal cation is sodium and/or potassium, the amount of
sodium and/or potassium may range from greater than 30 mg to
1250 mg per litre of aqueous neutral to mildly alkaline metal
bicarbonate solution, typically 50 mg to 1000 mg or 50 mg to 750
mg or 50 mg to 500 mg or 75 mg to 1250 mg or 75 mg to 1000 mg or
75 mg to 500 mg or 100 mg to 1000 mg or 100 mg to 500 mg or 250
mg to 1000 mg or 250 mg to 500 mg per litre of aqueous neutral
to mildly alkaline metal bicarbonate solution. Typically when
the metal cation is calcium, the amount of calcium may range
from greater than 20 mg to 1250 mg per litre of aqueous neutral
to mildly alkaline metal bicarbonate solution, typically 20 mg
to 1000 mg or 20 mg to 750 mg or 20 mg to 500 mg or 20 mg to 250
mg or 20 mg to 200 mg or 20 mg to 150 mg or 20 mg to 100 mg per
litre of aqueous neutral to mildly alkaline metal bicarbonate
solution. Typically the amount of bicarbonate anion present will
be stoichiometric with the amount of metal cation in solution so
as to form the metal bicarbonate. Alternatively, the
concentration of the metal bicarbonate can be based on the
bicarbonate anion concentrations in which case the amount of
bicarbonate anion (which will depend on the saturation
solubility of the actual metal bicarbonate anion(s) used). The
concentration of bicarbonate typically ranges from 120 mg or 150
mg to 3500 mg per litre of aqueous neutral to mildly alkaline
metal bicarbonate solution, typically 120 mg or 150 mg to 3000
mg or 200 mg to 3000 mg per litre of aqueous neutral to mildly
alkaline metal bicarbonate solution, more typically 250 mg to
2100 mg or 300 mg to 2000 mg or 200 mg to 1500 mg or 300 mg to
1500 mg or 400 mg to 1500 mg or 500 mg to 1500 mg or 600 mg to
1500 mg or 700 mg to 1500 mg or 800 mg to 1500 mg or 900 mg to
1500 mg or 1000 mg to 1500 mg or 200 mg to 1000 mg or 300 mg to
1000 mg or 400 mg to 1000 mg or 500 mg to 1000 mg or 600 mg to
1000 mg or 700 mg to 1000 mg or 800 mg to 1000 mg or 900 mg to
1000 mg or 1000 mg to 1500 mg or 1200 mg to 1500 mg per litre of
aqueous neutral to mildly alkaline metal bicarbonate solution,
even more typically 600 mg to 1000 mg or 500 mg to 1500 mg per
litre of aqueous neutral to mildly alkaline metal bicarbonate
solution, most typically 950 mg or 200 mg to 2000 mg or 200 mg
to 1750 mg or 200 mg to 1250 mg or 200 mg to 100 mg per litre of
aqueous neutral to mildly alkaline metal bicarbonate solution.
Typically at least 600 mg of bicarbonate anions per litre of
solution is present, more typically 600-1800 mg/l, 600-1500
mg/l, 600-1350 mg/l, 600-1200 mg,/l 600-1100 mg/l, 600-1000
mg/l, 600-950 mg/l, 600-900 mg/l, 600-850 mg/l, 600-800mg/l,
600-750 mg/l, 600-700 mg/l or 600-650 mg/l. Typically a mildly
alkaline saturated magnesium bicarbonate solution is used or a
mildly alkaline solution comprising a mixture of sodium and/or
potassium and magnesium bicarbonate, more typically sodium and
magnesium bicarbonate. Typically the range for a mixture of
sodium and/or potassium and magnesium bicarbonate, more
typically sodium and magnesium bicarbonate varies from 20 mg to
1250 mg or 25 mg to 1250 mg per litre of aqueous neutral to
mildly alkaline metal bicarbonate solution, typically 20 mg to
1000 mg or 50 mg to 1000 mg per litre of aqueous neutral to
mildly alkaline metal bicarbonate solution, more typically 20 mg
to 750 mg or 50 mg to 750 mg or 20 mg to 600 mg or 50 mg to 600
mg per litre of aqueous neutral to mildly alkaline metal
bicarbonate solution, even more typically 20 mg to 500 mg or 30
mg to 500 mg or 50 mg to 500 mg per litre of aqueous neutral to
mildly alkaline metal bicarbonate solution, even more typically
20 mg to 250 mg or 50 mg to 250 mg or even more typically 20 mg
to 300 mg or 50 mg to 300 mg per litre of aqueous neutral to
mildly alkaline metal bicarbonate solution, most typically 75 mg
to 1000 mg or 75 mg to 500 mg or 100 mg to 1000 mg or 100 mg to
500 mg or 100 mg to 400 mg or 100 mg to 300 mg or 100 mg to 250
mg per litre of aqueous neutral to mildly alkaline metal
bicarbonate solution, even most typically 20 mg to 200 mg or 20
to 150 mg or 20 mg to 120 mg or 120 mg to 300 mg or 120 mg to
200 mg. Usually the ratio (weight to weight) of magnesium to
sodium is in the range 25:1 to 1:4, typically 1:1.125.
Generally the aqueous diluent is water or comprises water.
Generally the carbon dioxide-containing-aqueous diluent may be
carbonic acid in water, hydrated carbon dioxide in water, carbon
dioxide gas dissolved in water, carbonated soft drinks,
carbonated mineral water, soda water or other carbon
dioxide-containing-aqueous diluents. If carbon dioxide gas is
used, the carbon dioxide may be either bubbled into aqueous
solutions containing metal carbonate or metal carbonate
hydroxide or metal oxide or mixture thereof or the carbon
dioxide may be introduced in the form of a blanket over aqueous
solutions containing metal carbonate or metal carbonate
hydroxide or metal oxide or mixture thereof. Typically the
carbon dioxide-containing-aqueous diluent is pharmaceutically
acceptable. Typically carbonated mineral water, carbonic acid,
hydrated carbon dioxide in water or carbonated water is used.
The amounts of carbon dioxide-containing-aqueous diluent and
metal carbonate or metal carbonate hydroxide or metal oxide or
mixture thereof used are sufficient to obtain a clear solution
at a neutral to mildly alkaline pH, typically pH 7 to 9 or pH 7
to 8.6, more typically pH 7.5 to 8.8 or pH 7.5 to 8.5 or pH 7.8
to 8.6, pH 7.8 to 8.5, pH 7.8 to 8.4, pH 7.8 to 8.3, pH 7.8 to
8.2, pH 7.8 to 8.1, pH 7.8 to 8.0, pH 7.8 to 7.9, pH 7.9 to 8.6,
pH 7.9 to 8.5, pH 7.9 to 8.4, pH 7.9 to 8.3, pH 7.9 to 8.2, pH
7.9 to 8.1, pH 7.9 to 8.0, pH 8.0 to 8.6, pH 8.0 to 8.5, pH 8.0
to 8.4, pH 8.0 to 8.3, pH 8.0 to 8.2, pH 8.0 to 8.1, pH 8.1 to
8.6, pH 8.1 to 8.5, pH 8.1 to 8.4, pH 8.1 to 8.3, pH 8.1 to 8.2,
pH 8.2 to 8.6, pH 8.2 to 8.5, pH 8.2 to 8.4, pH 8.2 to 8.3, pH
8.3 to 8.6, pH 8.3 to 8.5, pH 8.3 to 8.4, pH 8.4 to 8.6, pH 8.4
to 8.5, pH 8.5 to 8.6, even more typically pH 8 to 8.5 or pH 8.2
to 8.6, most typically pH 8.3. Usually 10 to 60 mL, typically 25
to 55 mL, more typically 40 to 50 mL, most typically
approximately 45 mL of chilled carbonated mineral water per
litre of water is used. Usually the chilled carbonated mineral
water is at a temperature of 0 to 25° C., 0 to 20° C. 0.5 to 25°
C., 0.5 to 20° C., 0.5 to 15° C., 0.5 to 10° C., 0.5 to 9° C.,
0.5 to 8° C., 0.5 to 7° C., 1 to 20° C., 1 to 15° C., 1 to 10°
C., 1.5 to 20° C., 1.5 to 15° C., 1.5 to 10° C., 2 to 20° C., 2
to 15° C., 2 to 10° C., 3 to 20° C., 3 to 15° C., 4 to 20° C., 4
to 15° C., 4 to 10° C., 5 to 10° C., 5 to 15° C., 6 to 20° C., 6
to 15° C., 6 to 10° C., 7 to 20° C., 7 to 15° C., 7 to 10° C., 8
to 20° C., 8 to 15° C., 8 to 10° C., 9 to 20° C., 9 to 15° C., 9
to 10° C., 10 to 15° C., typically 0 to 15° C., more typically 0
to 10° C., even more typically 3° C. to 10° C., most typically
5° C. to 10° C. and even most typically 5° C. Alternatively the
metal carbonate or metal carbonate hydroxide or metal oxide or
mixture thereof can be added after the carbon dioxide has been
added.
Generally the metal bicarbonate in aqueous solution may be
derived from a metal carbonate or metal carbonate hydroxide or
metal oxide or metal bicarbonate or metal hydroxide or other
appropriate metal compound or any mixture thereof. Examples
include magnesium, sodium, potassium, calcium, lithium carbonate
or carbonate hydroxide or oxide or bicarbonate or a mixture of
any two or more thereof. For example magnesium carbonate
hydroxide pentahydrate, the calcite series or dolomite series of
minerals (Mg, Ca)CO3 or limestone or dolomite rocks
is used. Generally magnesium carbonate hydroxide pentahydrate or
a mixture of magnesium carbonate hydroxide pentahydrate and
sodium bicarbonate is used.
Generally the pH of the aqueous metal bicarbonate solution for
oral administration is neutral to mildly alkaline, typically in
the range pH 7 to 9 or pH 7 to 8.6, more typically pH 7.5 to 8.8
or pH 7.5 to 8.5 or pH 7.8 to 8.6, pH 7.8 to 8.5, pH 7.8 to 8.4,
pH 7.8 to 8.3, pH 7.8 to 8.2, pH 7.8 to 8.1, pH 7.8 to 8.0, pH
7.8 to 7.9, pH 7.9 to 8.6, pH 7.9 to 8.5, pH 7.9 to 8.4, pH 7.9
to 8.3, pH 7.9 to 8.2, pH 7.9 to 8.1, pH 7.9 to 8.0, pH 8.0 to
8.6, pH 8.0 to 8.5, pH 8.0 to 8.4, pH 8.0 to 8.3, pH 8.0 to 8.2,
pH 8.0 to 8.1, pH 8.1 to 8.6, pH 8.1 to 8.5, pH 8.1 to 8.4, pH
8.1 to 8.3, pH 8.1 to 8.2, pH 8.2 to 8.6, pH 8.2 to 8.5, pH 8.2
to 8.4, pH 8.2 to 8.3, pH 8.3 to 8.6, pH 8.3 to 8.5, pH 8.3 to
8.4, pH 8.4 to 8.6, pH 8.4 to 8.5, pH 8.5 to 8.6, even more
typically pH 8 to 8.5 or pH 8.2 to 8.6, most typically pH 8.3.
Generally the pH of the aqueous metal bicarbonate solution for
parenteral administration is neutral to very mildly alkaline,
typically in the range pH 7 to 7.6, or pH 7.0 to 7.5, or pH 7.1
to 7.5, more typically pH 7.2 to 7.5 or pH 7.3 to 7.5 or pH 7.4
to 7.5. Generally the aqueous neutral to mildly alkaline metal
bicarbonate solution is prepared and stored at a temperature
ranging from 0 to 25° C., 0 to 20° C. 0.5 to 25° C., 0.5 to 20°
C., 0.5 to 15° C., 0.5 to 10° C., 0.5 to 9° C., 0.5 to 8° C.,
0.5 to 7° C., 1 to 20° C., 1 to 15° C., 1 to 10° C., 1.5 to 20°
C., 1.5 to 15° C., 1.5 to 10° C., 2 to 20° C., 2 to 15° C., 2 to
10° C., 3 to 20° C., 3 to 15° C., 4 to 20° C., 4 to 15° C., 4 to
10° C., 5 to 10° C., 5 to 15° C., 6 to 20° C., 6 to 15° C., 6 to
10° C., 7 to 20° C., 7 to 15° C., 7 to 10° C., 8 to 20° C., 8 to
15° C., 8 to 10° C., 9 to 20° C., 9 to 15° C., 9 to 10° C., 10
to 15° C., typically 0 to 15° C., more typically 0 to 10° C.,
even more typically 3° C. to 10° C., most typically 5° C. to 10°
C. and even most typically 5° C.
Generally the pH adjusting agent is carbon dioxide gas,
carbonic acid in water, hydrated carbon dioxide in water, carbon
dioxide gas in water, carbonated soft drinks, carbonated mineral
water, soda water or other carbon dioxide-containing-aqueous
diluents or an alkali or any mixture thereof. Examples of
alkalis are water soluble drinkable alkalis such as sodium
hydroxide, sodium carbonate, potassium carbonate or potassium
hydroxide or any mixture thereof.
Typically additives may be added during the process of the
invention or to the aqueous neutral to mildly alkaline metal
bicarbonate solution. The additives may be 0 mg or 0.5 mg to
1000 mg sodium bicarbonate per litre of aqueous neutral to
mildly alkaline metal bicarbonate solution, typically 25 mg to
900 mg per litre of aqueous neutral to mildly alkaline metal
bicarbonate solution, typically 50 mg to 800 mg or 50 mg to 500
mg per litre of aqueous neutral to mildly alkaline metal
bicarbonate solution, more typically 100 mg to 700 mg per litre
of aqueous neutral to mildly alkaline metal bicarbonate
solution, even more typically 200 mg to 600 mg per litre of
aqueous neutral to mildly alkaline metal bicarbonate solution,
most typically 300 mg to 500 mg per litre of aqueous neutral to
mildly alkaline metal bicarbonate solution, even most typically
500 mg per litre of aqueous neutral to mildly alkaline metal
bicarbonate solution. The additives may also be chlorides and
other appropriate salts of magnesium, sodium, potassium, calcium
and lithium, such as carbonates or hydroxides or sulfates, with
or without the addition of sodium bicarbonate. For example,
magnesium sulfate, magnesium chloride or other soluble salts of
magnesium. Further additives may include potassium bicarbonate,
calcium bicarbonate or lithium bicarbonate. Generally calcium
bicarbonate is prepared by adding carbonic acid or carbonated
water or hydrated carbon dioxide or carbon dioxide gas to a
mixture of calcium carbonate in water. Generally lithium
bicarbonate is prepared by adding carbonic acid and/or
carbonated water and/or hydrated carbon dioxide and/or carbon
dioxide gas and/or solid carbon dioxide to a mixture of lithium
carbonate in water.
The aqueous neutral to mildly alkaline metal bicarbonate
solution may further include a stabilising agent. The
stabilising agent may also be a pH adjusting agent. Typically
the stabilising agent is a gaseous phase, for example carbon
dioxide gas, which maintains and/or stabilises the solution at a
pH of 7 to 9 and at a temperature of 0 to 55° C. more typically
0 to 25° C.
Generally once the solution is prepared, the solution may be
stored under a blanket of carbon dioxide gas or a mixture of
carbon dioxide gas and a nondeleterious inert gas, for example,
argon, helium, air, oxygen and/or nitrogen wherein the amount of
carbon dioxide present in the inert gas is sufficient to
maintain the solution at a pH of 7 to 9 and at a temperature of
0 to 25° C. and to prevent the metal bicarbonate from forming
insoluble compounds which can precipitate out of solution.
Typically the carbon dioxide gas above the solution prevents
loss of carbon dioxide from the solution. The amount of carbon
dioxide in the gaseous mixture provides partial pressure on the
liquid which is substantially equal to the partial pressure
which is produced from equilibrium of bicarbonate in the
solution at the mixing temperature.
Magnesium Bicarbonate Particularly
Typically the production of magnesium bicarbonate utilises the
dissolution of magnesium carbonate by carbonic acid or hydrated
carbon dioxide solutions. Ideally, the dissolution is produced
within a defined range of conditions --- a defined range of pH
values, a defined range of temperature values and a defined
minimum time. For optimal biological and medical activities, and
for therapeutic safety, the concentrations of the component ions
are defined also.
Typically to prepare the aqueous neutral to mildly alkaline
metal bicarbonate solution, crushed or powdered metal carbonate,
or metal carbonate hydroxide or metal oxide, such as magnesium
carbonate MgCO3, or commercial magnesium carbonate
hydroxide pentahydrate (MgCO3)4.Mg(OH)2.5H2O,
or
other commercial magnesium carbonate hydroxides, or hydrated
magnesium oxides, or magnesium oxides heated with carbon
dioxide, or the calcite series or dolomite series of minerals
(Mg, Ca)CO3, or limestone or dolomite rocks is mixed
with water. A cloudy suspension is obtained. Sufficient carbonic
acid and/or hydrated carbon dioxide and/or carbon dioxide gas
and/or solid carbon dioxide is added to obtain a solution having
a pH 7 to 9 or pH 7 to 8.6, more typically pH 7.5 to 8.8 or pH
7.5 to 8.5 or pH 7.8 to 8.6, pH 7.8 to 8.5, pH 7.8 to 8.4, pH
7.8 to 8.3, pH 7.8 to 8.2, pH 7.8 to 8.1, pH 7.8 to 8.0, pH 7.8
to 7.9, pH 7.9 to 8.6, pH 7.9 to 8.5, pH 7.9 to 8.4, pH 7.9 to
8.3, pH 7.9 to 8.2, pH 7.9 to 8.1, pH 7.9 to 8.0, pH 8.0 to 8.6,
pH 8.0 to 8.5, pH 8.0 to 8.4, pH 8.0 to 8.3, pH 8.0 to 8.2, pH
8.0 to 8.1, pH 8.1 to 8.6, pH 8.1 to 8.5, pH 8.1 to 8.4, pH 8.1
to 8.3, pH 8.1 to 8.2, pH 8.2 to 8.6, pH 8.2 to 8.5, pH 8.2 to
8.4, pH 8.2 to 8.3, pH 8.3 to 8.6, pH 8.3 to 8.5, pH 8.3 to 8.4,
pH 8.4 to 8.6, pH 8.4 to 8.5, pH 8.5 to 8.6, even more typically
pH 8 to 8.6 or pH 8.2 to 8.6, most typically pH 8.3. The
solution is then typically placed in a closed or sealed
container at 0 to 20° C. or 0 to 15° C. with occasional mixing
until a clear solution develops. The amount of carbonic acid
and/or hydrated carbon dioxide and/or carbon dioxide gas bubbled
through the solution and dissolved therein and/or solid carbon
dioxide is sufficient to prevent precipitation of water
insoluble metal compounds (such as magnesium or calcium
carbonate). A clear solution is generally obtained in about 6
hours to 7 days, typically 12 hours to 5 days, more typically 24
hours to 5 days, most typically 24 hours to 3 days. Generally
the aqueous neutral to mildly alkaline metal bicarbonate
solution is prepared and stored at a temperature ranging from 0
to 55° C., 0 to 25° C., 0 to 20° C. 0.5 to 25° C., 0.5 to 20°
C., 0.5 to 15° C., 0.5 to 10° C., 0.5 to 9° C., 0.5 to 8° C.,
0.5 to 7° C., 1 to 20° C., 1 to 15° C., 1 to 10° C., 1.5 to 20°
C., 1.5 to 15° C., 1.5 to 10° C., 2 to 20° C., 2 to 15° C., 2 to
10° C., 3 to 20° C., 3 to 15° C., 4 to 20° C., 4 to 15° C., 4 to
10° C., 5 to 10° C., 5 to 15° C., 6 to 20° C., 6 to 15° C., 6 to
10° C., 7 to 20° C., 7 to 15° C., 7 to 10° C., 8 to 20° C., 8 to
15° C., 8 to 10° C., 9 to 20° C., 9 to 15° C., 9 to 10° C., 10
to 15° C., typically 0 to 15° C., more typically 0 to 10° C.,
even more typically 3° C. to 10° C., most typically 5° C. to 10°
C. and even most typically 5° C. Alternatively the crushed or
powdered metal carbonate, or metal carbonate hydroxide or metal
oxide or mixture thereof is added to an aqueous solution of the
carbonic acid and/or hydrated carbon dioxide and/or to an
aqueous solution through which carbon dioxide gas is bubbled
and/or solid carbon dioxide has been added. The amount of
carbonic acid and/or hydrated carbon dioxide and/or carbon
dioxide gas bubbled through the solution and dissolved therein
and/or solid carbon dioxide is sufficient to prevent
precipitation of water insoluble metal compounds (such as
magnesium or calcium carbonate).
Typically one litre of water is placed in a container and
sufficient carbonic acid and/or carbonated water and/or hydrated
carbon dioxide and/or carbon dioxide gas and/or solid carbon
dioxide is added to produce a pH value of approximately pH 5.2.
(In practice, approximately 40 to 45 mL of chilled (5° C.)
carbonated mineral water is used depending on the initial pH of
the water). The container is sealed and the contents are mixed.
485 mg magnesium carbonate hydroxide pentahydrate powder (MgCO3)4.Mg(OH)2.5H2O,
molecular
weight 485 is added. The container is again sealed and the
contents are mixed.
The container is stored at a temperature of 0 to 10° C. and the
contents mixed regularly. Sufficient time is allowed for a clear
solution of magnesium bicarbonate to develop at a range of pH
8.0 to pH 8.6, preferably pH 8.3. This takes approximately 24 to
72 hours. Alternatively the carbonic acid and/or carbonated
water and/or hydrated carbon dioxide and/or carbon dioxide gas
and/or solid carbon dioxide is added to the magnesium carbonate
hydroxide pentahydrate powder in water. Alternatively one litre
of water is placed in a container and sufficient carbonic acid
and/or carbonated water and/or hydrated carbon dioxide and/or
solid carbon dioxide is added to produce a pH value less than pH
5.2. (In practice, approximately 30 mL to 40 mL of chilled water
is used depending on the initial pH of the water). The container
is sealed and the contents are mixed. 485 mg magnesium carbonate
hydroxide pentahydrate powder (MgCO3)4.Mg(OH)2.5H2O,
molecular
weight 485 is added. The container is again sealed and the
contents are mixed. The container is stored at a temperature of
0 to 10° C. and the contents mixed regularly. The pH of the
water is then adjusted with an alkali such as sodium hydroxide
or potassium hydroxide to a pH of 8 to 8.6, typically pH 8.3.
Alternatively the carbonic acid or carbonated water and/or
hydrated carbon dioxide and/or carbon dioxide gas and/or solid
carbon dioxide is added to the magnesium carbonate hydroxide
pentahydrate powder in water.
The above processes may optionally be conducted under an
atmosphere of carbon dioxide or a gas comprising carbon dioxide.
Generally once the solution is prepared, it may be stored under
a blanket of carbon dioxide gas to maintain the solution at a pH
of 7 to 9 and at a temperature of 0 to 25° C.
Usually one litre of the magnesium bicarbonate solution
prepared above contains approximately 120 mg of magnesium per
litre of aqueous neutral to mildly alkaline metal bicarbonate
solution and approximately 600 mg of bicarbonate. 500 mg sodium
bicarbonate (or potassium bicarbonate) is added to the magnesium
bicarbonate solution and mixed. The mixture is stored in a
sealed container in a refrigerator. The mixture contains
approximately 120 mg magnesium per litre of aqueous neutral to
mildly alkaline metal bicarbonate solution, 135 mg sodium per
litre of aqueous neutral to mildly alkaline metal bicarbonate
solution and 950 mg bicarbonate per litre of aqueous neutral to
mildly alkaline metal bicarbonate solution.
Generally the aqueous neutral to mildly alkaline metal
bicarbonate solution of the invention is administered or
consumed orally. Typically the solution is an orally drinkable
solution. Typically the solution is a therapeutic orally
drinkable solution. Alternatively a gelling agent may added to
the solution and the solution subjected to gelling conditions to
gel the solution and the resultant gel may be consumed orally.
For example, the aqueous neutral to mildly alkaline metal
bicarbonate solution may be prepared as a solution or an iced
confectionary, such as an ice block or iced dessert, which is
ingested orally. Alternatively the aqueous neutral to mildly
alkaline metal bicarbonate solution may be prepared in the form
of a tablet, lozenge or lolly which is ingested orally. For
example, the aqueous neutral to mildly alkaline metal
bicarbonate solution may be administered for metabolic acidosis
or renal failure. Optionally the solution may be sterilised.
Typically the aqueous neutral to mildly alkaline metal
bicarbonate solution is prepared as a solution which is ingested
on a regular basis hourly, daily, monthly or yearly. The amount
and frequency of aqueous neutral to mildly alkaline metal
bicarbonate solution administered/consumed in a day is generally
sufficient so as to maintain a steady bicarbonate level in the
bicarbonate concentration of a taker's body fluids. It is
preferable to avoid a rapid increase in the bicarbonate level in
the bicarbonate concentration of a taker's body fluids. The
amount of aqueous neutral to mildly alkaline metal bicarbonate
solution administered in a day ranges from 250 mL to 6 litres,
typically 250 mL to 5.5 litres, 250 mL to 5 litres, 250 mL to
4.5 litres, 250 mL to 4 litres, 250 mL to 3.5 litres, 250 mL to
3 litres, 500 mL to 6 litres, 500 mL to 5.5 litres, 500 mL to 5
litres, 500 mL to 4.5 litres, 500 mL to 4 litres, 500 mL to 3.5
litres, 500 mL to 3 litres, more typically 1 litre to 6 litres,
1 litre to 5.5 litres, 1 litre to 5 litres, 1 litre to 4.5
litres, 1 litre to 4 litres, 1 litre to 3.5 litres, even more
typically 1 litre to 3 litres, 1.5 litres to 6 litres, 1.5
litres to 5.5 litres, 1.5 litres to 5 litres, 1.5 litres to 4.5
litres, 1.5 litres to 4 litres, 1.5 litres to 3.5 litres, 1.8
litres to 3.3 litres, 1.8 to 2.8 litres, 1.8 to 2.5 litres, 1.8
to 2.3 litres, 1.8 to 2.0 litres, most typically 2 to 3 litres,
typically 2.3 to 2.8 litres, more typically 2.3 to 2.6 litres,
usually 2.1 to 3 litres. The aqueous neutral to mildly alkaline
metal bicarbonate solution may be administered on a full or
empty stomach, typically the aqueous neutral to mildly alkaline
metal bicarbonate solution is administered on an empty stomach.
Usually 1.5 to 3.5 litres, typically 1.8 to 3 litres, more
typically 1.5 to 2.4 litres, even more typically 1.8 to 2.1
litres and usually between 1.8 and 2.7 litres of aqueous neutral
to mildly alkaline metal bicarbonate solution is ingested,
administered or consumed on an empty stomach by a mammal
(typically a human) in equal or non equal volume amounts (100
mL-1000 mL, 200-800 mL, 250-750 mL, 275-700 mL, 300-650 mL,
350-600 mL, 400-550 mL, 450-500 mL, typically about 300-400 mL,
more typically about 375 mL volume amounts a number of times
(typically at set times) each day for the required number of
times per day to drink the desired daily amount of the
solution). For example if 1800 mL per day is to be consumed then
a user may drink six 300 mL amounts of the solution every 2 to
2.5 hours throughout the day. The oral consumption of the
solution three or more times at roughly equally spaced apart
intervals throughout the day is more desirable than consuming
the solution in one or two lots throughout the day. The idea of
taking the solution is to take it regularly throughout the day
so that a simulated continuous oral intake or a close to
continuous regular oral intake of the solution occurs. Thus
depending on the condition and the subject one suitable
administration/consumption regime could be nine by 200 mL
amounts of the solution, each 200 mL amount being orally
administered/consumed about every 1.5-1.75 hours to provide a
total daily intake of 1800 mL. Alternatively, once again
depending on the condition and the subject one suitable
administration/consumption regime could be nine by 300 mL
amounts of the solution, each 300 mL amount being orally
administered/consumed about every 1.5-1.75 hours to provide a
total daily intake of 2700 mL. Alternatively, once again
depending on the condition and the subject one suitable
administration/consumption regime could be nine by 350 mL
amounts of the solution, each 350 mL amount being orally
administered/consumed about every 1.5-1.75 hours to provide a
total daily intake of 3150 mL. Typically the solution is
administered/consumed 3 to 30, 3-25, 3-20, 3-15, 3-12, 3-10,
3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-30, 4-25, 4-20, 4-15, 4-12,
4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-30, 5-25, 5-20, 5-15, 5-12,
5-11, 5-10, 5-9, 5-8, 5-7, 5-6, 6-30, 6-25, 6-20, 6-15, 25 6-12,
6-11, 6-10, 6-9, 6-8, 6-7, 7-30, 7-25, 7-20, 7-15, 7-12, 7-11,
7-10, 7-9, 7-8, 8-30, 8-25, 8-20, 8-15, 8-12, 8-11, 8-10, 8-9
times per day at regular or irregular intervals or a mixture of
both regular and irregular intervals, throughout each day.
Typically the solution is administered/consumed every 0.3-10,
0.3-8, 0.3-7, 0.3-6, 0.3-5, 0.3-4.5, 0.3-4, 0.3-3.5, 0.3-3,
0.3-2.5, 0.3-2, 0.3-1.5, 0.3-1, 0.3-0.75, 0.3-0.5 hours/day when
the subject is awake. More typically the solution is
administered/consumed every 0.5-8, 0.5-7, 0.5-6, 0.5-5, 0.5-4.5,
0.5-4, 0.5-3.5, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1, 0.5-0.8,
0.5-0.75 hours/day when the subject is awake. Where possible the
solution is consumed/administered on an empty (e.g. before
eating). The solution may be administered according to these
latter dosages over short (for: example 1 to 60 days, 10 to 40
days, 3 months to 6 months, 1 day to 6 months) or long (for
example 6 months to 10 years or more, 9 months to 18 months, 1
year to 3 years, 1 year to 5 years, 2 to 6 years) periods as
required. Usually the amount of aqueous neutral to mildly
alkaline metal bicarbonate solution administered to a mammal is
5 to 100 mL per Kg, more usual 10 to 50 mL per Kg, most usual 14
to 29 mL per Kg or 25 to 43 mL per Kg.
The solution may include other additives such as sweeteners,
preservatives, flavourings and other suitable additives.
Examples of suitable sweetners include sucrose, lactose,
glucose, aspartame or saccharine. Examples of suitable
flavouring agents include peppermint oil, oil of wintergreen,
cherry, orange or raspberry flavouring. Examples of suitable
preservatives include sodium benzoate, vitamin E,
alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben
or sodium bisulphite.
Typically the aqueous neutral to mildly alkaline metal
bicarbonate solution is orally administered/consumed on an empty
stomach. Usually consumption in this manner avoids the mixing of
bicarbonate anions with stomach acid which may result in the
loss of bicarbonate. Usually the aqueous neutral to mildly
alkaline metal bicarbonate solution is consumed in small amounts
a number of times through a day typically at set times each day
to avoid a rapid increase in the bicarbonate concentration of
body fluids. Usually the amount of aqueous neutral to mildly
alkaline metal bicarbonate solution consumed at commencement is
500 mL per day and is increased by increments over a period of
one month to the maximum consumption. This start-up schedule
generally avoids any gastrointestinal side effects due to the
smooth muscle relaxation properties of magnesium.
The aqueous neutral to very mildly alkaline metal bicarbonate
solution of the invention may be administered intravenously
(e.g. by discrete injection, semi continuous injection or drip
feed or continuous injection or drip feed) or by other
parenteral routes. Another embodiment of the invention is
directed to a pharmaceutical composition comprising the solution
of the first or eleventh embodiments together with one or more
pharmaceutically acceptable carriers, diluents, adjuvants and/or
excipients. Typically the pharmaceutical composition is suitable
for oral or parenteral administration. Another embodiment of the
invention is directed to a veterinary composition comprising the
solution of the first or eleventh embodiments together with one
or more veterinarily acceptable carriers, diluents, adjuvants
and/or excipients. Typically the veterinary composition is
suitable for oral or parenteral administration. The amount and
frequency of aqueous neutral to mildly alkaline metal
bicarbonate solution administered/consumed in a day is generally
sufficient so as to maintain a steady bicarbonate level in the
bicarbonate concentration of a taker's body fluids. It is
preferable to avoid a rapid increase in the bicarbonate level in
the bicarbonate concentration of a taker's body fluids. For
parenteral administration, the solution is generally sterile.
Suitable mono-toxic parenterally acceptable diluents or solvents
include water, Ringer's solution, isotonic salt solution,
1,3-butanediol, ethanol, propylene glycol or polyethylene
glycols in mixtures with water. Aqueous solutions or suspensions
may further comprise one or more buffering agents. Suitable
buffering agents include sodium borate, sodium acetate, sodium
citrate, or sodium tartrate, for example. Typically the solution
is administered on a regular basis throughout a day to a patient
requiring treatment. For example a patient may be parenterally
administered the solution by way of a continuous drip feed or
alternatively by way of a number of injections of the solution
throughout a day (e.g. every 0.5-8 hours, more typically every
1-4 hours). The treatment is generally continued as long as
required to alleviate the patient's symptons to a satisfactory
level. For concentration of metal bicarbonate in the
compositions, frequency of administration and amount
administered see discussion under oral administration.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 are plots of the survival curves for a control group of
sheep and a treatment group of sheep;
FIG. 2 is a photograph showing osteoarthritis in the joints of
the fingers and thumb. Osteoarthritis before the consumption of
aqueous metal bicarbonate solution. Note the swelling and
`claw-like` hand resulting from joint flexion and joint
displacement. (The patient was pushing down with her hand `as
hard as possible` in an attempt to place her hand flat on the
underlying surface.); and
FIG. 3 is a photograph showing osteoarthritis in the joints of
the fingers and thumb. Osteoarthritis twelve months after
commencement of the consumption of aqueous metal bicarbonate
solution. Note that the fingers can be extended and the joints
are `straighter` than twelve months previously. (The patient had
placed her hand flat on the underlying surface without exerting
any force.)
BEST MODE AND OTHER MODE(S) FOR CARRYING OUT THE INVENTION
Magnesium bicarbonate is a natural hydrated salt which exists
only in an aqueous solution. It may be formed in spring water by
an ion exchange process between the protons in carbonic acid
(formed from the hydration of carbon dioxide located in the
atmosphere, organic material, soils and rocks) and the magnesium
in the constituent minerals of rocks (particularly the
ferromagnesian minerals known as pyroxene and olivine that
constitute basalt rocks).
The ion exchange process can be represented by the following
equations:
##STR1##
The term magnesium bicarbonate is used universally to describe
the mixture of magnesium cations and bicarbonate anions found in
spring waters and mineral waters. Most spring waters and mineral
waters have acidic pH values (about pH 6.0). If the pH value of
the water rises (due to contact with hydroxides), the magnesium
cations and bicarbonate anions "attract" each other (reversibly)
to form the true salt. The chemical formula of magnesium
bicarbonate may be written as Mg(HCO3)2,
or (more accurately) Mg(H2O)4 (HCO3)2.
This latter formula takes into account the hexahydrated
magnesium cation Mg(H2O)6sup.2+.
In essence, magnesium bicarbonate exists in aqueous solution
probably as an hydrated salt of indeterminate hydration size due
to the hydrogen bonds between linked water dipoles centred
around the hydrated magnesium cation.
The chemical processes occurring in magnesium bicarbonate
solutions are complex and depend on the concentrations of
magnesium cations and other ions. The following reactions are
considered to occur:
##STR2##
There exists also a range of possible acid-base equilibria
involving HCO3-, H3O.sup.+, CO3sup.2-
and OH.sup.- ions and CO2 and H2CO3.
Usually the pH adjusting agent (and/or stabilising agent)
maintains the acid-base equilibria.
Typically to prepare the aqueous neutral to mildly alkaline
metal bicarbonate solution, crushed or powdered metal carbonate,
or metal carbonate hydroxide or metal oxide, such as magnesium
carbonate MgCO3, or commercial magnesium carbonate
hydroxide pentahydrate (MgCO3)4.Mg(OH)2.5H2O,
or
other commercial magnesium carbonate hydroxides, or hydrated
magnesium oxides, or magnesium oxides heated with carbon
dioxide, or the calcite series or dolomite series of minerals
(Mg, Ca)CO3, or limestone or dolomite rocks is mixed
with water. A cloudy suspension is obtained. Sufficient carbonic
acid or hydrated carbon dioxide or carbon dioxide gas is added
to obtain a solution having a pH 7 to 9 or pH 7 to 8.6, more
typically pH 7.5 to 8.8 or pH 7.5 to 8.5 or pH 7.8 to 8.6, pH
7.8 to 8.5, pH 7.8 to 8.4, pH 7.8 to 8.3, pH 7.8 to 8.2, pH 7.8
to 8.1, pH 7.8 to 8.0, pH 7.8 to 7.9, pH 7.9 to 8.6, pH 7.9 to
8.5, pH 7.9 to 8.4, pH 7.9 to 8.3, pH 7.9 to 8.2, pH 7.9 to 8.1,
pH 7.9 to 8.0, pH 8.0 to 8.6, pH 8.0 to 8.5, pH 8.0 to 8.4, pH
8.0 to 8.3, pH 8.0 to 8.2, pH 8.0 to 8.1, pH 8.1 to 8.6, pH 8.1
to 8.5, pH 8.1 to 8.4, pH 8.1 to 8.3, pH 8.1 to 8.2, pH 8.2 to
8.6, pH 8.2 to 8.5, pH 8.2 to 8.4, pH 8.2 to 8.3, pH 8.3 to 8.6,
pH 8.3 to 8.5, pH 8.3 to 8.4, pH 8.4 to 8.6, pH 8.4 to 8.5, pH
8.5 to 8.6, even more typically pH 8 to 8.5 or pH 8.2 to 8.6,
most typically pH 8.3. The solution is then typically placed in
a sealed container at 0 to 20° C. with occasional mixing until a
clear solution develops. A clear solution is generally obtained
in about 6 hours to 7 days, typically 12 hours to 5 days, more
typically 24 hours to 5 days, most typically 24 hours to 3 days.
Generally the aqueous neutral to mildly alkaline metal
bicarbonate solution is prepared and stored at a temperature
ranging from 0 to 25° C., 0 to 20° C. 0.5 to 25° C., 0.5 to 20°
C., 0.5 to 15° C., 0.5 to 10° C., 0.5 to 9° C., 0.5 to 8° C.,
0.5 to 7° C., 1 to 20° C., 1 to 15° C., 1 to 10° C., 1.5 to 20°
C., 1.5 to 15° C., 1.5 to 10° C., 2 to 20° C., 2 to 15° C., 2 to
10° C., 3 to 20° C., 3 to 15° C., 4 to 20° C., 4 to 15° C., 4 to
10° C., 5 to 10° C., 5 to 15° C., 6 to 20° C., 6 to 15° C., 6 to
10° C., 7 to 20° C., 7 to 15° C., 7 to 10° C., 8 to 20° C., 8 to
15° C., 8 to 10° C., 9 to 20° C., 9 to 15° C., 9 to 10° C., 10
to 15° C., typically 0 to 15° C., more typically 0 to 10° C.,
even more typically 3° C. to 10° C., most typically 5° C. to 10°
C. and even most typically 5° C. Alternatively the crushed or
powdered metal carbonate, or metal carbonate hydroxide or metal
oxide or mixture thereof is added to an aqueous solution of the
carbonic acid or hydrated carbon dioxide or carbon dioxide gas.
Typically one litre of water is placed in a container and
sufficient carbonic acid or carbonated water or hydrated carbon
dioxide or carbon dioxide gas is added to produce a pH value of
approximately pH 5.2. (In practice, approximately 40 to 45 mL of
chilled (5° C.) carbonated mineral water is used depending on
the initial pH of the water). The container is sealed and the
contents are mixed. 485 mg magnesium carbonate hydroxide
pentahydrate powder (MgCO3)4Mg(OH)25H2O,
molecular
weight 485 is added. The container is again sealed and the
contents are mixed. The container is stored at a temperature of
0 to 10° C. and the contents mixed regularly. Sufficient time is
allowed for a clear solution of magnesium bicarbonate to develop
at a range of pH 8.0 to pH 8.5, typically pH 8.3. This takes
approximately 24 to 72 hours. Alternatively the carbonic acid or
carbonated water or hydrated carbon dioxide or carbon dioxide
gas is added to the magnesium carbonate hydroxide pentahydrate
powder in water.
Alternatively one litre of water is placed in a container and
sufficient carbonic acid or carbonated water or hydrated carbon
dioxide gas is added to produce a pH value less than pH 5.2. (In
practice, approximately 30 mL to 40 mL of chilled water is used
depending on the initial pH of the water). The container is
sealed and the contents are mixed. 485 mg magnesium carbonate
hydroxide pentahydrate powder (MgCO3)4Mg(OH)25H2O,
molecular
weight 485 is added. The container is again sealed and the
contents are mixed. The container is stored at a temperature of
0 to 10° C. and the contents mixed regularly. The pH of the
water is then adjusted with an alkali such as sodium hydroxide
or potassium hydroxide to a pH of 8 to 8.5, typically pH 8.3.
Alternatively the carbonic acid or carbonated water or hydrated
carbon dioxide or carbon dioxide gas is added to the magnesium
carbonate hydroxide pentahydrate powder in water.
Generally once the solution is prepared, the solution may be
stored in a closed container under a blanket of carbon dioxide
gas or a mixture of carbon dioxide gas and usually a
nondeleterious inert gas, for example, argon, helium and/or
nitrogen to maintain the solution at a pH of 7 to 9 and at a
temperature of 0 to 25° C. and at 0.8 to 5 atm. The carbon
dioxide gas blanket prevents loss of carbon dioxide from the
solution. The amount of carbon dioxide in the gaseous mixture
provides partial pressure on the liquid which is substantially
equal to the partial pressure of carbon dioxide from carbon
dioxide from the solution which is produced from equilibrium of
bicarbonate in the solution at the particular temperature. In
this way the solution is stabilised. If the solution were left
in an open container for any substantial length of time
precipitation of metal carbonate from the solution would occur
as a result of decomposition of the bicarbonate in the solution
as carbon dioxide is liberated from the solution. By using a
stabilising agent in and/or above the solution such
decomposition is substantially minimised or prevented.
Alternatively the solution may be stored in a closed or sealed
container (generally airtight) which is substantially filled
with the solution whereby there is substantially no gas in the
container or little gas compared to the amount of liquid in the
container.
The relevant chemical reactions may be represented by the
following equations:
##STR3##
Usually one litre of the magnesium bicarbonate solution
prepared above contains approximately 120 mg of magnesium per
litre of aqueous neutral to mildly alkaline metal bicarbonate
solution and approximately 600 mg of bicarbonate. 500 mg sodium
bicarbonate (or potassium bicarbonate) is added to the magnesium
bicarbonate solution and mixed. The mixture is stored in a
sealed container in a refrigerator. The mixture contains
approximately 120 mg magnesium per litre of aqueous neutral to
mildly alkaline metal bicarbonate solution, 135 mg sodium per
litre of aqueous neutral to mildly alkaline metal bicarbonate
solution and 950 mg bicarbonate per litre of aqueous neutral to
mildly alkaline metal bicarbonate solution.
In the body, normal intracellular pH value is pH 7.2. Under
acidic conditions, such as adenosine triphosphate (ATP)
hydrolysis, intracellular pH value may decrease to pH 6.5. In
practice, a pH value is chosen for bicarbonate solutions that
exceeds normal blood plasma pH value (pH>7.38).
A low temperature, between 0 and 10° C., typically 5 to 10° C.,
ensures that carbon dioxide stays dissolved in solution to
maximise carbon dioxide hydration. Above 15 to 20° C., the
solubility of carbon dioxide is low, the carbon dioxide leaves
the solution, and particles and sediments may occur in the
solution. Above 15 to 20° C., the solution may be cloudy in
appearance.
At high magnesium concentrations, a minimum time, at least 24
to 72 hours at 5° C., is required for completion of the kinetic
processes that produce a clear solution of magnesium
bicarbonate. (The kinetic processes include the hydration of
carbon dioxide, the dissolution of magnesium carbonate and the
dissolution of magnesium hydroxide.) The concentration of
magnesium cations (in association with bicarbonate anions) is
generally in the range 25 mg to 250 mg per litre aqueous neutral
to mildly alkaline metal bicarbonate solution (depending on the
pH value of the metal bicarbonate solution). Usually the maximum
magnesium concentration that can be maintained in solution as
magnesium bicarbonate may be approximately 120 mg per litre
aqueous neutral to mildly alkaline metal bicarbonate solution at
pH 8.3. As the pH value decreases, the concentration of
magnesium that can be maintained in solution increases. Because
magnesium chloride is soluble, higher concentrations of
magnesium can be maintained in solution if chlorides (such as
sodium chloride) are added to the aqueous neutral to mildly
alkaline metal bicarbonate solution.
The solubility product constant for magnesium carbonate is
reported to be approximately 3.5.times.10.sup.-8. The solubility
product constant for magnesium hydroxide is reported to be
approximately 1.1.times.10.sup.-11. Calculated from these
values, the maximum concentrations of magnesium cations that can
exist in solution as carbonates or hydroxides are approximately
20 mg per litre aqueous metal bicarbonate solution and 10 mg per
litre aqueous neutral to mildly alkaline metal bicarbonate
solution respectively.
Generally the aqueous neutral to mildly alkaline metal
bicarbonate solution of the invention is administered or
consumed orally. Typically the solution is an orally drinkable
solution. Typically the solution is a therapeutic orally
drinkable solution. For example, the aqueous neutral to mildly
alkaline metal bicarbonate solution may be prepared as a
solution or an iced confectionary, such as an ice block or iced
dessert, which is ingested orally. Alternatively the aqueous
neutral to mildly alkaline metal bicarbonate solution may be
prepared in the form of a tablet, lozenge or lolly which is
ingested orally. For example, the aqueous neutral to mildly
alkaline metal bicarbonate solution may be administered for
metabolic acidosis or renal failure. Optionally the solution may
be sterilised. Typically the aqueous neutral to mildly alkaline
metal bicarbonate solution is prepared as a solution which is
ingested hourly, daily, monthly or yearly. The amount of aqueous
neutral to mildly alkaline metal bicarbonate solution
administered in a day ranges from 250 mL to 6 litres, typically
250 mL to 5.5 litres, 250 mL to 5 litres, 250 mL to 4.5 litres,
250 mL to 4 litres, 250 mL to 3.5 litres, 250 mL to 3 litres,
500 mL to 6 litres, 500 mL to 5.5 litres, 500 mL to 5 litres,
500 mL to 4.5 litres, 500mL to 4 litres, 500 mL to 3.5 litres,
500 mL to 3 litres, more typically 1 litre to 6 litres, 1 litre
to 5.5 litres, 1 litre to 5 litres, 1 litre to 4.5 litres, 1
litre to 4 litres, 1 litre to 3.5 litres, even more typically 1
litre to 3 litres, 1.5 litres to 6 litres, 1.5 litres to 5.5
litres, 1.5 litres to 5 litres, 1.5 litres to 4.5 litres, 1.5
litres to 4 litres, 1.5 litres to 3.5 litres, most typically 2
to 3 litres, usually 2.1 to 3 litres. The aqueous neutral to
mildly alkaline metal bicarbonate solution may be administered
on a full or empty stomach, typically the aqueous neutral to
mildly alkaline metal bicarbonate solution is administered on an
empty stomach. Usually 1.5 to 3 litres, more typically 1.5 to
2.4 litres, even more typically 1.8 to 2.1 litres and usually
between 1.8 and 2.7 litres of aqueous neutral to mildly alkaline
metal bicarbonate solution is ingested on an empty stomach in
approximately 300 mL volumes at set times each day. The solution
may be administered according to these latter dosages over short
(for example 1 to 10 days) or long (for example 6 months to 10
years or more) periods as required. Usually the amount of
aqueous neutral to mildly alkaline metal bicarbonate solution
administered to a mammal is 5 to 100 mL per Kg, more usual 10 to
50mL per Kg, most usual 14 to 29 mL per Kg or 25 to 43 mL per
Kg.
Typically the aqueous neutral to mildly alkaline metal
bicarbonate solution is consumed on an empty stomach. Usually
consumption in this manner avoids the mixing of bicarbonate
anions with stomach acid which may result in the loss of
bicarbonate. Usually the aqueous neutral to mildly alkaline
metal bicarbonate solution is consumed in small amounts at set
times each day to avoid a rapid increase in the bicarbonate
concentration of body fluids. Usually the amount of aqueous
neutral to mildly alkaline metal bicarbonate solution consumed
at commencement is 500 mL per day and is increased by increments
over a period of one month to the maximum consumption. This
start-up schedule generally avoids any gastrointestinal side
effects due to the smooth muscle relaxation properties of
magnesium.
The advantages of the aqueous neutral to mildly alkaline metal
bicarbonate solution of the invention are that the magnesium
cations function as bicarbonate transporters into body cells.
Magnesium bicarbonate enters body cells and the bicarbonate
anions function to displace from equilibrium the dissociation
reaction of intracellular carbonic acid. Magnesium bicarbonate
enters body cells and the bicarbonate anions function as an
intracellular proton sink (or proton scavenger). These reactions
can be represented by the one equation
##STR4##
Magnesium bicarbonate enters body cells and the bicarbonate
anions function to displace from equilibrium the hydration
reaction of carbon dioxide which is catalysed by the enzyme
carbonic anhydrase. This reaction can be represented by the
equation
##STR5##
Usually appropriate salts of magnesium, sodium, potassium,
calcium and lithium should not exceed the concentrations of the
component elements recommended by health authorities. The
concentrations of component elements cannot exceed
concentrations restricted by the solubility product constants of
respective hydroxides and carbonates.
EXAMPLE 1
An Experiment to Decrease Intracellular Proton Concentrations
and to Increase Intracellular Bicarbonate Concentrations in
Mammalian Cells in Vitro
Aqueous bicarbonate anions act as proton sinks in the presence
of excess proton concentrations in solution. This reaction can
be represented by the chemical equation
##STR6##
In the presence of sufficient concentrations of bicarbonate
anions, the reaction is essentially complete and proton
concentrations decrease. The pH value of the solution increases.
When plasma bicarbonate anions are present outside mammalian
body cells in sufficient concentrations, they are translocated
into the cytoplasm of the cells across the cell plasma
membranes. Indeed, bicarbonate anions equilibrate rapidly across
mammalian cell membranes. Bicarbonate translocation into cells
takes place via several processes. These processes include a
chloride-bicarbonate anion exchange and a sodium dependent
chloride-bicarbonate anion exchange and potassium co-transport
and magnesium co-transport.
An experiment was conducted to decrease intracellular proton
concentrations and to increase intracellular bicarbonate
concentrations in mammalian body cells in vitro. Throughout the
experiment, extracellular pH determinations were made using a pH
electrode and intracellular pH determinations were made using a
trapped fluorescein derivative. An increase in intracellular
proton concentrations (intracellular acidification) was achieved
by applying 10 mmol ammonium chloride (NH4Cl)
solution to a suspension of cells and then removing the NH4Cl.
An increase in intracellular bicarbonate concentrations was
achieved by applying an aqueous metal bicarbonate solution to a
suspension of cells. The aqueous metal bicarbonate solution
contained approximately Mg.sup.2+ 120 mg per litre, Na+ 135 mg
per litre and HCO.sub.3.sup.- 950 mg per litre at pH 8.3. This
aqueous metal bicarbonate solution was equivalent to 15 mmol
bicarbonate approximately. Blood was collected in sodium heparin
from a range of mammals and the leucocytes removed. The
leucocytes were washed and re-suspended in isotonic saline.
Intracellular pH determinations were made by loading leucocytes
for 15 minutes with (10 micromol in saline)
2,7-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF). Cells were
illuminated at 440 nm and 490 nm and fluorescence was measured
at 530 nm.
The experiment utilising sheep leucocytes is given stepwise
below:
Step 1. Increase in intracellular proton concentrations
(cytoplasmic acidification)
A. Leucocytes suspended in normal saline after pretreatment
with fluorescein.
Extracellular pH 7.2
Intracellular pH 7.1
B. 10 mmol ammonium chloride (NH4Cl) solution pH 7.5
applied to suspension of leucocytes for 10 minutes.
C. Leucocytes washed and re-suspended in normal saline.
Extracellular pH 7.3
Intracellular pH 6.1
Result: Cells have increased intracellular proton
concentrations. Cytoplasm is acidified.
Step 2. Decrease in intracellular proton concentrations
A. Acidified leucocytes (from Step 1.) divided into two groups;
Control group and Treatment group.
B. Treatment group of leucocytes exposed to aqueous metal
bicarbonate solution.
After 3 minutes:
Extracellular pH 7.5
Intracellular pH 7.0
C. Control group of leucocytes not exposed to aqueous metal
bicarbonate solution.
After 5 minutes:
Extracellular pH 7.2
Intracellular pH 6.6
Result: Cells treated with aqueous metal bicarbonate solution
rapidly decrease intracellular proton concentrations. Cytoplasm
shows rapid recovery from acidification relative to non-treated
cells.
Step 3. Increase in intracellular bicarbonate concentrations
A. Leucocytes suspended in normal saline after pretreatment
with fluorescein.
Extracellular pH 7.2
Intracellular pH 7.1
B. Aqueous metal bicarbonate solution applied to suspension of
leucocytes for 20 minutes.
Extracellular pH 7.9
Intracellular pH 7.4
Result: Cells treated with aqueous metal bicarbonate solution
have increased intracellular bicarbonate concentrations which
are manifested by an increase in pH value of cytoplasm.
The experiment was repeated with leucocytes from mice, rats,
guinea pigs, cattle, horses, dogs, cats and humans. In all
cases, acidified cells treated with aqueous metal bicarbonate
solution had decreased intracellular proton concentrations. In
all cases, cells treated with aqueous metal bicarbonate solution
had increased intracellular bicarbonate concentrations which
were manifested by increased pH values of cytoplasm.
The experiment was repeated with aqueous metal bicarbonate
solutions that contained a range of concentrations of Mg.sup.2+,
Na.sup.+, HCO3sup.- and K.sup.+ and Ca.sup.2+ ions.
Significant results were obtained for the following range of
concentrations:
Range
of concentrations to achieve
Ion
significant
results
Mg.sup.2+
20
to 120
mg/litre
Na.sup.+
50
to 500
mg/litre
K.sup.+
50
to 500
mg/litre
Ca.sup.2+
20
to 150
mg/litre
HCO.sub.3.sup.-
250
to 2,100 mg/litre
(HCO.sub.3.sup.-)
(4 mmol to 35 mmol)
Significant results were obtained for pH range pH 7.5 to 9.5.
(pH 9.5 was achieved by the addition of NaOH).
Aqueous metal bicarbonate solutions, containing a range of
cation and bicarbonate anion concentrations, decrease
intracellular proton concentrations and increase intracellular
bicarbonate concentrations in mammalian cells in vitro.
EXAMPLE 2
An Experiment to Demonstrate Bicarbonate Anion Translocation
from Aqueous Metal Bicarbonate Solution into the Mammalian Body
Against a Bicarbonate Anion Concentration Gradient
Mammalian plasma contains bicarbonate anions at a concentration
about 25 mmol (HCO3sup.- 1,500 mg per litre). When
ingested, aqueous metal bicarbonate solution produces
biochemical, physiological and medical effects at bicarbonate
anion concentrations about 16 mmol (HCO3sup.- 950 mg
per litre). Aqueous metal bicarbonate solution, at bicarbonate
anion concentration about 16 mmol, contains two thirds the
bicarbonate anion concentration of plasma, so bicarbonate anions
must be translocated into the mammalian body against a
bicarbonate anion concentration gradient.
Mammalian plasma contains cations at concentrations around
Mg.sup.2+ 24 mg per litre, Na.sup.+ 3,300 mg per litre, K.sup.+
175 mg per litre and Ca.sup.2+ 100 mg per litre. Aqueous metal
bicarbonate solution commonly contains cations at concentrations
around Mg.sup.2+ 120 mg per litre, Na.sup.+ 135 mg per litre,
K.sup.+ 100 mg per litre and Ca.sup.2+ 20 mg per litre. Aqueous
metal bicarbonate solution commonly contains 5 times the
magnesium cation concentration of plasma. Other cations are
present commonly in aqueous metal bicarbonate solution in
concentrations lower than plasma.
The concentrations of cations and anions in plasma can be
compared with concentrations of cations and anions in aqueous
metal bicarbonate solution by examination of the following
table:
Concentrations
of cations and anions
Aqueous
metal
Ion
Plasma
bicarbonate
solution
Cl.sup.- 3,600
mg/litre
0
mg/litre
Na.sup.+ 3,300
mg/litre
135 mg/litre
HCO.sub.3.sup.- 1,500 mg/litre 950
mg/litre
K.sup.+ 175
mg/litre
100 mg/litre
Ca.sup.2+ 100
mg/litre
20 mg/litre
Mg.sup.2+ 24
mg/litre
120 mg/litre
It is suggested that sodium cations and chloride anions leave
plasma along their respective concentration gradients and
magnesium and bicarbonate ions enter plasma along a magnesium
cation concentration gradient. Magnesium functions as a
bicarbonate transporter. In addition, it is suggested that
bicarbonate anions enter plasma by chloride-bicarbonate exchange
processes along a chloride anion concentration gradient
(chloride `out`, bicarbonate `in`).
In mammals, any large increases in plasma bicarbonate
concentrations can be decreased normally by a number of
biochemical and physiological homeostatic control processes.
These processes occur in time frames that range from minutes to
hours and longer. One of the main control processes that occurs
as a result of increased plasma bicarbonate concentration is an
alteration in bicarbonate chemistry in the kidneys. This is
manifested by a decrease in proton concentration in urine and by
a pH value of urine that is less acidic. In the presence of
increased plasma bicarbonate, kidney tubule cells decrease their
excretion of protons. Kidney control of bicarbonate
concentration is not instantaneous and occurs within a time
frame of several hours to several days. Unless a mammal has
physiological or clinical acidosis, it is difficult to detect
small increases in plasma bicarbonate concentration. Any
increases in plasma bicarbonate concentration are taken up by
body cells. Indeed, plasma bicarbonate equilibrates with
intracellular bicarbonate rapidly. In a normal mammal, a
measurable increase in plasma bicarbonate concentration occurs
only during an artificially induced alkalosis and is detectable
either when the consumption of bicarbonate anions (as NaHCO3)
greatly exceeds the concentration of bicarbonate in normal
plasma or when bicarbonate anions (as NaHCO3) are
administered intravenously.
An experiment was conducted to determine if bicarbonate anions
in aqueous metal bicarbonate solutions are translocated against
a bicarbonate concentration gradient into the body. Bicarbonate
translocation against a concentration gradient could occur
either via energy (ATP) dependent processes or via anion
(chloride-bicarbonate) exchange or via co-transport with cations
along cation concentration gradients. There are also complex
thermodynamic processes involving intracellular and
extracellular concentrations of bicarbonate anions, hydroxide
anions, protons and carbon dioxide that may assist in the
overall translocation of bicarbonate anions. These processes
often involve the production of bicarbonate anions by carbonic
anhydrase enzymes. In the experiment, entry of bicarbonate
anions into the body was assessed by determinations of proton
concentration in urine; that is, the pH value of urine.
Ten people had urine pH value assessed once per week for 3
months. Urine pH values were assessed once per week for a
further 3 months after commencement of consumption of aqueous
metal bicarbonate solution. The aqueous metal bicarbonate
solution contained approximately Mg.sup.2+ 120 mg per litre,
Na.sup.+ 135 mg per litre and HCO3 950 mg per litre.
The major component of the solution was magnesium bicarbonate
Mg(HCO3)2 720 mg per litre approximately.
Results are given below:
Mean pH value of urine
(Early Morning Sample)
Prior to consumption of aqueous metal bicarbonate solution: pH
5.9
After commencement of consumption of aqueous metal bicarbonate
solution: pH 6.7
The consumption of aqueous metal bicarbonate solution decreases
proton excretion by the kidneys. The pH value of urine
increases.
These results demonstrate that bicarbonate anions from aqueous
metal bicarbonate solution are translocated against a
bicarbonate anion concentration gradient into the body. This may
occur either via co-transport with cations along a cation
concentration gradient or via chloride-bicarbonate exchange
processes along a chloride anion concentration gradient
(chloride `out`, bicarbonate `in`). In the case of aqueous metal
bicarbonate solution, the only cation concentration gradient
possible is that involving magnesium cation concentrations.
The consumption of aqueous metal bicarbonate solution leads to
an increase in bicarbonate anion concentration in the body which
is manifested by a decrease in proton concentration in urine; an
increase in pH value of urine.
EXAMPLE 3
An Experiment to Improve the Buffering Capacities of the
Extracellular and Intracellular Bicarbonate Buffers and to
Decrease Senescence and to Increase Longevity in a
Representative Mammal
Mammalian body cells produce continuously concentrations of
carbon dioxide. Upon hydration, carbon dioxide increases proton
concentrations in the cytoplasm of body cells. The pH values of
the cytoplasm of body cells are lowered. The production of
protons in cytoplasm by the hydration of carbon dioxide can be
represented by the following chemical equations:
##STR7##
The protons produced in the cytoplasm of body cells by the
hydration of carbon dioxide, and other intracellular reactions,
are buffered normally by intracellular bicarbonate buffers. The
bicarbonate anions in intracellular buffers derive manly from
the extracellular bicarbonate of blood plasma. The bicarbonate
anions in blood plasma originate from erythrocytes as products
of erythrocyte carbonic anhydrase enzyme reactions.
When plasma bicarbonate anions are present outside mammalian
body cells in sufficient concentrations, they are translocated
into the cytoplasm of the cells across the cell plasma
membranes. Indeed, plasma bicarbonate equilibrates with
cytoplasmic bicarbonate rapidly. Bicarbonate translocation into
cells takes place via several processes. These processes include
a chloride-bicarbonate anion exchange and a sodium dependent
chloride-bicarbonate anion exchange and potassium co-transport
and magnesium co-transport. There are also complex thermodynamic
processes involving intracellular and extracellular
concentrations of bicarbonate anions, hydroxide ions, protons
and carbon dioxide that may assist in the overall translocation
of bicarbonate anions. These processes often involve the
production of bicarbonate anions by carbonic anhydrase enzymes.
Concentrations of bicarbonate anions that are translocated into
mammalian body cells improve the buffering capacity of the
cytoplasm of the cells. Concentrations of bicarbonate anions and
concentrations of carbon dioxide form a buffer system described
by the Henderson-Hasselbalch equation:
pH = pK + log ([HCO3sup.-]/[H2CO3
])
(Where pK is the pK of hydrated carbon dioxide H2CO3
and has an approximate numerical value of 6.35)
For a classical (closed system) buffer to be effective, the
ratio of the conjugate base to the acid (in the above case [HCO3sup.-
]/[H2CO3 ]) must be between 0.1 and 10.
This ratio applies also to buffers in biological (open) systems.
In mammalian body cells, the continuous and open production of
carbon dioxide means that continuous supplies of bicarbonate
anions are required to maintain effective and optimal buffering
capacities. Under conditions of excess proton concentrations,
from carbon dioxide production and ATP hydrolysis and other
metabolic processes, the supply of bicarbonate fails and the
effective and optimal buffering capacities of mammalian body
cells falter.
The vitality of mammalian body cells is linked critically to
the buffering capacities of the extracellular fluids and the
cytoplasm of the cells. Processes of cellular degeneration occur
when buffering capacities falter in the presence of excess
proton concentrations. Cellular degenerations are manifested in
the mammalian body by degenerative diseases and senescence.
Examples of degenerative diseases in mammals that are linked
casually to extracellular and intracellular proton
concentrations include osteoporosis, osteoarthritis, the
diseases associated with chronic inflammation, the diseases
associated with lysosomal enzyme activities, the diseases
associated with oxidations of cell nucleic acids, cell protein
amino acids and cell membrane lipids, and the diseases
associated with aberrations of mitochondrial respiration.
An experiment was conducted to improve the buffering capacities
of the extracellular and intracellular bicarbonate buffers and
to consequently decrease senescence and increase longevity in a
representative mammal. One hundred and ten Merino ewe lambs were
divided randomly at weaning into a control group and a treatment
group. The groups were of equal size and were maintained under
similar conditions except for the pH values and aqueous metal
bicarbonate concentrations of drinking water supplies. Sheep
were selected as the representative mammal because their life
span and body weight are more representative of typical mammals
than laboratory rodents, their life span is not excessively
long, their body size permits multiple blood and tissue sample
collections, they are easy to handle and their husbandry is
suited to experimental conditions. The control group was
maintained, for the full life span of the sheep, in small
experimental paddocks with slightly acidic (less than pH 6.5)
drinking water supplies that contained bicarbonate
concentrations less than 30 mg per litre. The treatment group
was maintained, for the full life span of the sheep, in small
experimental paddocks with slightly alkaline (pH 7.8 to 9.0)
drinking water supplies that contained bicarbonate
concentrations between 300 mg per litre and 800 mg per litre.
The drinking water supplies for the treatment group were loaded
with the appropriate concentrations of bicarbonate anions by the
addition of crushed and powdered magnesite MgCO3 to
the water. The magnesite frequently contained calcite CaCO3
and dolomite (Ca,Mg)CO3. The magnesite was dissolved
in the drinking water either with the assistance of commercial
supplies of carbon dioxide gas or carbonic acid or with local
supplies of hydrated carbon dioxide. This dissolution process
can be represented by the following chemical equations:
##STR8##
The treatment group of sheep consumed slightly alkaline (pH 7.8
to 9.0) drinking water that contained bicarbonate concentrations
between 300 mg per litre and 800 mg per litre. At this pH value,
and this bicarbonate concentration, bicarbonate was mostly in
the form of magnesium bicarbonate Mg (HCO3)2 :
##STR9##
In addition, some sediments of carbonate (Ca,Mg)CO3
were present in the drinking water during summer months:
##STR10##
The mean pH values and the mean magnesium, calcium and
bicarbonate concentrations in the drinking water supplies are
given below (the concentrations of cations and bicarbonate
anions were not stoichiometric in the drinking water --
particularly the drinking water of the control group -- because
of the presence of some concentrations of sulphate, chloride and
sodium ions):
Means
of parameters in drinking water
Control
Group Treatment Group
pH
6.1
8.4
Mg.sup.2+
mg/litre
13
110
Ca.sup.2+
mg/litre
20
30
HCO.sub.3.sup.-
mg/litre
25 660
In the late stages of pregnancy, there is a tendency for
pregnant mammals to become hypoglycaemic and hyperketonaemic.
Hyperketonaemia subjects the pregnant mammal to an acid load
(increase in proton concentrations). This acid load may result
in clinical acidosis. Like all mammals, pregnant ewes tend to be
hypoglycaemic and hyperketonaemic late in pregnancy. In ewes
affected clinically with acidosis, bicarbonate concentrations
range between 14 to 20 mmol per litre plasma.
Over several years, plasma bicarbonate concentrations were
determined for the control group and the treatment group one
week prior to lambing. Determination of plasma bicarbonate
concentrations prior to lambing is a direct measure of
extracellular and intracellular bicarbonate buffering capacity.
In ewes with effective extracellular and intracellular
bicarbonate buffers, bicarbonate concentrations are maintained
in a range between 24 to 27 mmol per litre plasma. Plasma
bicarbonate concentrations are given below:
Mean plasma bicarbonate concentrations
one week prior to
lambing
(mmol per litre)
Age
(years) Control
Group Treatment Group
4
24.9
26.1
6
22.8
25.9
8
22.2
26.4
10
21.9
25.8
The treatment group had larger plasma
bicarbonate concentrations than the
control group.
The consumption of aqueous metal bicarbonate solution,
principally magnesium bicarbonate solution, improves the
buffering capacities of extracellular and intracellular
bicarbonate buffers in mammals.
In mammalian demography, there are two measurements utilised
commonly in the experiment study of degenerative diseases and
senescence. The first measurement is called fifty percent
survival. Fifty percent survival describes the chronological age
at which half an original population has died. The second
measurement is called maximum life span. Maximum life span
describes the age of the longest lived survivors of a
population. The fifty percent survival measurement is considered
to reflect susceptibility to accidents and infectious and
degenerative diseases in mammals. The maximum life span
measurement is considered to reflect the innate processes of
senescence in mammals. The fifty percent survival measurement
and the maximum life span measurement for the control group and
the treatment group are given below:
Fifty
percent survival
Control
group
8
years
Treatment
group
11
years
Maximum
life span
Control
group
13
years
Treatment
group
17
years
