U.S. patent application number 11/279838 was filed with the patent office on 2006-10-19 for anti-inflammatory humate compositions and methods of use thereof.
Invention is credited to Horace G. Cutler, Stephen J. Cutler, Kevin Gill, John F. Lown, Stanley H. Pollock.
Application Number | 20060233894 11/279838 |
Document ID | / |
Family ID | 32681023 |
Filed Date | 2006-10-19 |
United States Patent
Application |
20060233894 |
Kind Code |
A1 |
Lown; John F. ; et
al. |
October 19, 2006 |
Anti-Inflammatory Humate Compositions and Methods of Use
Thereof
Abstract
The disclosure relates to an anti-inflammatory composition
containing humate, such as insoluble, granular, other insoluble, or
soluble humate, particularly Menefee Humate.RTM.. The disclosure
also includes other anti-inflammatory compositions containing
humate and at least one additional anti-inflammatory agent such as
indomethacin or another nonsteroidal anti-inflammatory drug. The
disclosure includes a method of treating acute or chronic
inflammation in an animal, including a human, by administering one
of these compositions. A method of facilitating the therapeutic
effect of a therapeutic drug in an animal by co-administering
humate is also provided.
Inventors: |
Lown; John F.; (Dallas,
TX) ; Gill; Kevin; (Dallas, TX) ; Cutler;
Stephen J.; (Roswell, GA) ; Cutler; Horace G.;
(Watkinsville, GA) ; Pollock; Stanley H.;
(Atlanta, GA) |
Correspondence
Address: |
BAKER BOTTS L.L.P.
2001 ROSS AVENUE
SUITE 600
DALLAS
TX
75201-2980
US
|
Family ID: |
32681023 |
Appl. No.: |
11/279838 |
Filed: |
April 14, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10336484 |
Jan 3, 2003 |
7067155 |
|
|
11279838 |
Apr 14, 2006 |
|
|
|
Current U.S.
Class: |
424/725 ;
514/420 |
Current CPC
Class: |
Y10S 514/866 20130101;
A61K 31/405 20130101 |
Class at
Publication: |
424/725 ;
514/420 |
International
Class: |
A61K 36/18 20060101
A61K036/18; A61K 31/405 20060101 A61K031/405 |
Claims
1. An anti-inflammatory composition comprising: humate as a primary
anti-inflammatory agent; and a pharmaceutically acceptable
carrier.
2. The composition of claim 1, wherein the humate is prehistoric
humate.
3. The composition of claim 2, wherein the humate is derived from
the Menefee Geological Formation in N. Mex.
4. The composition of claim 1, wherein the humate comprises at
least 50% humic acids.
5. The composition of claim 1, wherein the composition is for oral
or topical administration and the humate is insoluble, granular
humate.
6. The composition of claim 1, wherein the composition is for
injection administration and the humate is soluble.
7. The composition of claim 1, wherein the humate comprises between
approximately 0.1% and 1.0% by weight of the composition.
8. The composition of claim 7, wherein the humate comprises
approximately 0.1- 0.5% by weight of the composition.
9. The composition of claim 1, wherein humate constitutes the sole
anti-inflammatory agent.
10. The composition of claim 9, wherein at least one additional
anti-inflammatory agent is a nonsteroidal anti-inflammatory
drug.
11. The composition of claim 10, wherein the nonsteroidal
anti-inflammatory drug is an indole derivative.
12. The composition of claim 11, wherein the nonsteroidal
anti-inflammatory drug is indomethacin.
13. A method of reducing inflammation in a tissue of an animal
comprising supplying a composition containing humate as a primary
anti-inflammatory agent to the tissue through oral, topical or
injection administration.
14. The method of claim 13, wherein the humate is supplied orally
and constitutes approximately 0.1 to 0.5% by weight of the total
food consumed by the animal.
15. The method of claim 13, wherein the method comprises supplying
a composition containing humate as the sole anti-inflammatory
agent.
16-20. (canceled)
21. The method of claim 13, wherein the composition containing
humate is supplied orally and wherein the humate constitutes
approximately 0.1- 0.5% by weight of the animal's food intake
22. The method of claim 13, wherein the animal is a human.
23. The method of claim 13, wherein the inflammation is acute.
24. The method of claim 13, wherein the inflammation is
chronic.
25. The method of claim 24, wherein the inflammation is a result of
arthritis.
26-31. (canceled)
Description
PRIORITY CLAIM
[0001] The present application is a continuation under 35 U.S.C.
.sctn.120 of U.S. patent application Ser. No. 10/336,484, filed
Jan. 3, 2003, titled "Anti-Inflammatory Humate Compositions and
Methods of Use Thereof", issued as U.S. Pat. No. ______ on
______.
FIELD OF THE INVENTION
[0002] The present invention relates to anti-inflammatory humate
compositions and their methods of use. In particular, it relates to
humate compositions containing natural humate and other
anti-inflammatory chemicals. It additionally relates to the use of
humate in treating inflammation either alone or in combination with
other anti-inflammatory chemicals.
BACKGROUND OF THE INVENTION
[0003] Chemical studies of the composition of humates such as
Menefee Humate.RTM. and leonardite have revealed that they are
mainly composed of the mixed salts of acid radicals found in soil
humus, a product of the decay of organic matter that contains both
humic and nonhumic material. Such acid radicals are collectively
termed "humic acids", having individual factions named humin, humic
acid, ulmic acid and fulvic acid.
[0004] Humic acids, defined as the portion of soil humus that is
soluble in alkaline solution, but insoluble in acid solution, are a
form of organic matter that often is added to the soil to increase
fertility. Humic acids are found in rotting vegetable matter and
can be detected in the black slime of an ordinary compost pit in a
home garden. They are also found in the brown organic matter of a
variety of soils, as well as in peats, manure, lignite, leonardite,
brown coals, and the Menefee Humate.RTM..
[0005] The exact structure of the humic acids is unknown. However,
humic acids appear to be associations of molecules forming
aggregates of elongated bundles of fibers at low pH, and open
flexible structures perforated by voids at high pH. These voids, of
varying dimensions, trap organic or inorganic particles of
appropriate electronic charge. Humic acids do not have a single
unique structure, but are a mixture of intermediate chemical
products resulting from the decomposition and conversion of lignin
and other plant materials to hard coal. Humic acids apparently are
formed by the bacterial and chemical degradation of plant tissue,
but in soils they also may be formed by certain secondary processes
such as polymerization of polyphenols leached by rain from surface
leaf litter, and condensation of phenols, quinones, and proteins
that are provided by the action of soil micro-organisms and small
animals on soil carbohydrates. As a result, humic acids are best
characterized in terms of their origin and soil environment, rather
than in rigid terms of chemical composition or chemical
properties.
[0006] The humic acids have a large cation exchange capacity and
hold multivalent metallic elements, such as micronutrient elements,
very strongly. The molecular weight of the humic acids range from
800 to 500,000, with the weight average molecular weight ranging
from about 5,000 to about 50,000. The cation exchange capacity of
the humic acids varies from about 200 to about 600 meq CaCO.sub.2
per 100 grams at pH 7, depending upon the origin of the extracted
acids. Humic acids are polyelectrolytes and are believed to form
complexes with clay particles thus enabling humic acids to bind
multivalent elements with great tenacity. When the cation exchange
sites on the humic acid molecule are filled predominantly with
hydrogen ions, the material, considered to be an acid, is insoluble
in water. However, when the predominant cations at the exchange
sites are other than hydrogen, the material is called a "humate."
Humates of monovalent alkali metals or ammonia are soluble in
water. Such humates are referred to as "soluble". The humates of
most multivalent metals are insoluble in water. Such humates are
referred to as "insoluble". The term "humate" as used herein refers
to both humate as well as the humic acids found in humate.
[0007] Humate has been used for decades as plant fertilizer and as
an animal food supplement because of its general ability to produce
healthier animals. More recently it has been used as a dietary
supplement (See U.S. Pat. No. 5,626,881.) A variety of studies have
explored it effects in animals. For example, humic acids' capacity
to increase uptake of iron when administered as a humic acid/iron
chelate was studied by Fuchs and Kunhert (Dtsch. tierarzti, 97(5):
208-9 (1990)). Low molecular weight humic acids have been found to
be effective at crossing mitochondrial membranes (Viser, S.A. , The
Science of the Total Environment, 62: 347-354 (1987)). Humic acids
have also been shown to to absorb mutagenic chemicals and prevent
their disruptive effects in bacteria (Sato, T., et al., Mutation
Research, 162: 173-178 (1986); Sate, T., et al., Mutation Research,
176: 199-204 (1987)).
[0008] The effects of humate or humic acids on immune system
function have also been studied. Overall, humic acids and humate
have been found to stimulate immune cells or the immune response.
(See Gau, R.J., et al., Toxicol. Appl. Pharmacol. 166(1): 59-67
(2001); Lange, N., et al., Arch. Exper. Vet. Med., 2: 140-6 (1987);
Reide, U.N., et al., Virchows Archir. B. Cell Pathol., 60: 27-34
(1991); and Kuhnert et al., Dtsch. tierarztl. 96(1): 3-10 (1989).)
Thus it came as some surprise when Ye et al. (Ye, S.B., et al.,
Acta Acad. Med. Sichuan 2: 127-9 (1985)) reported that
intraperitoneal injection of Hong Yuan peat-derived sodium humate
reduced swelling of inflamed rat paws.
[0009] Although it is not impossible for an immune-stimulatory
agent to reduce inflammation, which is partially due to immune
response, agents with these properties in combination are not
common. Unfortunately, direct intraperitoneal injection of large
amounts of humate as described in Ye et al. is not practical for
non-experimental purposes. For example, Ye et al. injected 50 mg/kg
of soluble sodium humate; an equivalent amount for an adult human
weighing 100 kg would be 5 g of humate. Even if the humate were
solubilized in a very concentrated solution, this would require
injection of an uncomfortably large volume of liquid. Additionally,
although humate is generally beneficial, overly large amounts of it
are actually less effective as an anti-inflammatory agent than
smaller amounts and may cause other, unknown health problems.
[0010] Inflammation is signaled by redness, swelling, heat, and
pain as a reaction of the body against injury or assault. A variety
of chemicals have been implicated as chemical mediators of the
inflammatory reaction, including histamine, serotonin, kinins,
prostaglandins, platelet-activating factors, leukotrienes, and,
from nerve endings, substance P. Mediators of the acute
inflammatory reaction seem to play roles in one or more of
increasing vascular permeability, attracting leukocytes, producing
pain, local edema, and necrosis.
[0011] There are steroid and non-steroid, anti-inflammatory drugs
known to the art. U.S. Pat. No. 4,579,844, inventors Rovee et al.,
issued Apr. 1, 1986, discloses topically treating an inflammatory
condition of the skin by use of the prostaglandin synthetase
inhibitor concurrently with a corticosteroid. U.S. Pat. No.
4,404,198, inventor Kelley, issued Sep. 13, 1983, discloses the
topical application of a composition including phenyl salicylate to
treat inflammation. U.S. Pat. No. 3,980,778, inventors Ayer et al.,
issued Sep. 14, 1976, discloses asteroid for use in the topical,
oral or parenteral treatment of skin and mucous membrane
inflammations. Numerous other anti-inflammatory medications,
ranging from aspirin, acetaminophen and ibuprofen to newer COX-2
inhibitors and ketoprofin.
[0012] The wide variety of anti-inflammatory drugs is indicative of
the fact that not all drugs are suitable for every indication or
each individual patient. Despite this variety, there are still a
number of patients whose needs are not well-met by the available
range of anti-inflammatory drugs when administered in customary
fashions.
SUMMARY OF THE INVENTION
[0013] The present invention provides a novel anti-inflammatory
composition including humate as well as another composition
including humate with at least one other anti-inflammatory
chemical. The anti-inflammatory compositions may be for oral,
topical or injection administration to an animal, including a
human. In an exemplary embodiment, the humate is prehistoric humate
such as Menefee Humate.RTM. derived from the Menefee Geological
Formation in N. Mex. Additionally, in an exemplary embodiment the
humate comprises at least 50% humic acids.
[0014] When the mode of administration is oral or topical, the
humate may be insoluble, granular humate, other insoluble humate,
or soluble humate. When the mode of administration is by injection,
the humate is preferably soluble. In an exemplary embodiment, the
humate comprises between approximately 0.1% and 1.0% and, more
specifically, approximately 0.5% by weight of the composition.
Alternatively, the humate composition may be administered orally in
such a way that between approximately 0.1% and 1.0% and, more
specifically, approximately 0.5% by weight of the animal's total
food intake is humate.
[0015] The humate composition may also contain at least one
additional anti-inflammatory agent. In an exemplary embodiment,
this second agent is a nonsteroidal anti-inflammatory drug. For
example, it may be an indole derivative such as indomethacin.
[0016] The invention also includes a method of reducing
inflammation in a tissue of an animal, including a human, by
supplying a composition containing humate to the tissue through
oral, topical or injection administration. In an exemplary
embodiment, if the humate is supplied orally it may constitute
approximately 0.1% and 1.0% and, more specifically, approximately
0.5% by weight of the total food consumed by the animal.
[0017] The method may also include the additional step of supplying
a second anti-inflammatory agent to the tissue of an animal,
including a human, through oral, topical or injection
administration. In an exemplary embodiment, the dosage of the
second anti-inflammatory agent is reduced as compared with the
dosage that would be administered if no composition containing
humate were administered. The second anti-inflammatory agent may be
supplied in the composition containing humate or it may be supplied
in a separate composition from that containing humate. If the
second agent is supplied separately from the humate it may be
supplied approximately contemporaneously with the composition
containing humate using the same type of administration. In a
further exemplary embodiment, the humate acts a carrier to
facilitate transport of the second anti-inflammatory agent to the
tissue or cell where it exerts its activity. In another exemplary
embodiment, a synergistic effect between the humate and other
anti-inflammatory agent occurs.
[0018] In an exemplary embodiment, the composition containing
humate is supplied orally in such a manner that humate constitutes
approximately 0.1% and 1.0% and, more specifically, approximately
0.5% by weight of the animal's food intake and the second
anti-inflammatory composition is indomethacin administered in the
amount of approximately 3 mg/kg animal. The inflammation may be
acute or chronic. One example of chronic inflammation is
arthritis.
[0019] The invention additionally includes a method of increasing
the therapeutic effect in an animal, including a human, of a
therapeutic chemical by administering the therapeutic chemical with
humate. The administration of humate may be contemporaneous and in
the same manner as the administration of the therapeutic chemical,
such as when they are in a single composition.
[0020] In an exemplary embodiment, the humate serves as a carrier
for the therapeutic chemical and facilitates its delivery to a
tissue or cell of the animal where the therapeutic chemical exerts
its therapeutic effect. The humate and therapeutic chemical may be
administered orally, topically or by injection.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] The following drawings form part of the present
specification and are included to further demonstrate certain
aspects of the present invention. The invention may be better
understood by reference to one or more of these drawings in
combination with the detailed description of specific embodiments
presented herein.
[0022] FIG. 1 depicts the inhibitory effects of orally administered
insoluble, granular Menefee Humate.RTM. on carrageenan-induced
edema in rats. Percent inhibition reflects inhibition of swelling
in an edemic paw as compared to a non-edemic paw. Solution
percentages represent weight percentage of humate in powder
suspension with feed mix.
[0023] FIG. 2 depicts the inhibitory effects of orally administered
insoluble, granular Menefee Humate.RTM., indomethacin, and Menefee
Humate.RTM. plus indomethacin on carrageenan-induced edema in rats.
Percent inhibition reflects swelling in an edemic paw as compared
to a non-edemic paw. Solution percentages represent weight
percentage of humate in powder suspension with feed mix.
[0024] FIG. 3 depicts the anti-inflammatory effects of orally
administered insoluble, granular Menefee Humate.RTM. on
adjuvant-induced arthritis in rats. All results are from rats which
had received humate for 15 days. Solution percentages represent
weight percentage of humate in powder suspension with feed mix.
FIG. 3a depicts the effect of Menefee Humate.RTM. on % change in
arthrogram score after 15 days of humate administration. FIG. 3b
depicts the % change effect of Menefee Humate.RTM. on right hind
paw volume after 15 days of administration. FIG. 3c depicts the %
change effect of Menefee Humate.RTM. on left hind paw volume after
15 days of administration.
[0025] FIG. 4 depicts the anti-inflammatory effects of orally
administered insoluble, granular Menefee Humate.RTM. on
adjuvant-induced arthritis in rats. All results are from rats which
had received humate for 21 days. Solution percentages represent
weight percentage of humate in powder suspension with feed mix.
FIG. 4a depicts the effect of Menefee Humate.RTM. on arthrogram
score after 21 days of humate administration. FIG. 4b depicts the
effect of Menefee Humate.RTM. on right hind paw volume in mm of Hg
displaced after 21 days of administration. FIG. 4c depicts the
effect of Menefee Humate.RTM. on left hind paw volume in mm Hg
displaced after 21 days of administration.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The present invention relates to anti-inflammatory
compositions including humate, which may also contain or be
co-administered with at least one other anti-inflammatory agent.
The invention also includes methods of administering such
compositions to animals, including humans, with inflammation.
[0027] The humate may be administered in a soluble form or in a
granular, insoluble form or in other forms. In an exemplary
embodiment, granular, insoluble or soluble Menefee Humate.RTM. is
used. The mode of administration will depend upon the form of
humate, with soluble humate preferred for intravenous(IV),
intramuscular(IM) or other types of injection. Soluble humate may
also be used for oral ingestion or topical application, however,
insoluble, granular humate or other insoluble humate is also
suitable for these purposes. The humate may be administered to an
area of inflammation through injection or in topical applications.
Orally administered humate may be suitable to treat inflammation
anywhere in the body.
[0028] Humate may also be combined with at least one other
anti-inflammatory agent. Such combination may be effected by
preparing a composition containing both humate and at least one
other anti-inflammatory agent or by co-administering separate
compositions, for example, one containing humate and another or
others containing at least one other anti-inflammatory agent. In an
exemplary embodiment, if the humate and anti-inflammatory agent or
agents are in separate compositions, administration is
approximately contemporaneous. In another embodiment, humate is
administered on a regular basis, such as daily, while the
anti-inflammatory agent or agents are administered periodically,
for example to treat or prevent increased inflammation.
[0029] All compositions of the present invention may be prepared in
a pharmaceutically acceptable carrier. Different carriers may be
required depending upon the solubility of the humate selected. The
selection of an appropriate carrier will be apparent to one skilled
in the art. It is known in the art that pH of the solution affects
the solubility of humate and its constituent parts, such as certain
humic acids.
[0030] The following examples are included to demonstrate preferred
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventor to
function well in the practice of the invention, and thus can be
considered to constitute preferred modes for its practice. However,
those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments which are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
invention.
EXAMPLES
Example 1-Composition of Menefee Humate.RTM.
[0031] Menefee Humate.RTM. is a humate of prehistoric origin found
in the Menefee Geological Formation of northern N. Mex. Humate
differs in its chemical and physical properties depending upon the
source. Menefee Humate.RTM. is one of the world's highest quality
humates for other known uses. Therefore, it was selected for use in
the examples that follow.
[0032] Insoluble, granular Menefee Humate.RTM. is prepared by
mining then screening the humate to a desired granule size. Because
this process does not chemically alter the humate, it remains
insoluble. The pH of the insoluble, granular Menefee Humate.RTM. is
approximately 3.4 and its composition is approximately as follows:
TABLE-US-00001 Humic Acids 50.00% Nitrogen (N) 1.00% Potassium
(K.sub.2O) <0.10% Phosphate (P.sub.2O.sub.5) <0.10% Calcium
(Ca) 1.04% Sulfur (S) 0.18% Magnesium (Mg) 0.14% Iron (Fe) 0.30%
Manganese (Mn) 0.0004% Copper (Cu) 0.0002%
[0033] Other trace minerals may also be present in some
samples.
[0034] Soluble Menefee Humate.RTM. is prepared by forming a
solution of granular humate with water, potassium phosphate and a
wetting agent. The solution is then screened and processed through
a spray-dryer to obtain a water-soluble powder. This powder may be
added to water to form a solution with a desired concentration. The
pH of soluble Menefee Humate.RTM. is approximately 6.2 and its
composition is approximately as follows: TABLE-US-00002 Humic Acids
60.0% Fulvic Acid 26.0% Carbon 11.5% Calcium (Ca) 1.7% Sulfur (S)
0.4% Magnesium (Mg) 0.3% Iron (Fe) 0.06%
[0035] Other trace minerals may also be present in some
samples.
Example 2-Effects of Humate on Acute Inflammatory Response
[0036] Male Sprague Dawley rats weighing approximately 50 g were
purchased from Harlan U.S. and housed in wire cages in the animal
facility at Mercer University School of Pharmacy. The animals were
given a short period of time to acclimate to the new environment
and received powdered rat chow from Purina and water ad libitum. At
the beginning of the experimental period, insoluble, granular
Menefee Humate.RTM. was mixed with the powdered rat chow and placed
in feeders. Rats received chow with either 0.1%, 0.5% or 1.0%
insoluble, granular Menefee Humate.RTM. by weight. After 54 days of
receiving humate in their food, the animals were injected in the
subplantar region of the left hind paw with carrageenan (2%; 0.5 mg
in 0.05 ml of saline). This substance produces an acute
inflammation in the infected paw that increases over time and
reaches a maximum approximately three hours post-injection. The
contralateral paw received only saline and served as the negative
control.
[0037] The paw volumes were measured plethysmographically by
displacement of mercury three hours post-injection of the
carrageenan. The volume of the negative control paw was subtracted
from the volume of the carrageenan-injected paw to determine the
degree of inflammation present. The average volume of edema
obtained from the Menefee Humate.RTM.-treated animals was divided
by the average volume of edema from the control animals (carageenan
only, no humate) and the quotient (multiplied by 100) subtracted
from 100 to obtain the percent inhibition of edema produced by
Menefee Humate.RTM..
[0038] The effect of insoluble, granular Menefee Humate.RTM. on
carrageenan-induced edema is shown in FIG. 1. The 0.1% and the 0.5%
concentrations of humate produced a similar and statistically
significant inhibition of hind paw inflammation. The inhibition was
approximately 27% (P<0.05). The higher concentration of humate
did not affect the inflammatory process.
[0039] In the 0.1% group, there was one animal whose response to
inflammation did not appear to be typical of animals of that group.
If that animal is eliminated from the results, there was actually a
48% inhibition of carrageenan-induced edema. Therefore, it appears
that at certain concentrations beginning at approximately 0.1% by
weight of food, orally administered insoluble, granular Menefee
Humate.RTM. inhibits acute inflammation. This effect does not
persist however, at higher concentrations of humate, beginning at
approximately 1.0% by weight of food.
Example 3-Effect of Insoluble, Granular Menefee Humate.RTM. on
Anti-Inflammatory Activity of Indomethacin
[0040] Male Sprague Dawley rats weighing approximately 50 g were
purchased from Harlan U.S. and housed in wire cages in the animal
facility at Mercer University School of Pharmacy. The animals were
given a short period of time to acclimate to the new environment
and received powdered rat chow from Purina and water ad libitum. At
the beginning of the experimental period, the rats were divided
into six groups of eight each. Control and indomethacin only groups
received only powdered rat chow for the entire length of the
experiment. For the four other groups, insoluble granular Menefee
Humate.RTM. was mixed with the powdered rat chow and placed in
feeders. Rats received chow with either 0.1%, 0.5% or 1.0%
insoluble, granular Menefee Humate.RTM. by weight. After 37 days of
receiving humate in their food, the animals weighed approximately
278 g, which in an appropriate size for inducing inflammation. An
amount of indomethacin sufficient to achieve 50% inhibition of
carrageenan-induced edema (3mg/kg) was administered to the
indomethacin only group and to the 0.1% humate plus indomethacin
group. The indomethacin was administered subcutaneously 30 minutes
before the administration of carageenan. The rats were then
injected in one hind paw with carrageenan (2%). After three hours,
the hind paws were measured by mercury displacement.
[0041] The results of this experiment are shown in FIG. 2. As in
Example 2, the animals receiving 0.1% or 0.5% humate exhibited
significant inhibition of inflammation (approximately 30%,
P<0.05). That receiving only 0.05% humate exhibited only around
a 10% inhibition of inflammation, indicating that this dose was too
low to have a significant effect on carrageenan-induced edema.
Those animals receiving only indomethacin exhibited around a 50%
inhibition of edema, as expected (P<0.05).
[0042] Surprisingly, the animals that received both indomethacin
and 0.1% concentration of humate exhibited a 66.8% inhibition of
carrageenan-induced edema (P<0.05). This represents a 28%
increase in the anti-inflammatory activity as compared to
indomethacin alone. These results suggest that a combination of
indomethacin or another anti-inflammatory agent with insoluble,
granular Menefee Humate.RTM. or another humate may allow the
administration of lower amounts of the non-humate anti-inflammatory
compound. Given the toxicity and side-effects of many known
anti-inflammatory compounds (which are much more dangerous or
discomforting than any known side-effects of humate), this capacity
to lower the dose of such compounds required to treat inflammation
may greatly benefit both human and animal patients.
[0043] The basis for this increase in the effectiveness of
indomethacin may be due to a synergistic combination of the
anti-inflammatory effects of humate and those of indomethacin.
However, given the tendency of humate to bind to other molecules
and transport them across lipid membranes, it is also possible that
the humate serves as a carrier of the indomethacin, allowing it to
reach target areas more readily.
Example 4-Effects of Menefee Humate.RTM. on Chronic,
Immunologically-Induced Inflammatory Response
[0044] Male Sprague Dawley rats weighing approximately 50 g were
purchased from Harlan U.S. and housed in wire cages in the animal
facility at Mercer University School of Pharmacy. The animals were
given a short period of time to acclimate to the new environment
and received powdered rat chow from Purina and water ad libitum. At
the beginning of the experimental period, the rats were divided
into six groups of eight each. Negative and positive control groups
received only powdered rat chow for the entire length of the
experiment. For the four other groups, insoluble, granular Menefee
Humate.RTM. was mixed with the powdered rat chow and placed in
feeders. Rats received chow with either 0.1%, 0.5% or 1.0%
insoluble, granular Menefee Humate.RTM. by weight. All rats
remained on their assigned diets for 17 days prior to mycobacterium
administration and for 21 days after the administration.
[0045] When the animals reached a body weight known to allow the
greatest amount of inflammation (around 180 g), a heat-killed and
dried Mycobacterium butyricum (10 mg) suspended in light mineral
oil was injected into the base of the tail of all animals except
the negative control animals. The negative control group received
an injection of mineral oil only.
[0046] The Mycobacterium Wax D fraction induces a cellular immune
response with the first signs of inflammation appearing
approximately 12 to 15 days post-injection. At that time, an
inflammatory response was observed in all but the negative control
animals. The inflammatory response occurred in both hind paws, both
fore paws and the ears of the animals. The inflammation of the hind
paws as measured plesthmographically by displacement of mercury was
measured at 15 and 21 days post-injection. The degree of
inflammation in the forepaws and ears as well as the degree of hind
paw ankylosis was determined using a grading system know to the art
as the arthrogram score.
[0047] The effect of insoluble, granular Menefee Humate.RTM. on
arthritis in rats 15 days after injection is shown in FIG. 3a, b
and c. The effects of humate on inflammation 21 days after
injection are shown in FIG. 4a, b and c. Arthrogram scores were
obtained by visually grading the following: fore paws, redness and
swelling; ear, redness and/or nodular lesions; hind paws,
ankylosis; and tail, ankylosis and/or nodules. The scoring system
ranged from 0 to 2+, where 0 indicates no indications, 1+ indicates
moderate indications and 2+ indicates severe indications. A maximal
score of 18 could this be obtained. The average score obtained by
the drug-treated group was divided by the average score obtained by
the arthritic control group time 100. This number was subtracted
from 100 to obtain the percent inhibition caused by the Menefee
Humate.RTM..
[0048] To obtain the percent inhibition of adjuvant arthritis
produced by the Menefee Humate.RTM., the following calculations
were made: the average hind paw volume obtained for each paw of the
negative control animals (no adjuvant, only mineral oil) was
subtracted from the average hind paw volume obtained for each paw
of the positive control animals (animals received mycobacterium).
This volume represents the true inflammation produced in the
controls. The same procedure was performed on the Menefee
Humate.RTM.-treated animals to obtain the inflammation produced in
these animals. The effect of the inflammation produced by the
Menefee Humate.RTM. was then obtained by dividing the inflammation
obtained in the Menefee Humate.RTM.-treated group by the
inflammation obtained in the positive control group times 100. The
number was then subtracted from 100 to obtain the % inhibition
produced by the Menefee Humate.RTM..
[0049] The 0.5% concentration of the insoluble, granular Menefee
Humate.RTM. produced a statistically significant inhibition of the
arthrogram score (FIG. 3a) and right hind paw swelling (FIG. 3b) on
the 15th day after Mycobacterium injection (P<0.05 for 0.5%
concentration in both). Although some inhibition was also seen in
the left paw, it was not statically significant (FIG. 3c). The
0.05%, 0.1% and 1% concentrations of humate did not produce a
significant inhibitory effect on either the arthrogram score or
swelling in the left or right hind paw. When the effects of
insoluble, granular Menefee Humate.RTM. on chronic inflammation
were evaluated again at 21 days post-injection so statistically
significant inhibition of inflammation was seen.
[0050] This suggests that Menefee Humate.RTM., when ingested orally
at a concentration of approximately 0.5% by food weight prior to
and during onset of chronic inflammation, has an inhibitory effect
on chronic inflammation. However, such inhibitory effect is not
maintained for the long-term. Nevertheless, these results indicate
that humate may serve a purpose in delaying the onset of
debilitating effects of chronic inflammatory diseases, such as
arthritis. Humate may also present a viable alternative to stronger
medications that may have harmful side effects during the early
stages of some chronic inflammations.
[0051] All of the compositions and methods disclosed and claimed
herein can be made and executed without undue experimentation in
light of the present disclosure. While the compositions and methods
of this invention have been described in terms of preferred
embodiments, it will be apparent to those of skill in the art that
variations may be applied to the compositions and methods and in
the steps or in the sequence of steps of the method described
herein without departing from the concept, spirit and scope of the
invention. More specifically, it will be apparent that certain
agents which are both chemically and physiologically related may be
substituted for the agents described herein while the same or
similar results would be achieved. All such similar substitutes and
modifications apparent to those skilled in the art are deemed to be
within the spirit, scope and concept of the invention as defined by
the appended claims
* * * * *