Note: Descriptions are shown in the official language in which they were submitted.
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Technical Field
This invention pertains to the administration of
chiro-inositol for the treatment of a variety of disease
conditions associated with a failure of pyruvate
dehydrogenase-mediated metabolic pathways, or disease
conditions otherwise linked to a failure of metabolic
activation of PDH pathways, glycogen synthase pathways
or other blood sugar maintenance pathways including
glucose 6-phosphatase and mechanisms of insulin
resistance in mammals. Specifically, çhiro-inositol
dietary supplements are provided for the biosynthesis of
a chiro-inositol containing insulin mediator capable of
stimulating PDH and glycogen synthase and inhibiting
glucose 6-phosphatase and thus overcoming insulin
resistance, lowering blood sugar and lowering elevated
tactic acid.
Background Art
The inventors have identified a high correlation
between insulin-resistant diabetic disease states and an
absence from the urine of D-chiro-inositol. This
correlation led to the observation that insulin
resistance may be due to an individual's inability to
synthesize chiro-inositol, leading to an inability to
form a specific insulin mediator, apparently responsible
for the activation of the pyruvate dehydrogenase
complex, and in particular, pyruvate dehydrogenase
phosphatase, or PDH-P. The mediator also activates
glycogen synthase (GS) by activating in particular
glycogen synthase phosphatase or
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GS-P. It also may inhibit glucose 6-phosphatase. Thus, the
administration of chiro-inositol, as a dietary supplement,
is demonstrated and claimed in that parent application as
an effective treatment for insulin-resistant diabetics and
lowering blood sugar. Other copending applications are
directed to the mediator itself, as well as a method of
screening individuals for diabetic conditions, involving
assaying body fluids, including urine and serum, for the
presence of chiro-inositol.
It has been widely reported that insulin resistance,
which is characterized by the manifestation of
non-insulin-dependent diabetes mellitus (NIDDM) is
frequently associated with hypertension, coronary artery
disease (arter-iosclerosis) lactic acidosis and obesity, as
well as related disease states. These disease states are
associated with a cluster of risk factors, including
hyperinsulinemia, high plasma triglyceride concentration,
low HDL cholesterol concentration, and other risk factors
traditionally associated with coronary artery disease
(CAD). Although a variety of possible genetic and treatment
methodologies have been proposed, the fundamental
connection between these disease states, and a method of
treating that fundamental problem remains elusive.
Accordingly, it remains an object of those of skill in
the art to establish a fundamental understanding of the
relationship between the above-identified disease states,
and a method of treating the same.
Disclosure of the Invention
Applicants have now determined that the insulin
mediator incorporating chiro-inositol is apparently
responsible for the activation of at least one or both of
the glycogen synthase metabolic pathway and the pyruvate
dehydrogenase complex, specifically, activation of pyruvate
dehydrogenase-phosphatase or PDH-P as well as a glycogen
WO92/12706 2 1 0 17 7 5 PCT/US91/06197
synthase phosphatase or GS-P. It also inhibits glucose
6-phosphatase. While applicants do not wish to be bound by
this theory, it appears that the chiro-inositol containing
insulin mediator, for which chiro-inositol is necessary,
activates PDH-P, thus initiating the conversion of
phosphorylated inactive PDH to dephobphorylated or active
PDH, which is responsible, among other things, for
oxidative glucose metabolism. This mediator also activates
GS-P thus initiating the conversion of phosphorylated
inactive GS to dephosphorylated active GS responsible among
other things for non-oxidative glucose metabolism. It also
inhibits glucose 6-phosphatase, the enzyme responsible for
increasing blood sugar. Thus, individuals exhibiting low
levels of chiro-inositol, whether due to an inability to
synthesize chiro-inositol, a relatively high removal rate
of chiro-inositol, or a failure to absorb chiro-inositol,
will characteristically exhibit a failure of the PDH
complex, central to oxidative glucose metabolism, and
particularly, the conversion of pyruvate to oxidative
acetyl Co-A. It further appears that the mediator may also
be involved in the glycogen synthase side of the metabolic
pathway. Specifically, the action of glycogen synthase
phosphatase may be inhibited by the absence of the mediator
central to non-oxidative glucose metabolism; namely,
glycogen storage. A third step in glucose production,
namely, glucose 6-phosphatase may also be sensitive to
inhibition by the mediator. Thus, in the absence of the
mediator, glucose will be produced by the liver.
This failure may be partial or compl~te. Clearly, a
failure of the body's glucose metabolism is directly
implicated in a wide variety of the disease states
associated, on a statistical basis, with insulin-
resistance, including obesity, and a predisposition to
coronary artery disease. Similarly, lactic acidosis
implicates at least a partial failure of the PDH complex.
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An active PDH complex would lower lactic acid
levels. Hypertension and its associated insulin
resistance may be directly related to a failure of
the PDH complex, although the specific pathway
remains unclear.
Accordingly, a failure of the PDH complex
or of the GS complex, or of the glucose 6-
phosphatase due to a low level or absence of chiro-
inositol mediator (referred to as insulin mediator
in the parent application), caused by a failure of
chiro-inositol synthesis, may be treated by
administration of a dietary Supplement of chiro-
inositol. High levels of chiro-inositol may lead to
synthesis of the insulin mediator, allowing a
restoration of "normal" insulin direction of PDH
complex and GS complex activity and glucose 6-
phosphatase activity pathways, through the role of
this critical mediator.
The present invention is therefore
directed to the use of D-chiro-inositol for the
treatment of a mammal exhibiting elevated blood
sugar levels and at least one of hypertension,
lactic acidosis, obesity or coronary artery disease.
The invention is also directed to the use
of D-chiro-inositol for the treatment of a mammal
exhibiting elevated blood sugar levels, insulin
resistance and at least one of hypertension, lactic
acidosis, obesity or coronary artery disease.
According to another aspect of the
invention, there is provided a pharmaceutical
composition for the treatment of a mammal exhibiting
elevated blood sugar levels and at least one of
hypertension, lactic acidosis, obesity or coronary
artery disease. The pharmaceutical composition of
the invention comprises (i) D-chiro-inositol in an
amount effective to raise metabolic levels of chiro-
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inositol in the mammal, and (ii) a pharmaceutically
acceptable carrier.
Brief Description of the Invention
The invention comprises the administration
of chiro-inositol to individuals suffering from
disease conditions related to a partial or complete
failure of the PDH complex, glycogen synthase
pathway or related blood sugar level maintenance
mechanisms including glucose 6-phosphatase, owing to
a low level or absence of chiro-inositol necessary
for the synthesis of the insulin mediator
responsible for the activation of PDH-P and GS-P and
inhibition of glucose 6-phosphatase or additional
unknown mechanisms involving chiro-inositol. Thus,
administration of chiro-inositol, through a variety
of pathways, makes possible the synthesis of this
essential mediator, alleviating the disease
condition by treating its source, rather than
symptomatic treatment as is generally prescribed in
the art. The net result is a substantial reduction
of hallmark elevated blood sugar levels. Of course,
treatment by the administration of chiro-inositol,
according to the claimed invention, may be
accompanied by
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symptomatic treatment, to the extent such remains
appropriate.
The essential, non-dietary carbohydrate that is the
focus of this invention, chiro-inositol, is related to
myo-inositol, the structures of the various optically
active compounds being set forth hereinbelow.
D Chiro-lnosi~l L{:hiro Inositol My~lnosi~l
chiro-inositol is available from non-dietary sources, in
forms that may not be readily assimilated by the body.
Thus, the methylester of chiro-inositol is found in
sugar pine hardwood (PINUS LAMBERTIANA DOUGL) (Anderson,
AB 1953 Ind. Ency. Chem. 45, 593-596). Various
esterified forms can also be isolated from legumes
(Schweizer, T.F., Horman, I., Wuersch, P., 1978, J. Sci.
Food Agric., 29, pages 148-154). However, the
assimilatable sugar itself is not believed to appear, in
sufficient quantities, in normal dietary foods, to make
up for a lack of the ability to synthesize the sugar.
This inability may prevent the formation of the chiro-
inositol containing insulin mediator responsible for the
activation of PDH-P, GS-P or other suitable pathways for
lowering blood sugar including glucose 6-phosphatase.
The provision of a dietary supplement, in vitamin
amounts, to provide an in vivo therapeutic level of
chiro-inositol, overcomes this deficiency. Administra-
tion of chiro-inositol to those identified, through an
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appropriate screening text, as exhibiting low levels of
chiro-inositol, may be employed to achieve the goals of
this invention. Similarly, those exhibiting clinical
symptoms of the identified disease states, to the extent
they are dependent on the
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absence of the mediators, may be treated by simple
administration of the dietary supplement.
As noted above, chiro-inositol can be isolated from
natural sources through purification and deesterification
reactions. It can also be synthesized directly from myo-
inositol, commonly available, by direct inversion of the
hydroxyl on the three position.
In the general population, and those not likely to
develop the elevated blood sugar-related disease states
addressed herein, chiro-inositol is not present in
substantial concentrations. Accordingly, the dietary
supplement need be present only in vitamin-like
concentrations to provide an adequate means of
intervening in clinical conditions, as well as preventing
the onset of clinical symptoms in those predisposed to
their development. In general, dosage values will range
from 250 to 5000 milligrains, and may be achieved through
a variety of pathways. An alternative dosage formulation
would be administered in the range of 3.5-300 mg/kg,
preferably 3.5-70 mg/kg of body weight, more preferably
5-20 mg/kg. Adequacy of dosage levels may be determined
by assaying patient urine or serum levels for
chiro-inositol. Urinary levels below about l.0 ~g/ml, or
serum levels below about 0.l ~g/ml, are indicative of
chiro-inositol insufficiency. As noted above, the
carbohydrate is directly absorbed, and thus may be most
conveniently administered orally. Other forms of
administration are also suitable.
The active agent, chiro-inositol, may be
administered alone, or together with other actives. The
actives may be combined, by oral administration, with
additives chosen from the group consisting of sweetening
agents, flavoring agents, coloring agents and preserving
agents, in order to provide a palatable preparation.
Tablets containing the active ingredient in admixture
WO92/12706 2 10 1~ 7 ~ PCT/US91/06197
with non-toxic pharmaceutically acceptable excipients
which are suitable for manufacture of tablets are
acceptable. These excipients may be, for example, inert
diluents, such as calcium carbonate, sodium carbonate,
lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, such as maize
starch, or alginic acid,; binding agents, such as starch,
gelatin or acacia; and lubricating agents, such as
magnesium stearate, stearic acid or talc. Tablets may be
uncoated or may be coated by known techniques to delay
disintegration and adsorption in the gastrointestinal
tract and thereby provide a sustained action over a
longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate alone or
with a wax may be employed.
Formulations for oral use may also be presented as
hard gelatin capsules wherein the active ingredient is
mixed with an inert solid diluent, for example calcium
carbonate, calcium phosphate or kaolin, or as soft
gelatin capsules wherein the active ingredient is mixed
with water or an oil medium, such as peanut oil, liquid
paraffin or olive oil.
Aqueous suspensions of the invention contain the
active materials in admixture with excipients suitable
for the manufacture of aqueous suspensions. Such
excipients include suspending agent, such as sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulobe, sodiumalginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and
dispersing or wetting agents such as a naturally
occurring phosphatide (e.g. lecithin), a condensation
product of an alkylene oxide with a fatty acid (e.g.,
polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
haptadecaethyleneoxycetanol), a condensation product of
WO92/12706 ~ 21 U 1 7 7 5 PCT/US91/06197
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ethylene oxide with a partial ester derived from a fatty
acid and a hexitol (e.g., polyoxyethylene sorbitol
mono-oleate), or a condensation product of ethylene oxide
with a partial ester derived from fatty acid and a
hexitol anhydride (e. g., polyoxyethylene sorbitan
mono-oleate). The aqueous suspension may also contain one
or more preservative such as ethyl or n-propyl
p-hydroxybenzoate, one or more coloring agent, one or
more flavoring agent, and one or more sweetening agent,
such as sucrose or saccharin.
Oil suspensions may be formulated by suspending the
active ingredient in a vegetable oil, such as arachis
oil, olive oil, sesame oil or coconut oil, or in a
mineral oil such as liquid paraffin. The oil suspensions
may contain a thickening agent, such as beeswax, hard
paraffin or cetyl alcohol. Sweetening agents, such as
those set forth above, and flavoring agents may be added
to provide a palatable oral preparation. These
compositions may be preserved by the addition of an
antioxidant such as ascorbic acid.
Dispersible powders and granules of the invention
suitable for the preparation of an aqueous suspension by
the addition of water provide the active ingredient in
admixture with a dispersing or wetting agent, a
suspending agent, and one or more preservative. Suitable
dispersing or wetting agents and suspending agents are
exemplified by those disclosed above. Additional
excipients, for example sweetening, flavoring and
coloring agents, may also be present.
The pharmaceutical compositions of the invention may
also be in the form of oil-in-water emulsions. The oily
phase may be a vegetable oil, such as olive oil or
arachis oil, a mineral oil, such as liquid paraffin, or a
mixture of these. Suitable emulsifying agents include
naturally-occurring gums, such as gum acacia and gum
WO92/12706 2 10 17 7 ~ PCT/US91/06197
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tragacanth, naturally occurring phosphatides, such as
soybean lecithin, esters or partial esters derived from
fatty acids and hexitol anhydrides, such as sorbitan
mono-oleate, and condensation products of these partial
esters with ethylene oxide, such as polyoxyethylene
sorbitan mono-oleate. The emulsion may also contain
sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening
agents, such as glycerol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a
preservative, a flavoring or a coloring agent.
The pharmaceutical compositions of the invention may
be in the form of a sterile injectable preparation, such
as a sterile injectable aqueous or oleaginous suspension.
This suspension may be formulated according to the known
art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The
sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, such as a
solution in 1,3-butanediol. Among the acceptable vehicles
and solvents that may be employed are water.
Derivatives of chiro-inositol designed to increase
absorption and cellular transfer may include fatty acid
short or long chain esters or ethers, succinates,
diacylglycerol derivatives, esters of lactic or pyruvic
acid or amino acid or peptide ester derivatives or other
derivatives to be defined on the basis of biological
activity in vivo to lower blood sugar levels.
There are no known toxic or deleterious side effects
from the administration of chiro-inositol. Due to the
very low concentrations at which therapeutic levels are
achieved, the chiro-inositol can be administered to
virtually all those diagnosed either exhibiting clinical
symptoms of elevated blood sugar-related hypertension,
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obesity, coronary artery disease, lactic acidosis, and
obesity in combination with insulin-resistant diabetes,
or genetically predisposed to the development, through
the screening test discussed above. Thus, the dietary
additive addressed herein may be administered to infants
over the age of one year, and all others at risk or
exhibiting clinical symptoms. Under the age of one year,
it is believed that the digestive system may be
insufficiently developed to achieve positive results
through the addition of the dietary supplement.
The invention disclosed abQve has been described
with regard to specific examples, dosage levels, carriers
and additives. Within the scope of the claims appended
hereto, other formats, variations and combinations will
occur to those of ordinary skill in the art, without the
exercise of inventive skill. Such alterations do not
depart from the invention, except as provided in the
claims appended hereto.
