U.S. patent application number 16/873379 was filed with the patent office on 2020-07-30 for methods for treatment of lung damage and for inhibition of lung fibrosis.
The applicant listed for this patent is Alain Martin. Invention is credited to Alain Martin.
Application Number | 20200237815 16/873379 |
Document ID | 20200237815 / |
Family ID | 1000004767583 |
Filed Date | 2020-07-30 |
United States Patent
Application |
20200237815 |
Kind Code |
A1 |
Martin; Alain |
July 30, 2020 |
Methods for treatment of lung damage and for inhibition of lung
fibrosis
Abstract
A method of stimulating the synthesis of human and animal
patient lung and sinus surfactants for treatment of lung damage
needed to increase lung functions, increase oxygen levels, increase
the synthesis of nasal nitric oxide and for inhibition of lung
fibrosis while reducing, coughing, lung tightness, mouth breathing,
and reducing congestion, for treating patients with a pulmonary
condition including asthma, chronic obstructive pulmonary disease,
cystic fibrosis, interstitial lung disease, pulmonary fibrosis,
allergic rhinitis, sinusitis, sleep apnea and lung cancer,
includes: contacting mammalian cells with a therapeutically
effective amount of a composition, said composition including the
following constituents: sodium pyruvate; a phosphate; a salt of
calcium; and, a salt of magnesium. Preferably, the composition is a
saline solution.
Inventors: |
Martin; Alain; (Flemington,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Martin; Alain |
Flemington |
NJ |
US |
|
|
Family ID: |
1000004767583 |
Appl. No.: |
16/873379 |
Filed: |
April 1, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15441552 |
Feb 24, 2017 |
|
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16873379 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0073 20130101;
A61K 31/19 20130101; A61P 11/06 20180101; A61P 11/00 20180101; A61K
9/08 20130101; A61K 33/06 20130101; A61K 33/42 20130101 |
International
Class: |
A61K 33/42 20060101
A61K033/42; A61K 31/19 20060101 A61K031/19; A61K 33/06 20060101
A61K033/06; A61K 9/08 20060101 A61K009/08; A61K 9/00 20060101
A61K009/00; A61P 11/00 20060101 A61P011/00; A61P 11/06 20060101
A61P011/06 |
Claims
1. A method of stimulating the synthesis of human and animal
patient lung and sinus surfactants for treatment of lung damage
needed to increase lung functions, increase oxygen levels, increase
the synthesis of nasal nitric oxide and for inhibition of lung
fibrosis while reducing, coughing, lung tightness, mouth breathing,
and reducing congestion, for treating patients with a pulmonary
condition including asthma, chronic obstructive pulmonary disease,
cystic fibrosis, interstitial lung disease, pulmonary fibrosis,
allergic rhinitis, sinusitis, sleep apnea and lung cancer, which
comprises: contacting mammalian cells with a therapeutically
effective amount of a composition, said composition including the
following constituents: a) sodium pyruvate; b) a phosphate; c) a
salt of calcium; and, d) a salt of magnesium; wherein said
composition contains the following amounts of said constituents:
sodium pyruvate ranges from about 0.0001 mg to about 1 gram; and
ranges from 0.0001 mg to about 1 gram for each of the following
constituents: phosphate, salt of calcium and salt of magnesium.
2. The method of claim 1 wherein said composition is a saline
solution.
3. The method of claim 1, wherein the phosphate is selected from
the group consisting of calcium phosphate, a potassium phosphate,
magnesium phosphate, and zinc phosphate, and combinations
thereof.
4. The method of claim 3, wherein said phosphate is a calcium
phosphate selected from the group consisting of calcium phosphate,
di-calcium phosphate and combinations thereof.
5. The method of claim 3, wherein said phosphate is a potassium
phosphate selected from the group consisting of potassium
phosphate, di-potassium phosphate, tri-potassium phosphate, and
combinations thereof.
6. The method of claim 1, wherein said salt of calcium is selected
from the group consisting of calcium chloride, calcium carbonate,
calcium acetate, calcium citrate, calcium lactate, calcium sulfate,
and combinations thereof.
7. The method of claim 1, wherein said salt of magnesium is
selected from the group consisting of magnesium chloride, magnesium
phosphate, magnesium sulfate, magnesium bicarbonate, and
combinations thereof.
8. The method of claim 1, wherein the phosphate is selected from
the group consisting of calcium phosphate, a potassium phosphate,
magnesium phosphate, and zinc phosphate, and combinations thereof,
and wherein said salt of magnesium is selected from the group
consisting of magnesium chloride, magnesium phosphate, magnesium
sulfate, magnesium bicarbonate, and combinations thereof.
9. The method of claim 1, wherein said salt of magnesium is
selected from the group consisting of magnesium chloride, magnesium
phosphate, magnesium sulfate, magnesium bicarbonate, and
combinations thereof, and wherein said salt of calcium is selected
from the group consisting of calcium chloride, calcium carbonate,
calcium acetate, calcium citrate, calcium lactate, calcium sulfate,
and combinations thereof.
10. The method of claim 1, wherein the phosphate is selected from
the group consisting of calcium phosphate, a potassium phosphate,
magnesium phosphate, and zinc phosphate, and combinations thereof,
and wherein said salt of calcium is selected from the group
consisting of calcium chloride, calcium carbonate, calcium acetate,
calcium citrate, calcium lactate, calcium sulfate, and combinations
thereof.
11. The method of claim 1, wherein the phosphate is selected from
the group consisting of calcium phosphate, a potassium phosphate,
magnesium phosphate, and zinc phosphate, and combinations thereof,
and wherein said salt of magnesium is selected from the group
consisting of magnesium chloride, magnesium phosphate, magnesium
sulfate, magnesium bicarbonate, and combinations thereof, and
wherein said salt of calcium is selected from the group consisting
of calcium chloride, calcium carbonate, calcium acetate, calcium
citrate, calcium lactate, calcium sulfate, and combinations
thereof.
12. The method of claim 1, wherein said composition is a saline
solution containing sodium pyruvate, calcium chloride, potassium
phosphate and magnesium chloride ions in solution.
13. The method of claim 1, wherein said composition contains the
following amounts of said constituents: sodium pyruvate ranges from
about 0.01 mg to about 1 gram; and ranges from 0.0001 mg to about 1
gram for each of the following constituents: phosphate, salt of
calcium and salt of magnesium.
14. The method of claim 1, wherein said composition contains the
following amounts of said constituents: sodium pyruvate ranges from
about 0.01 mg to about 1 gram; and ranges from 0.0001 mg to about 1
gram for each of the following constituents: phosphate, salt of
calcium and salt of magnesium.
15. The method of claim 11, wherein said composition contains the
following amounts of said constituents: sodium pyruvate ranges from
about 0.01 mg to about 1 gram; and ranges from 0.0001 mg to about 1
gram for each of the following constituents: phosphate, salt of
calcium and salt of magnesium.
16. The method of claim 12, wherein said composition contains the
following amounts of said constituents: sodium pyruvate ranges from
about 0.01 mg to about 1 gram; and ranges from 0.0001 mg to about 1
gram for each of the following constituents: phosphate, salt of
calcium and salt of magnesium.
17. The method of claim 1, wherein a therapeutic agent is
administered prior to contacting said mammalian cells with said
composition.
18. The method of claim 1, wherein a therapeutic agent is
administered simultaneously with contacting said mammalian cells
with said composition.
19. The method of claim 1, wherein a therapeutic agent is
administered after contacting said mammalian cells with said
composition.
20. The method of claim 1, wherein said method includes cancer
treatment and an oral diet is administered before and after said
cancer treatment and said oral diet includes the composition set
forth in the method of claim 1.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation-in-part of United
States co-pending utility application Ser. No. 15/441,552, filed on
Feb. 24, 2017, Official Docket No. CSI-011, and titled
"Compositions and Methods for the Treatment and Prevention of
Chronic Hypoxemia and Dyspnea" by the same inventor herein.
BACKGROUND OF INVENTION
a. Field of Invention
[0002] The present invention generally relates to methods utilizing
compositions that enhance the synthesis of lung surfactants that
have been decreased by lung diseases or injuries. The present
invention is based on the discovery that the pulmonary dysfunction,
characteristic of certain disease states, is attributable to the
decrease in the synthesis of a number of surfactant and other
secretory molecules normally produced by type II alveolar cells,
leading to lung tightness, reduced lung capacity and function and
volume, coughing, dyspnea and hypoxemia.
b. Description of Related Art
[0003] The following patents are representative of the field
pertaining to the present invention:
[0004] U.S. Pat. No. 5,210,098 issued to Nath discloses a method to
arrest or prevent acute kidney failure by administration of a
non-toxic pyruvate salt to a patient in need of such treatment. The
Nath invention provides a therapeutic method comprising
administration of an amount of pyruvate salt to a patient
experiencing, or in danger of, acute renal failure.
[0005] U.S. Pat. Nos. 3,920,835, 3,984,556, 3,988,470, and
4,234,599 all issued to Van Scott et al. disclose methods for
treating acne, dandruff, and palmar keratosis, respectively, which
consist of applying to the affected area a topical composition
comprising from about 1% to about 20% of a lower aliphatic compound
containing from two to six carbon atoms selected from the group
consisting of alpha-hydroxy acids, alpha-ketoacids and esters
thereof, and 3-hydroxybutryic acid in a pharmaceutically acceptable
carrier. The aliphatic compounds include pyruvic acid and lactic
acid.
[0006] U.S. Pat. Nos. 4,158,057, 4,351,835, 4,415,576, and
4,645,764, all issued to Stanko, disclose methods for preventing
the accumulation of fat in the liver of a mammal due to the
ingestion of alcohol, for controlling weight in a mammal, for
inhibiting body fat while increasing protein concentration in a
mammal, and for controlling the deposition of body fat in a living
being, respectively.
[0007] U.S. Pat. Nos. 5,798,388, 5,939,459, 5,952,384 and 6,623,723
to Katz and Martin, the inventor herein, pertain to methods for
treating inflammation in the lungs and compositions useful in the
method. The method comprises contacting the mammalian cells
participating in the inflammatory response with an inflammatory
mediator. The inflammatory mediator is present in an amount capable
of reducing the undesired inflammatory response and is an
antioxidant.
[0008] U.S. Pat. No. 6,689,810 to Martin, the inventor herein,
discloses a therapeutic composition for treating pulmonary diseases
states in mammals by altering indigenous in vivo levels of nitric
oxide. The therapeutic composition consists of pyruvates, pyruvate
precursors, alpha-keto acids having four or more carbon atoms,
precursors of alpha-keto acids having four or more carbons, and the
salts thereof. Martin also claimed that all salts of pyruvate were
equal.
[0009] U.S. Pat. Nos. 8,076,373 and 8,114,907 Martin, the inventor
herein, discloses a method for treating pulmonary disease state in
mammals by up or down regulating in vivo levels of inflammatory
agents (cytokines) in mammalian cells.
[0010] United States Patent Application Publication No.
2009/0181007 to Gennero et al describes a composition for in vitro
use to create a culture medium for accelerating the differentiation
of stem cells into cells with a chondrocytes phenotype and for
restoring the original trophism of chondrocytes, to increase the
synthesis of collagen, to repair joint damage. The increase in
collagen deposition increases fibrosis. This prior art reference,
as well as some Katz et al references, were cited in the parent
application of this instant application and are discussed in more
detail below.
SUMMARY OF THE INVENTION
[0011] The present invention is directed to a method of stimulating
the synthesis of human and animal patient lung and sinus
surfactants for treatment of lung damage needed to increase lung
functions, increase oxygen levels, increase the synthesis of nasal
nitric oxide and for inhibition of lung fibrosis while reducing,
coughing, lung tightness, mouth breathing, and reducing congestion,
for treating patients with a pulmonary condition including asthma,
chronic obstructive pulmonary disease, cystic fibrosis,
interstitial lung disease, allergic rhinitis, chronic
rhinosinusitis, sleep apnea and lung cancer. This method includes
contacting mammalian cells with a therapeutically effective amount
of a composition, said composition including the following
constituents: sodium pyruvate; a phosphate; a salt of calcium; and,
a salt of magnesium wherein said composition contains the following
amounts of said constituents: sodium pyruvate ranges from about
0.0001 mg to about 1 gram; and ranges from 0.0001 mg to about 1
gram for each of the following constituents: phosphate, salt of
calcium and salt of magnesium.
[0012] In some preferred embodiments of the present invention
method, the composition is a saline solution. In some preferred
embodiments of the present invention method, the phosphate is
selected from the group consisting of calcium phosphate, a
potassium phosphate, magnesium phosphate, and zinc phosphate, and
combinations thereof. In some preferred embodiments of the present
invention method, the phosphate is a calcium phosphate selected
from the group consisting of calcium phosphate, di-calcium
phosphate and combinations thereof. In some preferred embodiments
of the present invention method, the phosphate is a potassium
phosphate selected from the group consisting of potassium
phosphate, di-potassium phosphate, tri-potassium phosphate, and
combinations thereof. In some preferred embodiments of the present
invention method, the salt of calcium is selected from the group
consisting of calcium chloride, calcium carbonate, calcium acetate,
calcium citrate, calcium lactate, calcium sulfate, and combinations
thereof. In some preferred embodiments of the present invention
method, the salt of magnesium is selected from the group consisting
of magnesium chloride, magnesium phosphate, magnesium sulfate,
magnesium bicarbonate, and combinations thereof.
[0013] In some preferred embodiments of the present invention
method, the phosphate is selected from the group consisting of
calcium phosphate, a potassium phosphate, magnesium phosphate, and
zinc phosphate, and combinations thereof, and wherein said salt of
magnesium is selected from the group consisting of magnesium
chloride, magnesium phosphate, magnesium sulfate, magnesium
bicarbonate, and combinations thereof. In some preferred
embodiments of the present invention method, the salt of magnesium
is selected from the group consisting of magnesium chloride,
magnesium phosphate, magnesium sulfate, magnesium bicarbonate, and
combinations thereof, and wherein said salt of calcium is selected
from the group consisting of calcium chloride, calcium carbonate,
calcium acetate, calcium citrate, calcium lactate, calcium sulfate,
and combinations thereof. In some preferred embodiments of the
present invention method, the phosphate is selected from the group
consisting of calcium phosphate, a potassium phosphate, magnesium
phosphate, and zinc phosphate, and combinations thereof, and
wherein said salt of calcium is selected from the group consisting
of calcium chloride, calcium carbonate, calcium acetate, calcium
citrate, calcium lactate, calcium sulfate, and combinations
thereof.
[0014] In some preferred embodiments of the present invention
method, the phosphate is selected from the group consisting of
calcium phosphate, a potassium phosphate, magnesium phosphate, and
zinc phosphate, and combinations thereof, and wherein said salt of
magnesium is selected from the group consisting of magnesium
chloride, magnesium phosphate, magnesium sulfate, magnesium
bicarbonate, and combinations thereof, and wherein said salt of
calcium is selected from the group consisting of calcium chloride,
calcium carbonate, calcium acetate, calcium citrate, calcium
lactate, calcium sulfate, and combinations thereof.
[0015] In some most preferred embodiments of the present invention
method, the composition is a saline solution containing sodium
pyruvate, calcium chloride, potassium phosphate and magnesium
chloride ions in solution.
[0016] In some preferred embodiments of the present invention
method, the composition contains the following amounts of said
constituents: sodium pyruvate ranges from about 0.01 mg to about 1
gram; and ranges from 0.0001 mg to about 1 gram for each of the
following constituents: phosphate, salt of calcium and salt of
magnesium. In some more preferred embodiments of the present
invention method, the composition contains the following amounts of
said constituents: sodium pyruvate ranges from about 0.01 mg to
about 1 gram; and ranges from 0.0001 mg to about 1 gram for each of
the following constituents: phosphate, salt of calcium and salt of
magnesium.
[0017] In some preferred embodiments of the present invention
method, a therapeutic agent is administered prior to contacting
said mammalian cells with said composition. In some preferred
embodiments of the present invention method, a therapeutic agent is
administered simultaneously with contacting said mammalian cells
with said composition. In some preferred embodiments of the present
invention method, a therapeutic agent is administered after
contacting said mammalian cells with said composition.
[0018] In some preferred embodiments of the present invention
method, the method includes cancer treatment and an oral diet is
administered before and after said cancer treatment and said oral
diet includes any of the compositions set forth above.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The present invention is based on the discovery that the
pulmonary dysfunction, characteristic of certain disease states is
attributable to the decrease in the synthesis of surfactants and
other secretory molecules normally produced by type II alveolar
cells. This decrease in synthesis is believed to be caused by the
low levels of key lung nutrients that results in abnormally
functioning mitochondria in alveoli leading to lung tightness,
reduced lung capacity and functions and volume, coughing, dyspnea
and Hypoxemia. It is believed that nutrient depleted or injured or
damaged alveoli's cause a generalized decrease in the normal rate
of membrane trafficking within the type II cells results in a
generalized defect in the synthesis and secretory process,
including secondary effects which involve a significant decrease in
the level of the synthesis of membrane phospholipids. Type II
(Great Alveolar) cells that secrete pulmonary surfactants needed to
lower the surface tension of water and allows the membrane to
separate, therefore increasing its capability to exchange gases
that maintain SaO2 oxygen saturation at or near 100%. Surfactant is
continuously released by exocytosis. It forms an underlying aqueous
protein-containing hypo phase and an overlying phospholipid film
composed primarily of dipalmitoyl phosphatidylcholine.
[0020] This decrease in the synthesis of surfactants in turn causes
an increase in surface tension of the aqueous film bathing the
luminal aspect of the alveolar space, a decrease in the elastic
properties of pulmonary tissue, a concomitant decrease in the rate
of gas exchange within the alveolus, and an overall decrease in
pulmonary function causing lung tightness, breathlessness,
increased coughing, and a decrease in lung capacity. As a result,
the patient develops a pulmonary disease syndrome, including
hampered breathing and inefficient gas exchange, with low SaO.sub.2
levels called chronic hypoxemia. Reinflation of the alveoli
following exhalation is made easier by pulmonary surfactant, which
is a phospholipid and protein mixture that reduces surface tension
in the thin fluid coating within all alveoli. Insufficient
pulmonary surfactant in the alveoli can contribute to atelectasis
(collapse of part or all of the lung). Without pulmonary
surfactant, atelectasis is a certainty; however, there are other
causes of lung collapse such as trauma (pneumothorax), COPD, and
pleuritis.
[0021] Decrease in lung surfactants also cause coughing and
breathlessness. Cough is usually the first symptom to develop. It
is productive with sputum (phlegm). It tends to come and go at
first, and then gradually becomes more persistent (chronic). You
may think of your cough as a `smokers cough` in the early stages of
the disease. It is when the breathlessness begins that people often
become concerned.
[0022] Breathlessness (`shortness of breath`) and wheezing may
occur only when you exert yourself at first, for example, when you
climb stairs. These symptoms tend to become gradually worse over
the years if you continue to smoke. Difficulty with breathing may
eventually become quite distressing. The damaged airways generally
make a lot more mucus than normal. This forms sputum (phlegm). You
tend to cough up a lot of sputum each day. Chest infections are
more common if you have COPD. Wheezing with cough and
breathlessness may become worse than usual if you have a chest
infection. Sputum usually turns yellow or green during a chest
infection.
[0023] The phosphatidylcholine in some organs contains relatively
high proportions of desaturated molecular species. For example, it
is well known that lung phosphatidylcholine in most if not all
animal species studied to date contains a high proportion (50% or
more) of dipalmitoyl phosphatidylcholine. It appears that this is
the main surface-active component, providing alveolar stability by
decreasing the surface tension at the alveolar surface to a very
low level. Also, the internal lipids of the animal cell nucleus
(after the external membrane has been removed) contain a high
proportion of desaturated phosphatidylcholine, amounting to 10% of
the volume indeed. This is synthesized entirely within the nucleus,
unlike phosphatidylinositol for example, and in contrast to other
cellular lipids its composition cannot be changed by extreme
dietary manipulation. The components of pulmonary surfactant are
synthesized in the Golgi apparatus of the endoplasmic reticulum of
the type II alveolar cell and the secretion is induced by
endoplasmic reticulum Ca.sub.2 ATP-ase. Infant respiratory distress
syndrome (IRDS) is a syndrome caused by lack of surfactant in the
lungs of premature infants.
[0024] Hypoxemia is to be understood as and refers to low oxygen in
the blood which reduces oxygen to the whole body. Hypoxia is
abnormally low oxygen content in any tissue or organ caused by
injury, disease or drugs. Patients can have hypoxia, without
suffering from Hypoxemia. The two are separate diseases. Chronic
hypoxemia symptoms also include lung tightness, breathlessness,
coughing, low lung capacity and volume. Hypoxemia can be caused by
injury to the lungs, caused by lung and sinus diseases and
infections, including COPD, chemicals, ozone, lung cancer, and a
host of medications that can injure lung cells and decrease the
production of lung surfactants. Patients with hypoxemia are usually
on oxygen therapy. Hypoxemia is usually defined in terms of reduced
partial pressure of oxygen (mm Hg) in arterial blood, but also in
terms of reduced content of oxygen (ml oxygen per dl blood) or
percentage saturation of hemoglobin (the oxygen binding protein
within red blood cells) with oxygen, which is either found singly
or in combination. In an acute context, hypoxemia can cause
symptoms such as those in respiratory distress. These include
breathlessness, an increased rate of breathing, use of the chest
and abdominal muscles to breathe, and lip pursing. However, in a
chronic context, and if the lungs are not well ventilated
generally, this mechanism can result in pulmonary hypertension,
overloading the right ventricle of the heart and causing cor
pulmonale and right sided heart failure. Polycythemia can also
occur. In children, chronic hypoxemia may manifest as delayed
growth, neurological development and motor development and
decreased sleep quality with frequent sleep arousals. Other
symptoms of hypoxemia may include cyanosis, and digital clubbing.
Severe hypoxemia can lead to respiratory failure. Many patients
with lung or sinus diseases experience Hypoxemia. It can be due to
the destruction of the alveoli in the lungs or the inadequate
production of lung surfactants that enhance oxygen up take.
Hypoxemia can occur in patients with and without lung or sinus
diseases, in patients with lung infections, heavy metal poisoning
with metals like cyanide, and the use of inhaled or non-inhaled
drugs. It must be noted that there is a difference between people
who have transient hypoxemia vs. one that has permanent hypoxemia.
The patients respond differently to the inhalation of sodium
pyruvate by itself without calcium, phosphate and magnesium. Sodium
pyruvate in saline given both orally or by inhalation will increase
.sub.SaO2 levels in people without hypoxemia. Transient hypoxemia
(hypoxic endurance) is a self-correcting effect and does not
involve lung injury or the inability to synthesize lung
surfactants. It occurs in over exercising, mountain climbing
etc.
[0025] In controlled inhalation studies, patients without
hypoxemia, lung injuries or diseases, that produce normal levels of
lung surfactants, have shown an increase of .sub.SaO2 by an average
of 2%-3% when treated with sodium pyruvate in saline especially
after exercising. Sodium pyruvate solution was administered in
sterile water via a nebulizer to 54 patients and 15 healthy
subjects, and the concentrations of nitric oxide exhaled from
patients/healthy subjects were measured, as were their oxygen
saturation levels. Pyruvate was administered in a nebulizer 5 ml at
one time.
[0026] The pyruvate concentrations were 0.5 mMol, 1.5 mMol, 5.0
mMol and 20 mMol. Each concentration was inhaled once per day.
Prior to the inhalation of pyruvate, nitric oxide measurements were
taken, as were oxygen saturation levels. Those levels were then
taken one hour after the inhalation of the pyruvate solutions. The
results showed that the 5 mM and 20 mM solution increased nitric
oxide levels by 22% in all subjects. Saline alone did not increase
nitric oxide levels or .sub.SaO2 in any subject. Oxygen saturation
was increased by 3% in these patients.
[0027] In controlled inhalation studies, performed as part of this
patent, patients with hypoxemia or lung injuries or diseases, and a
decreased ability to synthesize lung surfactants, did not show an
increase of .sub.SaO2 or nitric oxide when treated with inhaled
sodium pyruvate in saline alone, and did not show a reduction in
lung tightness, Dyspnea, coughing and increase lung capacity or
volume.
[0028] Hypoxia in Cancer Cells:
[0029] Small cell lung cancer (SCLC) is an extremely aggressive
disease for which minimal therapeutic improvements have been made
over the last few decades. Patients still rely on non-targeted,
chemotherapeutic drugs complemented by irradiation. Although
initial response is very good, the majority of SCLC patients
invariably relapse with therapy-resistant tumors. Despite the link
between pathologically low oxygen levels and therapy resistant
tumors, hypoxia has gained little attention in the development of
novel therapies for SCLC. In contrast, the advantages of targeting
hypoxic cells in many other cancer types have been studied
extensively. Hypoxia is an important factor in tumor biology and is
both a predictive and a prognostic factor in non-small cell lung
cancer. The negative effect of low oxygenation on radiation therapy
effect has been known for decades, but more recent research has
emphasized that hypoxia also has a profound effect on a tumor's
aggression and metastatic propensity. Hypoxia is prevalent in small
cell lung cancer (SCLC) tumors and leads to cellular adaptations
associated with aggressive tumors. Many methods of targeting
hypoxia for cancer therapy have been explored; however, this
treatment remains relatively under-investigated for SCLC.
[0030] Low oxygen levels in cells may be a primary cause of
uncontrollable tumor growth in some cancers, according to a new
University of Georgia study. The authors' findings run counter to
widely accepted beliefs that genetic mutations are responsible for
cancer growth. If hypoxia, or low oxygen levels in cells, is proven
to be a key driver of certain types of cancer, treatment plans for
curing the malignant growth could change in significant ways.
[0031] The research team analyzed samples of messenger RNA
data--also called transcriptomic data--from seven different cancer
types in a publicly available database. They found that long-term
lack of oxygen in cells may be a key driver of cancer growth. The
study was published in the early online edition of the Journal of
Molecular Cell Biology.
[0032] Previous studies have linked low oxygen levels in cells as a
contributing factor in cancer development, but not as the driving
force for cancer growth. High incidence rates of cancer around the
world cannot be explained by chance genetic mutations alone.
[0033] In their study, the researchers analyzed data downloaded
from the Stanford Microarray Database via a software program to
detect abnormal gene expression patterns in seven cancers: breast,
kidney, liver, lung, ovary, pancreatic and stomach.
[0034] They relied on the gene HIF1A as a biomarker of the amount
of molecular oxygen in a cell. All seven cancers showed increasing
amounts of HIF1A, indicating decreasing oxygen levels in the cancer
cells.
[0035] Low oxygen levels in a cell interrupt the activity of
oxidative phosphorylation, a term for the highly efficient way that
cells normally use to convert food to energy. As oxygen decreases,
the cells switch to glycolysis to produce their energy units,
called ATP. Glycolysis is a drastically less efficient way to
obtain energy, and so the cancer cells must work even harder to
obtain even more food, specifically glucose, to survive. When
oxygen levels dip dangerously low, angiogenesis, or the process of
creating new blood vessels, begins. The new blood vessels provide
fresh oxygen, thus improving oxygen levels in the cell and tumor
and slowing the cancer growth but only temporarily.
[0036] This patent highlights various treatment options available
for increasing lung surfactants that are responsible for increasing
blood oxygen levels in cancer Patients thus targeting hypoxic cells
within tumors that could be highly beneficial in the treatment of
SCLC.
[0037] List of Conditions and Drugs that Impair the Synthesis of
Lung Surfactants that Cause Chronic Hypoxemia:
[0038] Hypoxemia is caused by insufficient synthesis of lung
surfactants that decreases lung gas exchange, increases lung
tightness, coughing and decreases lung capacity. Hypoxemia can be
caused by malnutrition, by injury to the lungs, caused by lung and
sinus diseases like COPD and asthma, and infections, chemicals,
ozone, lung cancer, pulmonary edema, bronchiectasis, bronchiolitis,
emphysema, bronchial pneumonia, allergic bronchopneumonia, Allergic
Rhinitis, viral pneumonia, Respiratory mucus, nasal congestion, and
encephalitis with retained secretions and a host of medications
that can injure lung cells that synthesize lung surfactants.
Patients with hypoxemia are usually on oxygen therapy.
[0039] Medications Administered by Respiratory Therapy that Cause
Hypoxemia:
[0040] The inhaled drugs listed below have some or many of these
adverse effects: Hypoxemia, Chest pain, nausea, vomiting, coughing,
bronchospasm, headaches, hypoventilation, hypotension, bradycardia,
increased infections, blurred vision, mucosal irritation, fatigue,
and shortness of breath. Epinephrine, Racemic Epinephrine
(Vaponephrine), Beta-Sympathomimetics:Isoetharine (Bronkosol), Beta
2 agonist: Metaproterenol (Alupent), Albuterol (Proventil,
Ventolin), Terbutaline, (Brethine, Bricanyl) Salmeterol (Serevent),
Lev-albuterol (Xopenex), Nonsteroidal Anti-Inflammatory Agents:
Cromolyn Sodium (Intal), Nedocromil sodium Tilade, Corticosteroids
aerosolized Steroids: a. Dexamethasone (Decadron) b. Beclomethasone
(Vanceril, beclovent) c. Triamcinolone (Azmacort) d. Flunisolide
(Aerobid) e. Fluticasone propionate (Flovent-a glucocorticoid) f.
Budesonide Suspension (Pulmocort), Anticholinergics: Atropine,
Ipratropium Bromide (Atrovent).
[0041] Mucolytics/Surface Active Agents Acetylcysteine (Mucomyst).
AntiProtozoal Agent:
[0042] Pentamidine Isethionate (Nebupent) Combination drugs:
Combivent (Ipratropium bromide and albuterol sulfate): Advair
Diskus (salmeterol and Flovent), Recombinant Human Deoxy
ribonuclease I Solution: Dornase Alfa (Pulmozyme, 25 Anti-Viral
Agent: Virazole (Ribavirin), Antibiotic: Tobramycin (Tobi)
Aminoglycoside antibiotic to treat Pseudomonas aeruginosa, Cancer
drugs that increase hypoxemia include 3-Bromopyruvate,
2-Deoxy-D-glucose, Dichloroacetic acid, and Acetylcysteine.
Antioxidants have been shown to inhibit damage associated with
active oxygen species. For example, pyruvate and other alpha
ketoacids have been reported to react rapidly and
stoichiometrically with hydrogen peroxide to protect cells from
cytolytic effects, O'Donnell-Tormey et al., J. Exp. Med., 165, pp.
500-514 (1987). U.S. Pat. No. 5,210,098, cited above, issued to
Nath discloses a method to arrest or prevent acute kidney failure
by administration of a non-toxic pyruvate salt to a patient in need
of such treatment. The Nath invention provides a therapeutic method
comprising administration of an amount of pyruvate salt to a
patient experiencing, or in danger of, acute renal failure. As
mentioned, U.S. Pat. Nos. 3,920,835, 3,984,556, 3,988,470, and
4,234,599 all issued to Van Scott et al. disclose methods for
treating acne, dandruff, and palmar keratosis, respectively, which
consist of applying to the affected area a topical composition
comprising from about 1% to about 20% of a lower aliphatic compound
containing from two to six carbon atoms selected from the group
consisting of alpha-15 hydroxy acids, alpha-ketoacids and esters
thereof, and 3-hydroxybutryic acid in a pharmaceutically acceptable
carrier. The aliphatic compounds include pyruvic acid and lactic
acid.
[0043] Pyruvate has been reported to exert a positive inotropic
effect in stunned myocardium, which is a prolonged ventricular
dysfunction following brief periods of coronary artery occlusions
which does not produce irreversible damage, Mentzer et al., Ann.
Surg., 209, pp 0.629-633 (1989).
[0044] U.S. Pat. Nos. 4,158,057, 4,351,835, 4,415,576, and
4,645,764, all issued to Stanko, disclose methods for preventing
the accumulation of fat in the liver of a mammal due to the
ingestion of alcohol, for controlling weight in a mammal, for
inhibiting body fat while increasing protein concentration in a
mammal, and for controlling the deposition of body fat in a living
being, respectively.
[0045] U.S. Pat. Nos. 5,798,388, 5,939,459, 5,952,384 and 6,623,723
(Katz) pertain to methods for treating inflammation in the lungs
and compositions useful in the method. The method comprises
contacting the mammalian cells participating in the inflammatory
response with an inflammatory mediator. The inflammatory mediator
is present in an amount capable of reducing the undesired
inflammatory response and is an antioxidant.
[0046] U.S. Pat. No. 6,689,810 (Martin) discloses a therapeutic
composition for treating pulmonary diseases states in mammals by
altering indigenous in vivo levels of nitric oxide. The therapeutic
composition consists of pyruvates, pyruvate precursors,
.quadrature.-keto acids having four or more carbon atoms,
precursors of .quadrature.-keto acids having four or more carbons,
and the salts thereof. Martin also claimed that all salts of
pyruvate were equal.
[0047] U.S. Pat. Nos. 8,076,373 and 8,114,907 (Martin) discloses a
method for treating pulmonary disease state in mammals by up or
down regulating in vivo levels of inflammatory agents (cytokines)
in mammalian cells.
[0048] While the above therapeutic compositions and methods are
reported to inhibit the production and reduce the amount of
reactive oxygen intermediates, such as hydrogen peroxide,
peroxynitrite or nitric oxide and reduce inflammation, none of the
disclosures describe a method and unique formula composition for
enhancing the synthesis of lung surfactants, to increase oxygen
saturation values (.sub.SaO2), increase nitric oxide generation,
decrease coughing, reduce drug side effects which cause hypoxemia,
reduce lung tightness, reduce the frequency of lung infections, and
enhance drug uptake and efficacy in patients with hypoxemia, with
and without lung or sinus diseases. Hypoxemia can be caused by
injury to the lungs, caused by lung and sinus diseases and
infections, including COPD, chemicals, ozone, lung cancer, and a
host of medications that can impair the synthesis of lung
surfactants. A number of these patents have claimed that all salts
of pyruvate were equal. We have shown in this patent that not all
salts of pyruvate are equal and when tested in humans, the zinc,
manganese, aluminum, ammonium, and lithium did not increase FEV-1
or .sub.SaO2 levels or reverse Hypoxemia or decrease oxygen
radicals as well as sodium pyruvate did. They were in fact
irritating.
[0049] While the method for treating insufficient lung surfactants
that cause hypoxemia in mammalian nasal and sinus cells involved in
the disease herein described constitute preferred embodiments of
this invention, it is to be understood that the invention is not
limited to this precise form or method and that changes may be made
therein without departing from the scope of the invention which is
defined in the appended claims. Thus, the sodium pyruvate solution
with concentrations of calcium, phosphate and magnesium as claimed
according to the present invention was superior and was synergistic
over our standard sodium pyruvate formula in saline in enhancing
the production of surfactants needed to improve lung functions in
patients with Hypoxemia and to increase SaO2 values, increase
nitric oxide, reduce coughing, reduce lung tightness and reduce
lung infections. We have shown that a sodium pyruvate with calcium,
phosphate and magnesium formula can reduce the concentrations of
inhaled steroids and produce equal or better results.
[0050] The present invention utilizes pyruvate delivered in an
inhaled sodium pyruvate formula with calcium, phosphate and
magnesium (a surfactant enhancer) that will enhance the synthesis
lung and sinus surfactants, phospholipids in lung cells to enhance
gas exchanges in the lung, increases oxygen saturation levels
(SaO2) that facilitates the removal of excess mucus that can block
the efficacy of inhaled drugs, thereby enhancing drug uptake and
efficacy, while reducing, congestion, breathlessness, coughing,
lung tightness, and increasing lung functions. Lung surfactants are
mostly phospholipids which are synthesized in the lungs and
sinuses.
[0051] Without these critical phospholipids, in mitochondria, the
lung cell would die. Most inhaled drugs cause damage to alveoli and
decrease the synthesis of lung surfactants needed to maintain
normal lung functions. This therapy consists of contacting the lung
or nasal cells with a therapeutically effective amount of the lung
surfactant enhancer, alone or in combination with inhaled drugs.
Wherein the drugs are selected form antivirals, antihistamines,
antibacterials, antifungal, proteins, steroids, cytokines,
nonsteroidal anti-inflammatory agents, antioxidants, insulin,
nicotine and anticancer drugs wherein the lung surfactant enhancer
is selected from the group consisting of pyruvates and pyruvate
precursors, various salts of calcium, phosphates and magnesium
which enhance the synthesis of lung surfactants to decrease
hypoxemia. Previous patents have claimed that pyruvate will work
with antibacterials, antivirals, antifungals, antihistamines,
proteins, enzymes, hormones, nonsteroidal anti-inflammatories,
cytokines, and steroids. We have found that sodium pyruvate will
work with some drugs and not with others and that an inhaled
formula of sodium pyruvate, calcium, phosphate and magnesium was
superior to sodium pyruvate by itself. This new formula increases
.sub.SaO2 values, reduced coughing and lung tightness and increased
lung capacity in patients with chronic hypoxemia including patients
with COPD and asthma and in patients without any lung or sinus
diseases. The surfactant enhancer of the present invention may be
administered prior to, after and/or with other therapeutic agents.
Obviously, numerous modifications and variations of the present
invention are possible in the light of the above teachings and the
invention is not limited to the example herein. It is therefore
understood that within the scope of the appended claims, the
invention may be practiced otherwise than as specifically described
herein.
[0052] The present invention provides novel methods for treating
insufficient synthesis of surfactants in patients with
non-pulmonary and pulmonary diseases or nasal diseases state in
mammals with a formula comprising a therapeutically effective
amount of a surfactant enhancer which is selected from the group
consisting of pyruvates and pyruvate precursors solution containing
the correct concentrations of calcium, phosphate and magnesium.
Pyruvate provides both the energy in the form of ATP to enhance the
synthesis of lung surfactants and as a component of the
phospholipids in lung surfactants, calcium and magnesium provide
the salts needed by cellular enzymes that produce cellular
phospholipids and phosphate is essential component of all
phospholipids that makeup all lung and sinus surfactants. Magnesium
is also needed for mitochondrial membrane stability and for the
production of ATP. This is a unique synergistic formula.
[0053] The present invention has shown that no inhaled formulas
with sodium pyruvate in saline, to date, have been shown to enhance
the synthesis of lung and sinus surfactants or increase .sub.SaO2
values for the treatment of chronic hypoxemia and that only the
combination of sodium pyruvate with calcium, phosphate, and
magnesium was synergistic in its ability enhance the synthesis of
lung surfactants, that enhance lung oxygen saturation (.sub.SaO2)
and FEV1 values, and reduce lung tightness, breathlessness,
coughing, reduce the number of lung or sinus infection, reduce drug
side effects that cause hypoxemia. Low .sub.Sa02 in humans is
called Hypoxemia and can occur in patients with and without lung
and sinus diseases, cancer and other conditions that injure lung
tissues that will increase mucus production, fatigue, shortness of
breath and increased susceptibility to all types of infections.
Lung and sinus surfactants mostly phospholipids, cannot be inhaled
because they will block oxygen uptake. The salt of calcium can be
delivered as calcium phosphate, dicalcium phosphate, and as calcium
pyruvate, calcium chloride or calcium citrate or many other forms.
The phosphate can be delivered as calcium phosphate, potassium
phosphate, magnesium phosphate and in other ways. Magnesium can be
delivered as magnesium chloride, magnesium phosphate, or magnesium
bicarbonate and magnesium sulfate. The sodium pyruvate formula with
calcium, phosphate and magnesium acted synergistically to enhance
the synthesis of key cellular phospholipids, thus enhance the
synthesis of lung surfactants that enhance lung alveoli functions
and oxygen saturation .sub.SaO2 values, better than the use of
sodium pyruvate or calcium pyruvate formulations by themselves or
in combination.
[0054] Lung surfactants are mostly phospholipids which are
synthesized in the cell and mitochondria. Without these critical
phospholipids, especially cardiolipin found in mitochondria, the
lung cell would die. This three-component system includes pyruvate,
which become a component of synthesized lung surfactants, and
calcium and magnesium provides the salts needed by cellular enzymes
that produce cellular phospholipids, magnesium is needed for
mitochondrial membrane stability and the production of ATP, and
phosphate is essential component of all phospholipids the makeup
all lung and sinus surfactants. Magnesium is an essential element
in biological systems. Magnesium occurs typically as the Mg.sup.2+
ion. It is an essential mineral nutrient (i.e., element) for life
and is present in every cell type in every organism. For example,
ATP (adenosine triphosphate), the main source of energy in cells,
must be bound to a magnesium ion in order to be biologically
active. What is called ATP is often actually Mg-ATP. As such,
magnesium plays a role in the stability of all polyphosphate
compounds in the cells, including those associated with the
synthesis of DNA and RNA. Over 300 enzymes require the presence of
magnesium ions for their catalytic action, including all enzymes
utilizing or synthesizing ATP, or those that use other nucleotides
to synthesize DNA and RNA. Patients with chronic Hypoxemia have low
magnesium levels in the lungs that impair lung enzyme
functions.
[0055] The inhalation of sodium pyruvate with calcium, phosphate
and magnesium (surfactant enhancer) also enhanced drug uptake and
efficacy, reducing hypoxemia caused by inhaled drugs. The
surfactant enhancer formula was superior over the sodium pyruvate
saline formulations used in the past without the addition of
calcium, phosphate and magnesium. The therapy consists of
contacting the lung or nasal cells with a therapeutically effective
amount of the lung surfactant enhancer (inhaled sodium pyruvate
formula with calcium, phosphate and magnesium), alone or in
combination with inhaled drugs that cause hypoxemia, while
enhancing gas exchanges in the lungs. Some inhaled medications
reduce the ability of the immune system to fight infections, and
some reduce the ability of lungs to synthesize lung surfactants,
like steroids, thus the addition of the sodium pyruvate, calcium,
phosphate and magnesium formula at higher concentrations will
reduce the amount of infections by maintaining a healthier lung
environment where Oxygen saturations are increased. Wherein the
drugs are selected form antivirals, antihistamines, antibacterials,
antifungal, proteins, steroids, cytokines, nonsteroidal
anti-inflammatory agents, antioxidants, insulin, nicotine and
anticancer drugs.
[0056] As used herein, the following terms have the given meanings:
The term "injured cell" as used herein refers to a cell which has
some or all of the following: (a) injured membranes with
insufficient synthesis of lung surfactants that reduce lung gas
exchange, that transport through the membranes is diminished and
may result in one or more of the following, an increase in toxins
and normal cellular wastes inside the cell and/or a decrease in
nutrients and other components necessary for cellular repair inside
the cell, (b) an increase in concentration of oxygen radicals
inside the cell because of the decreased ability of the cell to
produce antioxidants and enzymes, and (c) damaged DNA, RNA and
ribosomes which must be repaired or replaced before normal cellular
functions can be resumed.
[0057] The term "pharmaceutically acceptable," such as
pharmaceutically acceptable carriers, excipients, etc., refers to
pharmacologically acceptable and substantially non-toxic to the
subject to which the particular compound is administered. The term
"pharmaceutically acceptable salt" refers to conventional
acid-addition salts or base-addition salts that retain the
biological effectiveness and properties of the compounds of the
present invention and are formed from suitable non-toxic organic or
inorganic acids or organic or inorganic bases. Sample acid-addition
salts include those derived from inorganic acids such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric
acid, sulfamic acid, phosphoric acid and nitric acid, and those
derived from organic acids such as p-toluene sulfonic acid,
salicylic acid, methane sulfonic acid, oxalic acid, succinic acid,
citric acid, malic acid, lactic acid, fumaric acid, and the like.
Sample base-addition salts include those derived from calcium,
magnesium, ammonium, potassium, sodium, and quaternary ammonium
hydroxides, such as for example, tetramethylammonium hydroxide.
Chemical modification of a pharmaceutical compound (i.e., drug)
into a salt is a technique well known to pharmaceutical chemists to
obtain improved physical and chemical stability, hydroscopicity,
and solubility of compounds. See, e.g., H. Ansel et. al.,
Pharmaceutical Dosage Forms and Drug Delivery Systems (6.sup.th Ed.
1995) at pp. 196 and 1456-1457.
[0058] The term "prodrug" or "precursor" refers to compounds that
undergo biotransformation prior to exhibiting their pharmacological
effects. The chemical modification of drugs to overcome
pharmaceutical problems has also been termed "drug latentiation."
Drug latentiation is the chemical modification of a biologically
active compound to form a new compound, which upon in vivo
enzymatic attack will liberate the parent compound. The chemical
alterations of the parent compound are such that the change in
physicochemical properties will affect the absorption, distribution
and enzymatic metabolism. The definition of drug latentiation has
also been extended to include nonenzymic regeneration of the parent
compound. Regeneration takes place as a consequence of hydrolytic,
dissociative, and other reactions not necessarily enzyme mediated.
The terms prodrugs, latentiated drugs, and bio-reversible
derivatives are used interchangeably. By inference, latentiation
implies a time lag element or time component involved in
regenerating the bioactive parent molecule in vivo. The term
prodrug is general in that it includes latentiated drug derivatives
as well as those substances, which are converted after
administration to the actual substance, which combines with
receptors. The term 5 prodrug is a generic term for agents, which
undergo biotransformation prior to exhibiting their pharmacological
actions.
[0059] The term "therapeutically effective amount" refers to an
amount of a therapeutically effective compound, or a
pharmaceutically acceptable salt thereof, which is effective to
treat, prevent, alleviate or ameliorate symptoms of a disease. The
diseases listed below will cause oxygen saturation levels
(.sub.Sao2) to fall, is due to low lung surfactant synthesis and
causes Hypoxemia. In smokers 22% suffer from hypoxemia, and in COPD
patients 21% have hypoxemia. The pulmonary diseases which cause
Hypoxemia and are suitable for treatment by the lung surfactant
enhancer of the present invention (sodium pyruvate with calcium,
phosphate and magnesium), but are not limited to, acute respiratory
distress syndrome (ARDS), acute lung injury, pulmonary fibrosis
(idiopathic), Bleomycin induced pulmonary fibrosis, mechanical
ventilator induced lung injury, lung transplantation-induced acute
graft dysfunction and bronchiolitis obliterans after lung
transplantation, bronchial asthma, acute bronchitis, emphysema,
chronic obstructive emphysema, chronic obstructive pulmonary
disease, centrilobular emphysema, panacinar emphysema, chronic
obstructive bronchitis, smoker's disease, reactive airway disease,
cystic fibrosis, black lung disease, bronchiectasis, acquired
bronchiectasis, kartaagener's 25 syndrome, atelectasis, acute
atelectasis, chronic acelectasis, pneumonia, essential
thrombocythemia, legionnaire's disease, psittacosis, fibrogenic
dust disease, hypersensitivity diseases of the lung, idiopathic
infiltrative diseases of the lungs, chronic obstructive pulmonary
disorder, adult respiratory distress syndrome, pulmonary tumors,
pulmonary hypertension, and diseases caused by organic dust,
cyanide poisoning, nicotine, insulin, irritant gases, Alzheimer's,
nasal diseases like allergic rhinitis, sinusitis and chemicals like
Cyanide, ozone, lung or sinus infections, inhaled cancer drugs or
inhaled drugs, cancer, sleep apnea, and Migraines. Preferred
disease states are cystic fibrosis, bronchial asthma, allergic
rhinitis, sinusitis, Bleomycin (doxorubicin) injury, chronic
obstructive pulmonary disease, interstitial lung disease, lung
cancer and migraines.
[0060] The pulmonary tumors suitable for treatment by the
surfactant enhancer of the present invention include, but are not
limited to, epidermoid (squamous cell) carcinoma, small cell (oat
cell) carcinoma, adenocarcinoma, and large cell (anaplastic)
carcinoma.
[0061] The surfactant enhancers in the present invention are the
pyruvates and pyruvate precursors with the addition of calcium,
phosphate and magnesium. Non-limiting illustrative examples of
pyruvates include pyruvic acid, sodium pyruvate, potassium
pyruvate, magnesium pyruvate, calcium pyruvate, zinc pyruvate,
manganese pyruvate, aluminum pyruvate, ammonium pyruvate, lithium
pyruvate, and mixtures thereof. Non-limiting illustrative examples
of pyruvate precursors include ethyl pyruvate, methyl pyruvate,
pyruvyl-glycine, pyruvyl-alanine, pyruvyl-cysteine,
pyruvyl-leucine, pyruvyl-valine, pyruvyl-isoleucine,
pyruvyl-phenylalanine, pyruvamide, salts of pyruvic acid, and
mixtures thereof, with calcium, phosphate and magnesium.
[0062] The amount of the surfactant enhancer present in the
therapeutic compositions of the present invention is a
therapeutically effective amount. A therapeutically effective
amount of the surfactant enhancer is that amount of the surfactant
enhancer necessary to increase the synthesis of lung phospholipids
to treat Hypoxemia. The exact amount of surfactant enhancer is a
matter of preference subject to such factors as the type of
surfactant enhancer being employed, the type of condition being
treated as well as the other ingredients in the composition. The
exact amount of surfactant enhancer will also be determined by
whether the pulmonary disease is infected or uninfected. In
general, the dosage of the surfactant enhancer may range from about
0.0001 mg to about 1 gram, preferably from about 0.001 mg to about
0.8 gram, and more preferably from about 0.01 mg to about 0.6
gram.
[0063] In many cases, pulmonary diseases produce infections that
these surfactant enhancers can treat. Such infections may be
bacterial, viral, or fungal. The surfactant enhancer may be inhaled
first to regulate inflammatory agents followed by inhalation or
oral administration of a therapeutic agent. The therapeutic agent
may be administered prior to, concomitantly with, or after
administration of the inflammatory regulator. The therapeutic agent
may be selected from the group consisting of antibacterials,
antivirals, antifungals, antitumors, antihistamines, proteins,
enzymes, hormones, nonsteroidal anti-inflammatories, cytokines,
nicotine, insulin, and steroids.
[0064] The antibacterial agents which may be employed in the
therapeutic compositions may be selected from a wide variety of
water-soluble and water-insoluble drugs, and their acid addition or
metallic salts, useful for treating pulmonary diseases. Both
organic and inorganic salts may be used provided the antibacterial
agent maintains 15 its medicament value. The antibacterial agents
may be selected from a wide range of therapeutic agents and
mixtures of therapeutic agents, which may be administered in
sustained release or prolonged action form. Nonlimiting
illustrative specific examples of antibacterial agents include
bismuth containing compounds, sulfonamides; nitrofurans,
metronidazole, tinidazole, nimorazole, benzoic acid;
aminoglycosides, macrolides, penicillin's, polypeptides,
tetracyclines, cephalosporins, chloramphenicol, and clindamycin.
Preferably, the antibacterial agent is selected from the group
consisting of bismuth containing compounds, such as, without
limitation, bismuth aluminate, bismuth subcitrate, bismuth
subgallate, bismuth subsalicylate, and mixtures thereof; the
sulfonamides; the nitrofurans, such as nitrofurazone,
nitrofurantoin, and furazolidone; and miscellaneous antibacterials
such as metronidazole, tinidazole, nimorazole, and benzoic acid;
and antibiotics, including the aminoglycosides, such as gentamycin,
neomycin, kanamycin, and streptomycin; the macrolides, such as
erythromycin, clindamycin, and rifamycin; the penicillin's, such as
penicillin G, penicillin V, Ampicillin and amoxicillin; the
polypeptides, such as bacitracin and polymyxin; the tetracyclines,
such as tetracycline, chlortetracycline, oxytetracycline, and
doxycycline; the cephalosporins, such as cephalexin and
cephalothin; and miscellaneous antibiotics, such as
chloramphenicol, and clindamycin. More preferably, the
antibacterial agent is selected from the group consisting of
bismuth aluminate, bismuth subcitrate, bismuth subgallate, bismuth
subsalicylate, sulfonamides, nitrofurazone, nitrofurantoin,
furazolidone, metronidazole, tinidazole, nimorazole, benzoic acid,
gentamycin, neomycin, kanamycin, streptomycin, erythromycin,
clindamycin, rifamycin, penicillin G, penicillin V, Ampicillin
amoxicillin, bacitracin, polymyxin, tetracycline,
chlortetracycline, oxytetracycline, doxycycline, cephalexin,
cephalothin, chloramphenicol, clindamycin, Bactorban (Mupirocin),
Tobramycin, Pentamidine isethionate, Vancomycin, benzalkonium
chloride.
[0065] The amount of antibacterial agent which may be employed in
the therapeutic compositions of the present invention may vary
depending upon the therapeutic dosage recommended or permitted for
the particular antibacterial agent. In general, the amount of
antibacterial agent present is the ordinary dosage required to
obtain the desired result. Such dosages are known to the skilled
practitioner in the medical 15 arts and are not a part of the
present invention. In a preferred embodiment, the antibacterial
agent in the therapeutic composition is present in an amount from
about 0.01% to about 10%, preferably from about 0.1% to about 5%,
and more preferably from about 1% to about 3%, by weight.
[0066] The antiviral agents which may be employed in the
therapeutic compositions may be selected from a wide variety of
water-soluble and water-insoluble drugs, and their acid addition or
metallic salts, useful for treating pulmonary diseases. Both
organic and inorganic salts may be used provided the antiviral
agent maintains its medicament value. The antiviral agents may be
selected from a wide range of therapeutic agents and mixtures of
therapeutic agents, which may be administered in sustained release
or prolonged action form. Nonlimiting illustrative categories of
such antiviral agents include RNA synthesis inhibitors, protein
synthesis inhibitors, immune-stimulating agents, protease
inhibitors, and cytokines. Nonlimiting illustrative specific
examples of such antiviral agents include the following
medicaments. Acyclovir with inhibitory activity against human
herpes viruses including herpes simplex types 1 (HSV-1) and 2
(HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV),
and cytomegalovirus (CMV). Foscarnet sodium is an organic analogue
of inorganic pyrophosphate that inhibits replication of all known
herpes viruses in vitro including cytomegalovirus (CMV), herpes
simplex virus types 1 and 2 (HSV-1, HSV-2), human herpes virus 6
(HHV-6), Epstein-Barr virus (EBV), and varicellazoster virus
(VZV).
[0067] Ribavirin has antiviral inhibitory activity in vitro against
respiratory syncytial virus, influenza virus, and herpes simplex
virus. Vidarabine possesses in vitro and in vivo antiviral activity
against Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), and
in vitro activity against varicella-zoster virus (VZV). Ganciclovir
inhibits replication of herpes viruses both in vitro and in vivo.
Sensitive human viruses include cytomegalovirus (CMV), herpes
simplex virus-1 and -2 (HSV-1, HSV-2), Epstein-Barr virus (EBV),
and varicella zoster virus (VZV). Zidovudine is an inhibitor of the
in vitro replication of some retroviruses including HIV (also known
as HTLV III, LAV, or ARV). Phenol (carbolic acid) is a topical
antiviral, anesthetic, antiseptic, and antipruritic drug.
Amantadine hydrochloride (1-adamantanamine hydrochloride,
SYMMETREL.RTM.) has pharmacological actions as both an
anti-Parkinson and an antiviral drug against influenza A.
Interferon .quadrature.-n3 (human leukocyte derived, ALFERON.RTM.)
.quadrature. proteins for use by injection. Interferons are
naturally occurring proteins with both antiviral and
antiproliferative properties. Interferon .quadrature.-2a
(recombinant, ROFERON-A.RTM.). The mechanism by which Interferon
.quadrature.-2a, recombinant, exerts antitumor or antiviral
activity is not clearly understood. 20 Oseltamivir
((3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexenel-carbo-
xylic acid ethyl ester, TAMIFLU.RTM.) is a is an antiviral drug
that is used in the treatment and prophylaxis of both influenza
virus A and Influenza virus B. Zanamivir. Preferred antiviral
agents to be employed may be selected from the group consisting of
acyclovir, foscarnet sodium, Ribavirin, vidarabine, Ganciclovir
sodium, zidovudine, phenol, amantadine hydrochloride, and
interferon alpha-n3, interferon-2a, and Oseltamivir. In a preferred
embodiment, the antiviral agent is selected from the group
consisting of acyclovir, foscarnet sodium, Zanamivir, Ribavirin,
vidarabine, valacydvir, famiclour, Tenofovir Viread and Ganciclovir
sodium. In a more preferred embodiment, the antiviral agent is
acyclovir.
[0068] The amount of antiviral agent which may be employed in the
therapeutic compositions of the present invention may vary
depending upon the therapeutic dosage recommended or permitted for
the particular antiviral agent. In general, the amount of antiviral
agent present is the ordinary dosage required to obtain the desired
result. Such dosages are known to the skilled practitioner in the
medical arts and are not a part of the present invention. In a
preferred embodiment, the antiviral agent in the therapeutic
composition is present in an amount from about 0.1% to about 20%,
preferably from about 1% to about 10%, and more preferably from
about 2% to about 7%, by weight.
[0069] The antifungal agents which may be employed in the
therapeutic compositions may be selected from a wide variety of
water-soluble and water-insoluble drugs, and their acid addition or
metallic salts, useful for treating pulmonary diseases. Both
organic and inorganic salts may be used provided the antifungal
agent maintains its medicament value. The antifungal agents may be
selected from a wide range of therapeutic agents and mixtures of
therapeutic agents, which may be administered in 15 sustained
release or prolonged action form. Nonlimiting illustrative specific
examples of antifungal agents include the following medicaments:
miconazole, clotrimazole, tioconazole, terconazole,
povidone-iodine, and butoconazole. Other antifungal agents are
lactic acid and sorbic acid. Preferred antifungal agents are
miconazole and clotrimazole. The amount of antifungal agent, which
may be employed in the therapeutic compositions of the present
invention may vary depending upon the therapeutic dosage
recommended or permitted for the particular antifungal agent. In
general, the amount of antifungal agent present is the ordinary
dosage required to obtain the desired result. Such dosages are
known to the skilled practitioner in the medical arts and are not a
part of the present invention. In a preferred embodiment, the
antifungal agent in the therapeutic composition is present in an
amount from about 0.05% to about 10%, preferably from about 0.1% to
about 5%, and more preferably from about 0.2% to about 4%, by
weight.
[0070] The antitumor agents which may be employed in the
therapeutic compositions may be selected from a wide variety of
water-soluble and water-insoluble drugs, and their acid addition or
metallic salts, useful for treating pulmonary diseases. Both
organic and inorganic salts may be used provided the antitumor
agent maintains its medicament value. The antitumor agents may be
selected from a wide range of therapeutic agents and mixtures of
therapeutic agents, which may be administered in sustained release
or prolonged action form. Nonlimiting illustrative specific
examples include anti-metabolites, antibiotics, plant products,
hormones, and other miscellaneous chemotherapeutic agents.
Chemically reactive drugs having nonspecific action include
alkylating agents and N-alkyl-N-nitroso compounds. Examples of
alkylating agents include nitrogen mustards, aziridines
(ethylenimines), sulfonic acid esters, and epoxides.
Anti-metabolites are compounds that interfere with the formation or
utilization of a normal cellular metabolite and include amino acid
antagonists, vitamin and coenzyme antagonists, and antagonists of
metabolites involved in nucleic acid synthesis such as glutamine
antagonists, folic acid antagonists, pyrimidine antagonists, and
purine antagonists. Antibiotics are compounds produced by
microorganisms that have the ability to inhibit the growth of other
organisms and include actinomycins and related antibiotics,
glutarimide antibiotics, sarkomycin, fumagillin, streptonigrin,
tenuazonic acid, actinogan, peptinogan, and anthracyclic
antibiotics such as doxorubicin. Plant products include colchicine,
podophyllotoxin, and vinca alkaloids. Hormones include those
steroids used in breast and prostate cancer and corticosteroids
used in leukemia and lymphomas. Other miscellaneous
chemotherapeutic agents include urethane, hydroxyurea, and related
compounds; thiosemicarbazones and related compounds; phthalanilide
and related compounds; and triazene's and hydrazines,
3Bromopyruvate, 2-Deoxy-D glucose, Dichloroacetic acid. The
anticancer agent may also be a monoclonal antibody or the use of
X-rays. In a preferred embodiment, the anticancer agent is an
antibiotic. In a more preferred embodiment, the anticancer agent is
doxorubicin. In a most preferred embodiment, the anticancer agent
is doxorubicin. Lung Cancer--Medications Chemotherapy is called a
systemic treatment because the medicines enter your bloodstream,
travel through your body, and kill cancer cells both inside and
outside the lung area. Some chemotherapy drugs are taken by mouth
(orally), while others are injected into a vein (intravenous, or
IV). Some of the more common chemotherapy medicines used for lung
cancer includes the following: Bevacizumab, Carboplatin, Cisplatin,
Crizotinib, Docetaxel, Erlotinib, Etoposide, Gemcitabine,
Irinotecan, Paclitaxel, Pemetrexed Vinorelbine.
[0071] Most chemotherapy causes some side effects, including
destruction of mitochondria which causes an insufficient synthesis
of lung surfactants that lead to hypoxemia and reduces the ability
of cancer cells to undergo Apoptosis.
[0072] The amount of antitumor agent, which may be employed in the
therapeutic compositions of the present invention may vary
depending upon the therapeutic dosage recommended or permitted for
the particular antitumor agent. In general, the amount of antitumor
agent present is the ordinary dosage required to obtain the desired
result. Such dosages are known to the skilled practitioner in the
medical arts and are not a part of the present invention. In a
preferred embodiment, the antitumor agent in the therapeutic
composition is present in an amount from about 1% to about 50%,
preferably from about 10% to about 30%, and more preferably from
about 20% to about 25%, by weight. The carrier composition is
selected from the group consisting of tablets, capsules, liquids,
isotonic liquids, isotonic media, enteric tablets and capsules,
parenteral, topicals, creams, gels, ointments, chewing gums,
confections and the like. The favored method of delivery is through
inhalation by mouth or sinuses.
[0073] Obviously, numerous modifications and variations of the
present invention are possible in the light of the above teachings
and the invention is not limited to the examples herein. It is
therefore understood that within the scope of the appended claims,
the invention may be practiced otherwise than as specifically
described herein. Throughout this application, various publications
have been referenced. The disclosures in these publications are
incorporated herein by reference in order to more fully describe
the state of the art.
[0074] The compounds of the present invention can be prepared
according to the examples set out below. The examples are presented
for purposes of demonstrating, but not 30 limiting, the preparation
of the compounds and compositions of this invention.
Example 1
Sodium Pyruvate Formula Containing Calcium, Phosphate and
Magnesium
[0075] All previous studies using pyruvate to treat Allergic
Rhinitis, Asthmatic and COPD patients used only the sodium salt
form of pyruvic acid in saline. The drug products that were tested
in the six Phase I/II clinical trial were differing concentrations
of sodium pyruvate dissolved in 0.9% sodium chloride solution
(Saline). These drug products contained 0.5 mM, 1.5 mM, or 5.0 mM
of sodium pyruvate in physiological saline. They were administered
to normal volunteers and COPD and asthmatics by inhalation therapy.
Even though other salts of pyruvic acid like calcium, potassium or
zinc etc. have been suggested, no one to date has evaluated the
different salts individually or in combination for their ability to
enhance lung function and reduce lung tightness due to low
surfactant production and help in mucus removal that can inhibit
drug efficacy. Removal of mucus will increase the efficacy of the
pyruvate membrane transport system. Various sodium pyruvate
solutions were evaluated in the lungs for their ability to enhance
FEV1 values and reduce coughing, and lung tightness. 5 ml 0.5 mM
solutions to 5 mM solutions of sodium pyruvate in saline were
evaluated in Asthmatic and COPD patients and the 5 ml of the 0.5 mM
solution produced the best results in increasing FEV1 values of
over 12% and reducing nitric oxide by 19.2%.
[0076] The products that were tested in the clinical trials were
differing concentrations of sodium pyruvate dissolved in 0.9%
sodium chloride solution. These drug products contained 0.5 mM, 1.5
mM, or 5.0 mM (275, 825, and 2750 .mu.g) of sodium pyruvate,
respectively delivered per dose per day. Of these, a 5 mL dose of
0.5 mM sodium pyruvate dissolved in 0.9% sodium chloride solution
proved to be the concentration and dosage of choice in past
clinical studies. Various investigators including Katz and Martin
discovered that the higher concentrations of sodium pyruvate 1.5
mM, or 5.0 mM (825, and 2750 .mu.g) in saline did not increase FEV1
values.
[0077] Blood levels of the various salts mg/liter are 3220 mg for
Sodium, 200 mg for potassium, 27 mg for magnesium, 70 mg for
calcium, 1.1 mg for zinc, 0.02 mg for manganese, 6 mg for lithium,
0.03 mg for aluminum, 0.06 mg for ammonium and 0.36 mg for
phosphate. To evaluate the irritation or toxicity levels of these
elements 5 mls of 0.5 mM solution of each salt of pyruvate, was
tested against the standard 5 mls of the 0.5 mM solution of sodium
pyruvate that was shown to be non-toxic in humans and animal
studies. In fact, in rat studies, 100.times. concentrations of the
5 mM sodium pyruvate was tested and shown not to have any
irritation or toxicity. Using 5 mls of a 0.5 mM pyruvate inhalation
solution of each salt in COPD and asthmatic patients, the use of
potassium pyruvate, magnesium pyruvate, calcium pyruvate, zinc
pyruvate, manganese pyruvate, lithium pyruvate, aluminum pyruvate,
and ammonium pyruvate were evaluated. Potassium pyruvate, produced
lower FEV1 results in COPD patients as the sodium pyruvate solution
did (FEV1 of 12% or higher). The calcium pyruvate and magnesium
pyruvate increased FEV1 values to 10%. The zinc pyruvate, manganese
pyruvate, aluminum pyruvate, ammonium pyruvate, and lithium
pyruvate did produce slight increases in FEV1 of around 4-6% but
did not reduce nitric oxide and did not achieve the results that
sodium pyruvate produced, and they were irritating. The zinc
pyruvate increased nitric oxide levels by 10% instead of reducing
it, acting in the opposite direction that sodium pyruvate did. See
table I. A metal taste to these solutions was described by the
inhalers. The amount of the salts delivered in the 5 ml's of the
0.5 mM pyruvate solutions were compared to the amounts of the salts
in 5 ml's of human blood. The sodium, potassium, and calcium,
pyruvates were all under amounts found in human blood. The
delivered zinc in this solution (5 ml of a 0.5 mM) was 12.times.
blood levels, the 20 magnesium was 4.times. blood levels, the
manganese was 370.times. blood levels, aluminum was 61.times. times
blood levels, the ammonium was 53.times. times blood levels, and
lithium was 5.times. blood levels. These solutions were also
evaluated in the nasal cavities and were less irritating than in
the lungs except, the ammonium and lithium pyruvate was even more
irritating than its use in the lungs. The use of these elements at
these levels proved that one cannot assume that all the salts of
pyruvate are equal in efficacy or in irritation when compared to
the sodium salt see table I. Even though the use of some of these
salts of pyruvic acid showed similar FEV1 results, and the others
did not. The use of some of these salts over time may have a
negative effect. The sodium salt of pyruvate when tested at higher
levels in humans like the 5 ml of the 5 mM was 59 times lower than
sodium in 5 ml's of blood, the calcium was 1.5.times. times lower,
the potassium was 3.2.times. times lower than 5 ml's of blood, thus
they were well within the safe levels needed to deliver the
pyruvate. In small doses the salts of zinc, manganese can be used
to increase and up regulate the immune system cytokines to fight
infections, rather than their use as an anti-inflammatory agent
that increases lung functions and FEV1 values. Lithium pyruvate had
the unexpected result of acting as a bronchial dilator whereas the
other salts were weak or nonexistent as a bronchial dilator.
[0078] When the sodium pyruvate solution (0.5 mM, 0.274 mg) was
balanced with the salt of calcium pyruvate or calcium chloride to
the concentrations of the salts found in blood (formula was 97%
sodium pyruvate, 3% calcium pyruvate or 3% calcium chloride), it
produced equal results in FEV1 values when compared to the original
sodium pyruvate formula tested in the COPD patients. This formula
can also be made by adding 3% calcium phosphate or dicalcium
phosphate to the standard 0.5 mM to 30 mM sodium pyruvate saline
solution see Table I.
[0079] The sodium pyruvate formula with the calcium, phosphate and
magnesium was significantly superior to any other formula that only
deliver calcium with or without the phosphate or magnesium see
table I-II. In previous studies, sodium pyruvate solutions of 5 to
20 mM did not increase FEV1 values and did increase nitric oxide
levels significantly to 19%. The FEV1 values increase to 16% for
the sodium pyruvate calcium, phosphate and magnesium formula (20 mM
solution) and nitric oxide decreased by 70%, far different results
than the 5-20 mM straight sodium pyruvate formula without the
calcium, phosphate and magnesium, see table II. It was also
reported by the patients that the sodium pyruvate calcium,
phosphate and magnesium formula was the best formula to reduce lung
tightness coughing and mucus. The addition of all the other salts
of pyruvate including zinc, lithium, magnesium, aluminum, ammonium,
or manganese even at blood levels concentrations individually, gave
the formula a metal taste and was not preferred by 25 the patients
that inhaled it, see table II.
TABLE-US-00001 TABLE I Comparison of various inhaled salts of
pyruvate in 5 ml's of a 0.5 mM solution in patients with lung
diseases including COPD. Overall rating was 1-10 with 1 being the
most negative and 10 being the best result Percentage decrease or
Relief of Percentage Various Salts of Increased increase of
congestion, Increase in Overall pyruvate in in FEV-1% Nitric Oxide
coughing and SaO2 over Rating physiological saline lung function
over baseline Irritation lung tightness baseline 1-10 Sodium 13.0
-19.0 none 5 0.5 8 Calcium 10.0 -18 None 5 no 7 Potassium 8.0 -14
None 5 no 7 Magnesium 12.0 -2.0 None 6 no 7 Zinc 8.0 +10 Yes 4 No 4
Manganese 3.0 -2.0 Yes 4 No 3 Lithium 1.0 +6.0 Yes 2 No 2 Aluminum
0 +8.0 Yes 1 No 3 Ammonium 0 +5.0 Yes 1 No 1 Potassium Phosphate 0
0 Slight 4 No 3 sodium pyruvate & 12.2 -18 None 6 No 8 calcium
pyruvate sodium pyruvate & 11.8 -14 None 6 No 8 calcium
pyruvate & magnesium calcium & Phosphate & 0 0 None 1
No 2 magnesium Sodium Pyruvate & 16 -28 None 9 5% 10 calcium
&Phosphate &magnesium physiological 0 0 None 0 0 5 Saline
0.9% Pyruvyl-cysteine 11 0 None 5 0 8 N-acetylcysteine 6 0 None 8 0
7
TABLE-US-00002 TABLE II Comparison of various inhaled salts of
pyruvate in 5 ml's of a 5 mM solution in patients with lung
diseases including COPD. Overall rating was 1-10 with 1 being the
most negative and 10 being the best result Relief of Percentage
congestion, Percentage increase of coughing Increase in Overall
Various Salts of Increased Nitric Oxide and lung SaO2 over Rating
pyruvate in saline in FEV-1% over baseline Irritation tightness
baseline 1-10 Sodium 2.0 19.0 none 5 1 8 Calcium 1.0 17.0 None 5 1
7 Potassium 2.1 25.0 None 5 no 7 Magnesium 2.0 5.1 None 6 no 7 Zinc
1.0 22.0 Yes 4 No 3 Manganese 3.0 25.0 Yes 4 No 3 Lithium 1.0 28.0
Yes 2 No 2 Aluminum 0 15.0 Yes 1 No 4 Ammonium 0 35.0 Yes 1 No 1
Potassium Phosphate 0 0 Slight 4 No 3 sodium & calcium 2.2 16
None 6 No 8 pyruvate sodium & calcium 3.4 15 None 6 No 8
pyruvate & magnesium calcium & Phosphate & 0 0 None 1
No 2 magnesium Sodium Pyruvate & 16 70 None 9 5% 10 calcium
& Phosphate & magnesium Physiological 0 0 0 0 0 5 Saline
0.9% Pyruvyl-cysteine 5 1 Slight 8 0 8 N-acetylcysteine 2 1 yes 7 0
7
Example II
Effect of CO2 Concentration on Phospholipid Metabolism in the
Isolated Perfused Rat Lung
[0080] In Hypoxemia CO2 levels rise as SaO.sub.2 levels decline.
Studies have been carried out on the incorporation of
[U-(14)C]glucose, [2 (14)C]pyruvate, [2-(14)C]acetate, and
[1-(14)C]-palmitate into the phospholipids of the isolated perfused
rat lung in the presence of either 6 or 45 mm total CO(2)
concentration in the perfusion medium. Incorporation of
[U-(14)C]glucose into total phospholipid and into the
phosphatidylcholine fraction was increased 19-53% over the 2-hr
perfusion period in lungs perfused with medium containing 45 as
compared with 6 mm CO(2). The incorporation of [2-(14)C]acetate,
[2-(14)C]-pyruvate, and [1(14)C]palmitate was not affected by the
change in medium CO(2) concentration and incorporation of [U-(14)C]
pyruvate into total phospholipid and into the phosphatidylcholine
fraction was increased 1-3% over the 2-hr perfusion period in lungs
perfused. Increased incorporation of [1-(14)C]glucose combined with
a shift toward greater incorporation into the fatty acids of the
phosphatidylcholine fraction produced a maximum increase of 90% in
[U-(14)C]glucose incorporation into the fatty acids of
phosphatidylcholine after 2 hr of perfusion in the presence of
medium containing 45 mm CO(2) as compared with 6 mm CO(2). 45 mm
CO2 increases hypoxemia. The increase in medium CO(2) concentration
produced as much as a 150% increase in [U-(14)C]glucose
incorporation into palmitate derived from the phosphatidylcholine
fraction. The results provide evidence that glucose functions as an
important precursor of palmitate in the phosphatidylcholine
fraction of lung phospholipids and that the CO(2) concentration of
the perfusion medium affects the incorporation of glucose into
palmitate, whereas in hypoxemia states sodium pyruvate is not
incorporated into lung surfactants.
[0081] The combination of sodium pyruvate and calcium, phosphate
and magnesium was synergistic in its ability to increase the
incorporation of pyruvate into lung surfactant phospholipids. It
enhanced surfactant production, pyruvate uptake and mucus removal.
The production of phospholipids that make up the lung surfactants,
needed to enhance alveoli function, need trace minerals and salts
to be synthesized. The components of pulmonary surfactant are
synthesized in the Golgi apparatus of the endoplasmic reticulum of
the type II alveolar cell and the secretion is induced by
endoplasmic reticulum Ca2 ATPase. The addition of calcium,
phosphate and magnesium, not zinc or the other salts of pyruvate,
enhanced the production of the surfactants. In previous studies
with rat lungs, [2-(14) C]-pyruvate was not incorporated into lung
surfactants under high CO2 levels which produce hypoxemia. In
isolated perfused rat lungs, using [2-(14)C] labeled pyruvate; lung
surfactant analysis clearly showed that the sodium pyruvate
calcium, phosphate and magnesium formula increased the production
of surfactants over all other formulations with just sodium
pyruvate in saline alone. It was also discovered that 50% of the
radioactive pyruvate from this formula was incorporated into
phosphatidylcholine the main lung surfactant with 45 mm CO2
concentrations. In short, calcium, phosphate and magnesium is
needed by the enzyme systems to synthesize lung surfactants, while
phosphate provides some of the building components needed to make
surfactants, or to increase the synthesis of surfactants and, thus
decrease hypoxemia. Inhalation studies with just [2-(14)C] labeled
sodium pyruvate without calcium, phosphate and magnesium, showed
that pyruvate was converted in the lungs or sinuses to acetate and
carbon dioxide and higher levels of pyruvate increased the
synthesis of nitric oxide and was not incorporated into synthesized
phospholipids. In patients with excess mucus, the formula of sodium
pyruvate and calcium, phosphate and magnesium helped facilitate
mucus removal, by providing the energy and nutrients needed by the
cilia in the nasal and lung passages to remove the mucus. This
formula was evaluated in patients with excess mucus. See tables
I-III.
TABLE-US-00003 TABLE III Comparison of various 5 ml's of 5 mM
sodium pyruvate saline formulas in patients with hypoxemia with and
without lung diseases. Overall rating was 1-10 with 1 being the
most negative and 10 being the best result Relief of Percentage
Relief of coughing Percentage increase of Congestion percentage
Percentage Increase in Nitric and lung decrease Increase in Overall
Various Salts of FEV-1 over Oxide over tightness in four SaO2 over
Rating pyruvate in saline baseline baseline 1-10 hours baseline
1-10 Sodium pyruvate 4.0 18.0%.sup. 5 15 0 7 sodium pyruvate &
4.0 19.0%.sup. 5 16 0 7 calcium pyruvate sodium pyruvate & 3.0
18% 5 22 0 7 calcium & phosphate calcium & Phosphate &
0 0 1 1 0 3 magnesium Sodium Pyruvate & 15.2 80% 9 48 6% 10
calcium & Phosphate & magnesium Physiological Saline 0 2% 5
2 0 3 Sodium Pyruvate & 14.9 112% 9 44 5% 9 calcium &
Phosphate & Magnesium + N-acetylcysteine Sodium pyruvate + 4
15% 7 12 1 8 N-Acetylcysteine
Example III
Inhalation Formulation
[0082] Numerous inhaled formulas have been used alone or as part of
a solution to carry drugs into the lungs to treat lung diseases,
cancer, infections etc. To dated, none of these FDA approved
inhalation formulas, have been shown to enhance the synthesis of
lung surfactants, treat hypoxemia by increasing .sub.SaO2 levels,
while increasing the synthesis of nitric oxide. We assessed the
following formulas, physiological saline, lactated Ringers,
acetated Ringers, ethyl pyruvate Ringers, Phosphate buffered
saline, TRIS buffered saline, Hepes buffered saline, Citrate
saline, Hanks balanced salt solution, Eagles balanced salt
solution, Geys balanced slat solution, and Earls balanced salt
solution. All these formulas are the same in that they all use
sodium chloride at 0.8-0.9 grams per liter or higher and when
tested in patients with various sinus or lung diseases including
COPD patients with hypoxemia, none of these formula increased
.sub.SaO2 levels or decrease lung tightness, coughing or increase
lung capacity. None of these formulae have all of the correct
ingredients or the correct ratios of Sodium pyruvate, calcium,
phosphate, or magnesium. Most of these formulas also contain
glucose that inhibits the incorporation of pyruvate into
phospholipids.
[0083] Inhalation of sea salt aerosol is clinically proven and
cleans the respiratory system of the body and speeds up the
elimination of toxins. Salt therapy for Chronic Obstructive
Pulmonary Disease (COPD) is a natural and effective treatment for a
number of health issues, including emphysema and bronchitis that
relate to the lungs and that are grouped together under the banner
of Chronic Obstructive Pulmonary Disease. Salt therapy is 100%
natural, safe and drug-free, providing effective long-term relief.
Sodium and chloride are the most abundant ions in sea salt,
representing about 33 and 50.9 percent of total minerals,
respectively. Potassium is another important macro-mineral that
works with chloride to help regulate acid levels in your body. Sea
salt contains also contains Calcium and magnesium. Sea salt can
also contain numerous trace elements. Trace minerals you may find
in sea salt include, bromine, boron, zinc, iron, manganese, copper
and silicon. What's missing in sea salt is the correct composition
of ingredients, with the correct concentrations and ratios of
sodium pyruvate, calcium, magnesium and phosphate. In sea salt
phosphate is 125 times lower than blood levels and calcium is 50%
lower than blood levels. When tested by itself, in hundreds of
published clinical studies, or with the addition of sodium
pyruvate, sea salt did not increase the synthesis of lung
phospholipids, nor decrease hypoxemia, decrease lung tightness or
increase lung capacity or .sub.SaO2 levels. When the correct
composition of ingredients with the correct concentrations and
ratios of sodium pyruvate, calcium, phosphate, and magnesium were
added to sea salt, the synthesis of lung surfactants increased,
lung capacity increased, lung tightness decreased and hypoxemia
decreased.
[0084] 20 mM Sodium Pyruvate Formula for Inhalation:
[0085] The best formula we tested was
[0086] To one liter of saline, 0.65% Sodium Chloride (contains 6.5
grams of NaCl), add 0.22% (2.2 grams) of sodium pyruvate, 0.15%
calcium chloride (0.15 grams), 0.11% of magnesium chloride (0.11
grams), 0.03% potassium phosphate (0.03 grams). Tissue culture
studies with lung cells have shown that adding to much Chloride or
sodium will injure those cells. A 20 mM formula would contain 2.2
grams of sodium pyruvate. And a 0.5 mM solution would contain 0.055
grams of sodium pyruvate. A second approached tried with the same
effect was to first have the patients inhale physiological saline
with 0.15% calcium chloride (0.15 grams), 0.11% of magnesium
chloride (0.1 grams), 0.03% potassium phosphate (0.03 grams)
followed by the inhalation of sodium pyruvate in physiological
saline one hour later. This formula has many modifications to
deliver the correct amount of pyruvate, calcium, phosphate and
magnesium. Phosphate can be delivered as calcium phosphate,
dicalcium phosphate, potassium phosphate monobasic, dipotassium
phosphate, tri potassium phosphate, magnesium phosphate, zinc
phosphate and sodium phosphate dibasic. In certain liquid
inhalation formulations, dicalcium phosphate, is not as soluble as
potassium phosphate, which can substitute for it in any inhaled
formulation. Calcium can be delivered as calcium chloride, calcium
carbonate, calcium acetate, calcium citrate, calcium lactate, and
calcium sulfate and calcium pyruvate. Pyruvate can be delivered in
many salt forms. Sodium, Potassium, calcium, magnesium and the
other salts etc. Magnesium can be delivered as magnesium chloride,
magnesium phosphate, magnesium bicarbonate or magnesium sulfate.
The PH should be adjusted to 7.4 with sodium hydroxide. Calcium and
magnesium are needed for lung enzymes to make phospholipids and
phosphate and pyruvate are used as an ingredient in phospholipids.
Magnesium is also needed for mitochondrial membrane stability and
for the production of ATP. Without the addition of calcium,
phosphate or magnesium, pyruvate is converted in the lungs to
water, CO2 and acetate. See table III.
Example IV: Inhaled Sodium Pyruvate with and without Calcium,
Phosphate and Magnesium. .sub.SaO2 Pilot Study in Subjects with
Chronic Hypoxemia Due to Insufficient Synthesis of Lung Surfactants
in Patients with Lung Diseases, Including Asthmatics, Patients with
Interstitial Lung Disease, and COPD Patients
[0087] A total of five (5) subjects diagnosed with Severe COPD
(chronic bronchitis or emphysema) and requiring supplemental oxygen
at rest were enrolled in this study at the University of
Connecticut. Each subject received a single inhalation dose of
either 0.5 mM sodium pyruvate, 5.0 mM sodium pyruvate or 0.9%
sodium chloride at each Study Visit. The dose was administered in a
blinded cross-over manner at 1 week intervals; such that all
subjects received each study compound. Safety and therapeutic
efficacy were evaluated by the following measurements: spirometry,
expired breath NO level, .sub.SaO2, vital signs, and follow-up
telephone interviews.
[0088] The study was conducted in four visits: a Screening Visit
and Study Visits 1-3. The effect of the inhalation of a single dose
of sodium pyruvate (0.5 mM and 5.0 mM) or placebo (0.9% sodium
chloride) was studied in a double-blind protocol. The primary
efficacy outcome objective was the .sub.SaO2 levels for all
subjects. In addition, COPD subjects were evaluated by lung
function (FEV.sub.1 and PEF) and expired breath NO levels obtained
just prior to and then at 60 minutes and at 3 hours in the second
study, following the administration of the particular sodium
pyruvate dose. Since safety has been demonstrated in previous
studies, only vital signs were monitored prior to, and post
inhalation of, sodium pyruvate.
[0089] Pulse oximetry is a simple, cheap, and noninvasive procedure
used to measure the level of oxygen (or oxygen saturation) in the
blood. Oxygen saturation should always be above 95 percent.
However, oxygen saturation may be lower if you have a respiratory
disease or congenital heart disease. You can measure the blood's
percentage of oxygen saturation using a pulse oximeter, a clip-like
sensor device that is placed on your finger. A pulse oximeter may
also be used to assess, whether lung medications are working
effectively, and to determine patient tolerance to increased
activity levels, or patients that suffer from sleep apnea or have a
serious medical condition, such as heart attack, congestive heart
failure, chronic obstructive pulmonary disease (COPD), anemia, lung
cancer, asthma, or pneumonia. Oximeters use the light absorptive
characteristics of hemoglobin and the pulsating nature of blood
flow in the arteries to measure the level of oxygen in the body.
Your oxygen saturation level and pulse rate are displayed in
seconds on a lighted display screen. A range of 95% to 100% is
generally considered normal. If your oxygen level drops below 85%,
you should seek medical attention.
[0090] There were no Adverse Events noted in any of the subjects
studied. No physiological alterations occurred that caused study
termination of any of the participants after the inhalation of
sodium pyruvate. No significant change in the FEV.sub.1 or
.sub.SaO2 was observed in any of the subjects after the inhalation
of the 0.5 mM or 5.0 mM sodium pyruvate in saline or physiological
saline as compared to the pre inhalation values. Nitric oxide
levels were increased by 19% with the 5 mM inhaled solution. This
explains why sodium pyruvate by itself, without the correct ratio
of calcium, phosphate and magnesium did not increase .sub.SaO2
levels in patients with severe COPD that have hypoxemia.
Example V
[0091] A repeat of this study with 6 patients with various lung and
sinus diseases including moderate COPD patients, interstitial lung
disease and hypoxemia, showed an increase in FEV-1, .sub.SaO2 and
no increase level of NO in the patients treated with both the 0.5
mM or 5.0 mM surfactant enhancer (sodium pyruvate formula with
calcium, phosphate and magnesium). This formula was rated higher
than the standard sodium pyruvate solution without calcium,
phosphate and magnesium. See Tables I-III. Both the nasal spray and
the nebulized lung solution with the surfactant enhancer (sodium
pyruvate formula with calcium, phosphate and magnesium) increased
Sa02 in patients with COPD Cystic Fibrosis, Asthma, Allergic
Rhinitis, Alzheimer's, interstitial lung disease, cancer and in
other lung and sinus diseases by an average of 4%. The inhalation
of 20 mM of the surfactant enhancer increased .sub.SaO2 by 6% and
decreased coughing and lung tightness by 40% over the standard
sodium pyruvate formula without calcium, phosphate and magnesium.
See table IV.
[0092] In reviewing the literature, it was found that various salts
of chloride have been used as carriers of various inhalation drugs
for the nasal cavity or lungs, because they have provided no
clinical effects or efficacy for the treatment of lung diseases.
Sodium chloride is mainly used as nasal or lung moisturizer. All
the other salts, calcium chloride, potassium chloride, and
magnesium chloride, potassium phosphate, calcium phosphate, have
also been used as carrier vehicles and moisturizers. They produce
no change to FEV-1 or .sub.SaO2 measurements. It must be noted that
there is a difference between people who have transient hypoxemia
vs. one that has permanent hypoxemia. The patients respond
differently to the inhalation of sodium pyruvate by itself without
calcium, phosphate and magnesium. Sodium pyruvate formulations both
given orally or by inhalation will increase .sub.SaO2 levels in
people without lung injury to the alveoli structure especially the
mitochondria that can synthesis the phospholipids needed for oxygen
exchange and uptake. Transient hypoxemia is a self-correcting
effect. It occurs in over exercising, mountain climbing etc. In
controlled inhalation studies, patients with no lung injuries or
disease, showed an increase of .sub.SaO2 by an average of 3% after
exercising. Patients with lung damage, like in smokers, which have
a 50% rate of hypoxemia, did not show an increase saw levels after
inhaling sodium pyruvate without calcium, phosphate and magnesium.
See tables I-IV. In patients with infections, i.e. CF and allergic
Rhinitis, Nitric Oxide increase by over 400% over base line
measurements with the use of the sodium pyruvate, calcium,
phosphate and magnesium formula, needed to fight infections and
lung cancer (see table IV).
TABLE-US-00004 TABLE IV Percentage measurements in patients with
permanent hypoxemia against control group without Hypoxemia. 20 mM
sodium pyruvate formula with calcium, phosphate and magnesium were
inhaled. Overall rating was 1-10 with 1 being the most negative and
10 being the best result Percentage Lung Percentage Relief of
Percentage Percentage tightness Percentage increase in congestion
decrease Increase in Overall Various Lung and Increase in Nitric
oxide and lung in coughing SaO2 over Rating sinus diseases FEV-1
over baseline tightness in 4 hours baseline 1-10 Control group 5
4.0 10.0 15.0 12.0 0.5 8 Moderate COPD without Hypoxemia Patients
with Hypoxemia 15 moderate COPD 14.0 20.0 28.0 48.0 3.0 7 5
Asthmatics 8.0 14.0 25.0 10.0 4.0 7 13 CF 6.0 453.0 42.0 30.0 4.0
10 10 Allergic 12.0 43.0 68.0 22.0 5.0 10 Rhinitis and various
sinus diseases 5 Alzheimer's 12.0 41.0 38.0 14.0 4.5 9 patients 4
Interstitial lung 14.0 10.0 19.0 33.0 3.0 9 disease Three patients
with 11 422 15 25 4 10 lung cancer
[0093] Both the nasal spray and the nebulized lung solution with
the sodium pyruvate formula with calcium, phosphate and magnesium,
increased Sa02 in patients with COPD Cystic Fibrosis, Asthma,
Allergic Rhinitis, Alzheimer's, interstitial lung disease and in
other lung and sinus diseases by an average of 4%. The inhalation
of the nasal spray 20 mM sodium pyruvate with calcium, phosphate
and magnesium was administered first to all patients followed by
the inhalation by nebulization of the 20 mM sodium pyruvate with
calcium, phosphate and magnesium, increased .sub.SaO2 by 6% and
decreased coughing and lung tightness by 40% over the standard
odium pyruvate formula without calcium, phosphate and magnesium.
For the first time a way to increase SaO2 levels in Alzheimer's
patients that sodium pyruvate could not do without the addition of
calcium, phosphate and magnesium. The ability to enhance the
synthesis of brain or lung phospholipids had a dramatic effect on
Alzheimer's patient's cognitive ability increasing the score to
70%. Aside from Alzheimer's disease, Parkinson's disease is the
most well-known disease in the neurodegenerative disease group.
Parkinson's disease (PD) is a chronic and progressive degenerative
disease of the brain that impairs motor control, speech, and other
functions. Two patients suffering from Parkinson were given inhaled
lithium pyruvate (1 mM solution in the calcium, phosphate,
magnesium formula) every day for five weeks and in week one of
treatment the shaking was substantially reduced in both patients.
Pyruvate is one of major energy carriers in the brain, it is shown
to be protective against damaging consequences of neurotoxins, such
as hydrogen peroxide, glutamate, zinc, and copper/cysteine.
Supplementation of glucose containing culture media with energy
substrates, plus pyruvate, protected rat primary neurons from
degeneration and death caused by A-beta peptides characteristic for
Alzheimer's disease. Magnesium pyruvate also worked in these
patients.
Example VI
Patients with Severe Lung Injury or Mitochondrial Damage or COPD
and Hypoxemia with Reduced Lung Capacity
[0094] Total lung capacity is the volume in the lungs at maximal
inflation, the sum of VC and RV. RV is the residual volume of air
remaining in the lungs after a maximal exhalation. VC vital
capacity is the volume of air breath out after the deepest
inhalation. Vital capacity in males is 4.8 liters and in women 3.8
liters. Slow vital capacity (SVC) is the maximum volume of air that
can be exhaled slowly after slow maximum inhalation. Three male
patients suffering from severe lung injury or mitochondrial damage
or COPD and Hypoxemia were treated as described below for two (2)
months. Prior to treatment the subjects had limited capacity to
breathe, did not respond to any other treatment, were on oxygen
daily, and could not function. After two (2) months treatment they
showed marked improvement. In fact, dramatic results were observed
within two (2) weeks. These same three patients were treated in the
same way four months earlier using just the sodium pyruvate
formulas without the calcium, phosphate and magnesium and showed no
or little improvement in lung functions, especially in total lung
capacity. One of the three patients with COPD did show an
improvement in .sub.SaO2 levels at the end of the two months by 3%,
but total lung capacity did not change. The second treatment was
conducted as follows:
[0095] Five (5) milliliters of five (5) millimolar sodium pyruvate
with the calcium, phosphate, magnesium solution is filter
sterilized through a 0.2 micron filter. The sterile pyruvate 15
solution is placed into a "Pulmo Aid" nebulizer manufactured by
DeVilbiss Co., Somerset, Pa. 15501-0635. The sterile pyruvate
solution is nebulized by the Pulmo Aid device fitted with a
disposable nebulizer and inhaled by the patient. The patient
inhales normally from the Pulmo Aid nebulizer until all of the
solution has been nebulized and inhaled. This inhalation step
typically takes about ten (10) to twenty 20 (20) minutes. The
patients were treated with this inhalation therapy periodically.
Initially, treatments are about four (4) times a day at about six
(6) hour intervals. Treatments were reduced to three (3) times a
day at about eight (8) hour intervals after 20 days of therapy.
Treatments were further reduced to once a day 60 DAYS AFTER ONSET
OF TREATMENT. After sixty (60) days treatments are three to five
times a week. The following data shows results of various lung
capacity and lung function tests administered before treatment and
two (2) months after treatment was commenced.
[0096] Total vital capacity averaged in the three patients
increased from 2.2 liters to 3.5 liters, an increase of 33% and
.sub.SaO2 levels increased by over 6% in all the patients.
Conclusion: Treatment did the following: (1) Improved lung vital
capacity by 33% (2) Decreased some medication levels and ceased use
of oxygen. (3) COPD is reduced to the point that routine use of
inhalers is not needed. (4) Increased lung capacity by 34%.
Example VII: Clinical Trial 1
[0097] Eighteen subjects with allergic rhinitis and various other
sinus diseases, who were regular nasal spray users were given
EmphyClear.TM., a Sodium Pyruvate+Saline Nasal Spray to use at home
two or three times a day for seven days, in place of their regular
nasal spray. Several of these subjects regularly used saline, or
OTC nasal products and several used steroid-based nasal sprays.
Forty percent of subjects suffered from at least one oropharyngeal
disorder; the most frequently reported were hoarseness, tingling,
mouth irritation, and reddening due to the use of inhaled steroids.
Prior to, and at the end of the study period, the subjects'
nostrils were examined for mucosal fragility, lesions, erythema,
and edema using a rhinoscope. These pre- and post-study nasal
characteristics were rated on a five point zero ("none") to four
("severe") scale, and compared.
[0098] Conclusions:
[0099] All 18 subjects completed the study, and none opted to
return to their normal nasal spray therapy during this period. The
data obtained from the rhinoscopic examinations indicated that the
Sodium Pyruvate+Saline Nasal Spray did not induce dermal irritation
and was effective in significantly (p=0.006) reducing the erythema
in subjects who normally use either saline or non-saline nasal
sprays including steroids when pre-test ratings were compared to
post-test ratings. Further, subjective evaluations from the
subjects indicated a positive preference for the Sodium
Pyruvate+Saline Nasal Spray, with 83% of all subjects saying
EmphyClear.TM. was "Better Than" or "Comparable To" their present
therapy with regard to "Soothing;" and a like percentage of all
subjects saying EmphyClear.TM. was "Better Than" their present
therapy for relieving symptoms. 94% of all subjects said it was
"Better Than" their present therapy with regard to less 30
"Stinging." When questioned by the Investigator, 17 of 18 subjects
stated that EmphyClear.TM. "Opened Nasal Passages," and "Cleared
Congestion, reduced snoring, moisturized their nasal passages and
enhanced their ability to sleep all night." These results were
consistent whether the subject normally used a saline or
steroid-based nasal spray. This study clearly showed that delivery
of sodium pyruvate can reduce nasal congestion, swelling,
inflammation and enhanced their sleeping. When several of these
patients assessed the pyruvate formula with the calcium, phosphate
and magnesium against the standard sodium pyruvate solution in
saline, they reported the added benefits of, less lung tightness,
less mucus production which is due to an increase of sinus and lung
surfactants and reduction of one or more oropharyngeal disorder;
hoarseness, tingling, mouth irritation, and reddening.
Example VIII: Fourteen-Day in-Use Evaluation of Nasal Sprays
Containing Sodium Pyruvate and Reduced Steroids
[0100] Nasal Sprays are used by consumers to relieve congestion,
nasal dryness, inflammation, itchiness, redness, and other allergy
type symptoms. For mild symptoms, nasal sprays containing only
saline are typically used by people who suffer from nasal
congestion symptoms. However, individuals who have moderate to
severe chronic sinus problems with associated nasal inflammation,
use nasal sprays that contain steroids. These steroid-containing
sprays reduce inflammation and provide superior relief compared to
saline-only products. However, chronic use of these steroids can
cause problems in the respiratory tract and ultimately lead to 20
"rebound congestion" (Rhinitis Medicamentos). This "rebound
congestion" actually worsens the subject's nasal morphology and
physiology, leading to increased nasal congestion and inflammation.
As a result, the chronic use of steroid nasal sprays is discouraged
by the products' manufacturers' and most physicians. Excess use of
steroids has also been associated with hypoxemia. Nine regular
Flonase.RTM. subjects and eight regular Nasacort.RTM. subjects who
suffered chronically from nasal decongestion were recruited to
evaluate comparable products containing a reduced level of steroids
(50-70% reduction in the drug) in a 5 mM sodium pyruvate solution.
Prior to beginning the study, the subjects were asked to rate their
current product on a 10 point visual analogue scale (VAS) with 0
being "terrible" and 10 being "excellent" for the following
categories: soothing the nostrils, relieving symptoms, sting of
nostrils, and overall rating of satisfaction. The subjects on
average rated their current products "good," with little difference
between the two products except for a trend toward perceived better
"soothing" with Nasacort.RTM. than with Flonase.RTM..
[0101] Upon beginning the trial, the subjects were blinded
regarding their Test Product, and they used the Test Product
exclusively for 14 days. The subjects' nostrils were objectively
evaluated using a nasoscope at days 0, 7, and 14, and physical
exams, including vital signs were also administered on days 0, 7,
and 14. During the 14 day 5 test period the subjects subjectively
evaluated the Test Product on a daily basis using a 10-point VAS
questionnaire. The categories included comparison of the Test
Products to the subjects' normal therapy in their ability to sooth
the nostrils, relieve symptoms, cause/reduce stinging, relieve
decongestion, and quantify usage, and rate the product on an
"overall" basis. After seven and fourteen days, nasoscope
evaluations revealed a trend in reduction of aberrant morphologies
for the "Reduced-Strength Flonase.RTM." Test Product compared to
the nasoscope evaluations obtained on Day 0; and a significant
reduction in aberrant morphologies for the "Reduced-Strength
Nasacort.RTM." Test Product. These objective observations are
consistent with the subjective evaluations where the subjects rated
"Reduced-Strength Flonase.RTM." Test Product as "Comparable" or
"Better" in all categories, and rated "Reduced-Strength
Nasacort.RTM." Test Product as "Better" in all categories. The Test
Products were subjectively judged to be comparable or better than
the Flonase.RTM. or Nasacort.RTM. that the subjects typically used.
The subjects did not rate the Test Products lower than the
Flonase.RTM. or Nasacort.RTM. in any category. The Test Products
were rated as "Better" in comparison to the "Soothing," "Stinging"
and "Relief of Symptoms" characteristics of Flonase.RTM., and, with
regard to Nasacort.RTM., the 25 subjects rated the Test Product as
"Comparable" across all categories after 14 days of use.
End-of-Trial subjective comments were also highly favorable to the
Test Products compared to Flonase.RTM. and Nasacort.RTM..
Additionally, when asked if they might purchase the product, the
subjects' average result was 5.4.+-.1.0, indicating that the
subjects "Might Purchase," or were "Likely to Purchase," the Test
Product.
[0102] Conclusion:
[0103] "Reduced-Strength Flonase.RTM." and "Reduced-Strength
Nasacort.RTM." Test Product nasal sprays were found to be as
effective as the "full-strength" (i.e. commercial) Flonase.RTM. and
more effective than the commercial Nasacort.RTM. when the reduced
commercial "active ingredients" were delivered to the subjects in a
5 mM (0.55 mg/mL) sodium pyruvate saline solution. Pyruvate and
steroids acted synergistically. By themselves, steroids can be
toxic and irritating and habit forming. When placed together with
pyruvate, they acted synergistically to reduce inhaled steroid
levels and complemented their reactions in the human body. The 5 mM
pyruvate solution in combination with reduced steroids, balanced
the negative effect of steroids and enhanced the effect of steroids
allowing us to reduce steroids by 70% and obtain the same effect as
the full dose of steroids. The sodium pyruvate formula with
calcium, phosphate and magnesium, worked better and expectantly
less irritating to the nasal cavities and sinuses and reduction of
one oropharyngeal disorder; hoarseness, tingling, mouth irritation,
and reddening, than the sodium pyruvate in saline alone. In a
similar experiment described above, a commercial Rhinocort nasal
formula (32 mg of budesonide) was diluted with 5 mM sodium pyruvate
formulation to deliver 16 mg of budesonide (50% of the commercial
formulation) to the 4 patients that use Rhinocort and that suffered
with allergic rhinitis and sinusitis, and other nasal inflammatory
diseases. These patients rated budesonide 4 on a 1-10 irritation
scale with 1 being the most irritating and 10 being non irritating
to the sinuses. These patients were squirting each nostril 2-3
times each, two to three times daily, which is 12-18 daily squirts,
far exceeding FDA standards of 240 mg daily usage of this steroid.
When these patients tested the 50% formulation with sodium
pyruvate, they obtained the same efficacy, but with half the usage
of the steroid, but still using 12-18 squirts daily. They rated the
product a 5. When the budesonide was diluted with calcium pyruvate,
the patients rated this formula a 6 and reported that they used
equal or more squirts to obtain efficacy. When these patients
tested the 50% formula with the sodium pyruvate, calcium, phosphate
and magnesium formula, they rated the product a 8 and all the
patients recorded a 20%-30% reduction in usage, 8-12 squirts daily
usage, clearly showing that the sodium pyruvate with calcium,
phosphate and magnesium was synergistic and un expectantly less
irritating to the nasal cavities and sinuses and reduction of one
or more oropharyngeal disorder; hoarseness, tingling, mouth
irritation, and reddening. See table V.
TABLE-US-00005 TABLE V Comparison of various salts of pyruvate in 5
mM salt solutions with commercial steroids that were diluted by 50%
in patients with Allergic Rhinitis at 14 days. Overall rating was
1-10 with 1 being the most negative and 10 being the best result
Overall Various Salts Soothing Relief of Stinging Relief of
Comparison of Rating of pyruvate of Nostrils symptoms of Nostrils
congestion amount used 1-10 Sodium Nasacort 6.1 5.0 6.8 6.5 6.6 6.8
Flonase 6.0 6.1 6.2 6.8 5.9 7 Rhinocort 5.8 5.8 6.0 5.7 5.4 5.6
Calcium Nasocort 6.1 5.0 5.0 6.0 5.1 5.8 Flonase 5.0 5.1 5.7 5.8
5.9 6 Rhinocort 4.6 5.0 4.8 5.1 5.1 5.5 Sodium pyruvate &
calcium & phosphate & magnesium Nasocort 7.0 8.1 7.9 8.6
8.9 9 Flonase 7.8 8.5 8.6 8.5 8.8 8.9 Rhinocort 6.8 7.4 7.8 7.5 8.3
8.4
TABLE-US-00006 TABLE VI Comparison of 20 mM sodium pyruvate saline
nasal spray to the 20 mM sodium pyruvate formula with calcium,
phosphate and magnesium in COPD patients with Allergic Rhinitis
tested over a three months period. Overall rating was 1-10 with 1
being the most negative 5 and 10 being the best result Rating 1-10
Percentage Rating 1-10 Relief of Percentage decrease in decrease in
Congestion coughing. decrease in us Overall shortness COPD and lung
Percentage of RX Rating Formulas of breath symptoms tightness Daily
decrease medications 1-10 Sodium Pyruvate 6.0 18.0% 5 15% 20% 7 in
physiological saline Sodium Pyruvate & 8.0 52.0% 9 46% 48% 9
calcium & Phosphate & magnesium physiological Saline 2.0 6%
4 5% 1.0% 4
Example IX: Evaluation of the Sodium Pyruvate Formula with Calcium,
Phosphate and Magnesium to the Sodium Pyruvate Solution without
Calcium, Phosphate and Magnesium with Various Drugs in Patients
with Injured Lung Mitochondria that have Hypoxemia
[0104] With the hundreds of patients tested in our various clinical
trials, data was gathered as to the type of medications the
patients used and the frequency of their use over a six-month
period. The patients were asked to rate their medications form 1-10
with 1 being the most irritating with the most side effects and 10
being the best with no irritation and no side effects. In these
clinical trials, various drugs were evaluated for irritation, mucus
production, and efficacy in humans. The drugs were all evaluated
using their current formulations and concentrations against the
same formulations with the addition of sodium pyruvate, with the
calcium, phosphate and magnesium formula given just prior to the
use of their medications. They were instructed to 20 inhale this
formula just prior to the use of their medications and to evaluate
the effect of their medications on the 1-10 scale. Scores are based
on user scoring of the product and are on a 1-10 scale with a 1
score being very irritating and having side effects, 5 being
comparable to the current product and above 5 being better than the
current commercial product (less irritating and fewer side effects)
see table VII.
[0105] We evaluated the following medication and the ones that
worked with the sodium pyruvate, calcium, phosphate and magnesium
formula were the nasal and lung steroids Flonase, Nasacort,
Nasonex, Tobramyci an antibacterial, Aztreonam 10 lysine an
antimicrobial, Zanamivir for the treatment of influenza A and B,
Pentamidine isethionate--an antimicrobial, Bactroban (Mupirocin)
and antibacterial, Ribavirin (an antiviral), Vancomycin for the
treatment of Staph infections, Sprix (ketorolac Tromethamine),
Patanase for nasal allergies (antihistamine), nicotine,
Epinephrine, Cromoglycate, Combivent, acetylcysteine and insulin.
All of the medications listed above have three or more of the side
effects listed: Chest pain, nausea, vomiting, coughing,
bronchospasm, headaches, hypoventilation, hypotension, bradycardia,
increased infections, blurred vision, mucosal irritation, fatigue,
and shortness of breath and a decrease in .sub.SaO2 values. In
patients (36) with constant lung infections, bacterial or viral,
the 20 mM sodium pyruvate formula with calcium, phosphate and
magnesium reduced the amount lung or sinus infections by 54% over
the course of a year, which is very significant.
[0106] Patients on the various inhaled medications whether inhaled
or taken orally or by IV infusion, were enlisted in the evaluation
of the inhaled sodium pyruvate calcium, phosphate and magnesium
formula. The patients were tested for their .sub.SaO2 levels and
those that had .sub.SaO2 levels below 92% were asked to enlist in
the study. Nearly 50% of all patients on inhaled medications or
other non-inhaled medications exhibited Hypoxemia due to their
medical conditions or the medications they received. After the SaO2
levels were determined prior to and one hour after taking their
medications, the patients returned the following day, .sub.SaO2
measurements were taken one hour prior to taking their medications.
The patients were then handed the hypotonic inhalation formula of
sodium pyruvate with calcium, phosphate magnesium formula and
instructed to inhale it one hour before taking their medications,
.sub.SaO2 measurements were then taken one hour after taking their
medications. See table VII.
TABLE-US-00007 TABLE VII Comparison of various drugs administered
in patients with chronic Hypoxemia. Overall rating was 1-10 with 1
being non- effective and 10 being the best result for total lung
function tests. Lung functions were measured as reduction in lung
tightness and coughing, ease of breathing and decrease in hypoxemia
as measured by an increase in SaO2 levels Drug in Drug in
commercial Drug in commercial formula with Pre- commercial formula
with pre- inhaled sodium pyru- Drugs in Drugs in formula taken in
inhaled sodium py- vate, calcium & commercial commercial
prescribed way. ruvate saline only. phosphate & mag- Drugs
commercial formula with pre- formula Pre-inhaled SaO2 measurements
measurements taken nesium. measurements formula given as inhaled
sodium sodium pyruvate & taken after medica- after taking the
taken after taking instructed in the pyruvate in saline calcium
& phosphate tion and compared medication and com- medication
and package only & magnesium to baseline pared to baseline
compared to baseline Various Lung Lung Lung SaO2 SaO2 SaO2 Drugs
functions functions functions Measurements Measurements
measurements Pentamidine 4 5 8 -1 +1 +2 isethionate Mupirocin 4 6 8
0 0 +4 Tobramycin 5 5 6 -2 0 +3 Vancomycin 6 5 8 -1 0 +1 Aztreonam
8 8 7 -1 0 +4 Zanamivir 4 5 7 -2 0 +5 Ribavirin 5 6 7 -3 0 +2
Albuterol 8 8 8 0 +1 +4 Patanase 7 7 8 0 0 0 Chlotrimizole 4 6 8 -2
+1 +1 Epinephrine 3 4 5 +1 0 +6 Cromoglycate 3 6 7 0 0 +5
Flunisolide 6 6 6 -1 +1 +4 Nicotine 3 6 8 -3 +2 +4 Insulin 5 6 7 -2
+1 +4 Butorphanol 6 7 9 -2 0 0 Imetrex 7 7 7 -3 0 0 Acetylcysteine
4 6 8 +1 0 +4 Flonase 4 5 9 0 +1 +5 Levorphanol 2 6 8 -6 +1 +6
Tartrate
[0107] As can be seen in table VII, the best formula was the sodium
pyruvate formula with calcium phosphate and magnesium. The
commercial drug formulas listed above by themselves averaged a 5.1.
The addition of sodium pyruvate raised that to 6.1, an increase of
17%. The addition of the sodium pyruvate with calcium, phosphate
and magnesium raised that to an average of 7.3, a 31% reduction of
side effects. The commercial drug formulas listed above by
themselves averaged a zero for .sub.SaO2 whereas the pretreatment
with the inhalation of the sodium pyruvate, calcium, phosphate and
magnesium increased saw levels by 3% a clinically significant
improvement. Only the patients treated with the sodium pyruvate,
calcium, phosphate and magnesium formula stated they could breathe
better with less lung tightness.
Example X: Mucolytic
[0108] The sodium Pyruvate, calcium, phosphate and magnesium
solution was assessed with inhaled acetylcysteine which is FDA
approved. Inhaled acetylcysteine is indicated for mucolytic
("mucus-dissolving") therapy as an adjuvant in respiratory
conditions with excessive and/or thick mucus production. Such
conditions include emphysema, bronchitis, tuberculosis,
bronchiectasis, amyloidosis, pneumonia, cystic fibrosis and (COPD)
Chronic Obstructive Pulmonary Disease. It is also used
postoperatively, as a diagnostic aid, and in tracheotomy care. It
may be considered ineffective in cystic fibrosis. However, a recent
paper in the Proceedings of the National Academy of Sciences
reports that high-dose oral N-acetylcysteine modulates inflammation
in cystic fibrosis and has the potential to counter the intertwined
redox and inflammatory imbalances in CF. Oral acetylcysteine may
also be used as a mucolytic in less serious cases. Inhaled
acetylcysteine is indicated for mucolytic ("mucus-dissolving")
therapy as an adjuvant in respiratory conditions with excessive
and/or thick mucus production. For this indication, acetylcysteine
acts to reduce mucus viscosity by splitting disulfide bonds linking
proteins present in the mucus (mucoproteins). The sodium Pyruvate,
with the calcium, phosphate and magnesium formula was added to a
commercial formula of acetylcysteine and was found to enhance its
mucolytic activity. When many of these patients assessed the sodium
Pyruvate, calcium, phosphate and magnesium formula against the
standard sodium pyruvate solution in saline, they reported an added
benefit less lung tightness, less mucus production which is due to
an increase of sinus and lung surfactants. The use of
pyruvyl-cysteine was as effective as acetylcysteine.
Example XI: Horse Racing
[0109] When horses race, they sometimes bleed through the nostrils
and suffer from hypoxemia. Three horses with breathing and bleeding
problems were treated with a 20 mM nasal solution of sodium
pyruvate with calcium, phosphate and magnesium (surfactant
enhancer). The horses were treated by squirting each nostril 10
times each, one hour before racing and again just a few minutes
before racing. The use of the Surfactant enhancer eliminated the
bleeding and enhanced the horse's performances. They actually
started winning races, whereas they would always loose. Their
breathing problems disappeared.
Example XII: Treatment of Migraines
[0110] The use of the surfactant enhancer pyruvate nasal spray to
relieve migraines, blurred vision and sinus congestion. The nasal
spray relieved migraines and blurred vision and congestion in all
15 patients tested. The National Headache Foundation estimates that
28 million Americans suffer from migraines. More women than men get
migraines and a quarter of all women with migraines suffer four or
more attacks a month; 35% experience one to four severe attacks a
month, and 40% experience one or less than one severe attack a
month. Each migraine can last from four hours to three days. People
with migraines may inherit the tendency to be affected by certain
migraine triggers, such as fatigue, bright lights, weather changes,
and others. There is a migraine "pain center" or generator in the
brain. A migraine begins when hyperactive nerve cells send out
impulses to the blood vessels, causing them to clamp down or
constrict, followed by dilation (expanding) and the release of
prostaglandins, serotonin, and other inflammatory substances that
cause the 30 pulsation to be painful. Many migraines seem to be
triggered by external factors. Possible triggers include: Emotional
stress, Sensitivity to specific chemicals and preservatives in
foods, Caffeine, Changing weather conditions, Menstrual periods,
Excessive fatigue, Skipping meals, and Changes in normal sleep
pattern. It became obvious from the results of the clinical trials,
that the sodium pyruvate with calcium, phosphate and magnesium
formula nasal spray relieved migraines and reduced swelling and
congestion and the pain associated with migraines.
Example XIII: Sleep Aids
[0111] We tested a nasal formulation with sleep aids. All the
patients that used our 20 mM sodium pyruvate with calcium,
phosphate and magnesium formula nasal spray stated they slept
better. We then took this nasal spray and added tryptophan a known
sleep agent found in turkey meat. The addition of tryptophan worked
synergistically to enhance sleep in patients that used it.
Inhalation products for sleeping disorders were combined with the
sodium pyruvate with the calcium, phosphate and magnesium formula.
They included, migranal (dihydroergotamine mesylate) stadol,
(butorphanol) Imetrex, for anti-snoring. Two children with Autism,
reported that the use of the 20 mM sodium pyruvate with the
calcium, phosphate and magnesium formula nasal spray calmed them
down and allowed them to sleep all night.
Example XIV: Sleep Apnea
[0112] Sleep Apnea is a sleep disorder characterized by pauses in
breathing or instances of shallow or infrequent breathing during
sleep, with a reduction in .sub.SaO2 values caused by reduced
levels of synthesized phospholipids. Each pause in breathing,
called an apnea, can last for several seconds to several minutes,
and may occur, by definition, at least 5 times in an hour.
Similarly, each abnormally shallow breathing event is called a
hypopnea. When breathing is paused, carbon dioxide builds up in the
bloodstream. Chemoreceptor's in the blood stream note the high
carbon dioxide levels. The brain is signaled to wake the person
sleeping and breathe in air. Breathing normally will restore oxygen
levels and the person will fall asleep again. There are three forms
of sleep apnea: central (CSA), obstructive (OSA), and complex or
mixed sleep apnea (i.e., a combination of central and obstructive)
constituting 0.4%, 84%, and 15% of cases, respectively. In CSA,
breathing is interrupted by a lack of respiratory effort; in OSA,
breathing is interrupted by a physical block to airflow despite
respiratory effort, and snoring is common. According to the
National Institutes of Health, 12 million Americans have OSA. There
are more cases of sleep apnea still because people either do not
report the condition or do not know they have sleep apnea. In other
words, common effects of sleep apnea include daytime fatigue, a
slower reaction time, and vision problems. OSA may increase risk
for driving accidents and work-related accidents. If OSA is not
treated, one has an increased risk of other health problems such as
diabetes. Even death could occur from untreated OSA due to lack of
oxygen to the body. There is also evidence that the risk of
diabetes among those with moderate or severe sleep apnea is higher.
There is also increasing evidence that sleep apnea may also lead to
liver function impairment, particularly fatty liver diseases.
People who smoke have sleep apnea at three times the rate of people
who have never smoked. Mild occasional sleep apnea, such as many
people experience during an upper respiratory infection, may not be
important, but chronic severe obstructive sleep apnea requires
treatment to prevent low blood oxygen (hypoxemia), sleep
deprivation, and other complications. Snoring is a common finding
in people with this syndrome. Snoring is the turbulent sound of air
moving through the back of the mouth, nose, and throat.
[0113] The sodium Pyruvate formula with calcium, phosphate and
magnesium increased lung and sinus surfactants to decreases
congestion and inflammation and increases oxygen saturation to help
patients with Sleep Apnea. In all of the clinical studies,
approximately 20% of the patients treated with our nasal spray or
inhalation therapy (460 patients), reported that they suffered from
Sleep Apnea, and that the use of our inhaled surfactant enhancer
allowed them to sleep all night without snoring or waking up.
Example XV: Smokers, how Nicotine Inhalation in the Sinuses or
Lungs Increases Hypoxemia
[0114] The primary therapeutic use of nicotine is in treating
nicotine dependence in order to eliminate smoking with its health
risks. Nicotine can also be irritating and has the ability to lower
.sub.SaO2 values when inhaled in smoke while increasing hypoxemia.
We placed nicotine into a modified formula sodium pyruvate and
calcium, phosphate and magnesium and discovered that inhaled
nicotine (nasal or lungs) was well tolerated over nicotine by
itself, which was irritating. The combination was synergistic.
Smokers who used this formula rated the sodium pyruvate, calcium,
phosphate and magnesium nicotine formula much higher than nicotine
by itself. They reported that nicotine delivered this way was
faster than the patch and much less irritating. The patient
squirted each nostril three times which is equivalent to 0.66 mg of
pyruvate per dose per nostril which is 1.32 mg of pyruvate being
delivered per dose times 2 times per day is 2.64 mg of pyruvate
delivered per daily dose. Approximately 0.020 mg to 0.03 mg of
nicotine was delivered. Nicotine delivered only with sodium
pyruvate in saline solution, was a little more irritating and the
ability of each patient to determine the effect of nicotine was
delayed by 26%. .sub.Sa02 levels in these patients rose by 4% with
the sodium pyruvate, calcium, phosphate magnesium formula.
Example XVI: Cancer Drugs Often Cause Lung Cell Damage and Inhibit
the Synthesis of Membrane Phospholipids to Cause Lung Tightness,
Coughing and Hypoxemia
[0115] This treatment might offer promise in battling lung cancer,
the leading cause of cancer-related deaths in the United States,
and the second-most common cancer overall, according to the
National Cancer Institute (NCI). About 160,000 Americans died from
the disease last year, which costs the U.S. nearly $10 billion in
medical bills, according to the NCI. Some chemotherapy drugs can
affect the lungs (pulmonary toxicity). The exact effect of
chemotherapy drugs that cause lung problems is not fully known. It
may be that the drugs cause inflammation in the lung cells that
result in a lung infection (pneumonitis). The drugs may also cause
fibrous, scar-like tissue to form in the lungs (pulmonary fibrosis)
and restrict lung function. Lung damage is often related to the
dose of the drugs used. Chemotherapy drugs that are known to cause
lung damage are: Bleomycin (Blenoxane)--most common. Lung damage
occurs in up to 10% of people who receive this drug. The risk
increases when higher doses are used. With Carmustine (BiCNU, BCNU)
lung damage occurs in about 20%-30% of people who receive high-dose
therapy with this drug. Methotrexate pulmonary toxicity occurs in
up to 8% of people who receive this drug. With Alkylating drugs,
such as cyclophosphamide (Cytoxan, Procytox) or busulfan (Busulfex)
lung damage occurs in less than 1% of people who receive these
drugs. Lung damage occurs more often in people who: are elderly
People over 70 years of age, have a higher risk of developing lung
problems, have a personal history of lung disease, like COPD, or
have received radiation therapy to the lungs. Symptoms of lung
damage include: dry cough, shortness of breath (especially with
activity) lung tightness, and fatigue. Symptoms can occur during
treatment with chemotherapy or a few months after treatment ends.
Damage to the lung tissue is usually not reversible.
[0116] Changes to lung tissue may be detected with: blood tests to
check the level of oxygen in the blood, such as blood gas analysis
or oxygen saturation tests that measure lung function, such as
pulmonary function test (PFT). When shortness of breath occurs, it
may be treated with: oxygen therapy and drugs to reduce
inflammation, bronchodilator drugs to widen the bronchi (large
tubes, or airways, in 15 the lungs).
[0117] Hypoxia within regions of solid tumors including lung
cancers, is associated with resistance to standard treatments,
particularly radiotherapy. Conventional drug therapy, which depends
on reaching the cancer through the bloodstream, can be less
effective in hypoxic tumors. Low oxygen levels in a cell interrupt
the activity of oxidative phosphorylation, a term for the highly
efficient way that cells normally use to convert food to energy. As
oxygen decreases, the cells switch to glycolysis to produce their
energy units, called ATP. Glycolysis is a drastically less
efficient way to obtain energy, and so the cancer cells must work
even harder to obtain even more food, specifically glucose, to
survive. When oxygen levels dip dangerously low, angiogenesis, or
the process of creating new blood vessels, begins. The new blood
vessels provide fresh oxygen, thus improving oxygen levels in the
cell and tumor and slowing the cancer growth--but only
temporarily.
[0118] Drug designers have taken advantage of the hypoxic regions
in tumors and designed anticancer drugs that are specifically
active or activated under hypoxic conditions. For example,
hypoxia-activated prodrugs like 3-bromopyruvate, are chemically
modified to be inactive, but when administered to the body and
exposed to hypoxic conditions (such as in a tumor), they are
metabolized or otherwise converted into the active, anticancer
form. Despite these new drugs, there is an ongoing need for
innovative approaches to anticancer therapy. This patent highlights
various treatment options available for increasing lung surfactants
that are responsible for increasing blood oxygen levels in cancer
Patients thus targeting hypoxic cells within tumors that could be
highly beneficial in the treatment of SCLC.
Example XVII: Pretreatment of Normal Cells Co Cultured with Cancer
Cells, Followed by Treatment with Doxorubicin
[0119] Peripheral blood monocytes and U937 monocytic leukemia tumor
cells were placed in sterile culture flasks and maintained in
culture using Dulbecco's Minimal Essential Medium, with 10% fetal
calf serum, supplemented with 2 mM glutamine and Pen/Strep. The
cytotoxicity of the cytotoxic agent on the cells was analyzed by
propidium iodide exclusion techniques and flow cytometric
quantitation. Viability of the cells was quantified as the number
of cells that excluded the vital dye trypan blue. Sodium pyruvate
was dissolved in distilled water and the solution was adjusted to
pH 7.4 with calcium, phosphate and magnesium. Solutions were
sterile filtered. Stock solutions were prepared so that the vehicle
would not be more than 1% of the total volume of the culture media.
H-Thymidine Radiosotopic Incorporation Measurement of Cytotoxity.
The membrane surfactant enhancers agents (sodium pyruvate and
calcium, phosphate and magnesium), was examined for their ability
to decrease the Cytotoxity of Doxorubicin to U937 monocytic
leukemia cells and normal peripheral blood monocytes. The optimal
concentrations of the agents that were able to protect cells
against Doxorubicin induced Cytotoxity were the 5 mM of sodium
pyruvate, calcium, phosphate and magnesium formula. Susceptibility
studies were conducted to determine the optimal treatment time of
the cells with the cryoprotective agents prior to treatment of the
cells with the cytotoxic agent. The normal cells and U937 leukemic
tumor cells were pretreated separately in "wash out" studies with
the single agents alone, and in combination, at the optimal
concentration described above for various time periods, washed with
fresh medium to remove the agents, and treated with the cytotoxic
agent. The co-culture of normal and U937 leukemic minor cells was
treated essentially in the same manner except that the cells were
not treated separately, but co-cultured. The optimal pretreatment
time of the cells with the membrane enhancer agents was found to be
24 hours prior to treatment of the cells with Doxorubicin. The
cells were then placed in culture medium without the protective
agents. The length of time that the cytoprotection lasted was 24
hours following Doxorubicin treatment. At this time, peripheral
cell viability is a limiting factor because these cells are normal
cells and do not remain in culture for extended periods of time.
Normal and U937 tumor cells were co-cultured and the Cytotoxity of
Doxorubicin on the cells was determined by viability assays which
examined the differential ability of the cytoprotective
compositions alone, and in combinations, to protect the normal
cells from the Cytotoxity of the chemotherapeutic agent. The cells
were isolated and examined for morphological evidence of
cytotoxicity or prevention of cytotoxicity. These studies
determined the cytoprotective effect of the surfactant enhancer on
the normal and tumor cells. DNA synthesis studies using 3Hthymidine
(1 uCi/well) were carried out 4 hours prior to termination of the
experiment to determine the effect of the formulations on the
proliferation of the cells as a measure of the prevention of
cytotoxicity and the extent of Doxorubicin-induced cytotoxicity.
Propidium iodide exclusion analysis was carried out for direct
quantitation of the cytotoxicity and the prevention of
cytotoxicity. Each set of studies was performed in triplicate so
that statistical analysis of the significant differences between
the treatment groups could be conducted. The surfactant enhancer
combination of 5 mM sodium pyruvate and calcium, phosphate, and
magnesium formula, provided significant protection to the normal
peripheral monocytes and did not protect the tumor cells from the
effects of the Cytotoxic agent. Wash-out studies were conducted to
determine viability of the peripheral blood monocytes co-cultured
with U937 monocytic leukemia cells after 24 hour pretreatment of
the cells with the surfactant enhancer, which is also a
mitochondrial protective agent, followed by administration of
Doxorubicin. The viability of the control normal peripheral cells
was enhanced from 55% to 68% with the use of 5 mM sodium pyruvate
and calcium, phosphate and magnesium formula, whereas the viability
of the control U937 cells was decreased from 43% to 12%. Thus, the
use of the surfactant synthesis enhancer protected normal cells for
24 hours, while the leukemia cells died. See table VIII.
TABLE-US-00008 TABLE VIII Comparison of various cancer drugs in
various media. Percentage of viable non-cancerous cells after
incubation with anticancer drugs Drugs in Drugs in Drugs in
commercial commercial commercial formula with Percentage of Drugs
in formula with formula with sodium pyruvate viable commercial
sodium pyruvate sodium pyruvate with calcium & cells after
formula with without calcium & with calcium & phosphate
& incubation sodium phosphate & phosphate & Magnesium
Various Drugs with drugs chloride only magnesium magnesium repeat
study anastrozole 24 25 50 86 94 Bleomycin 31 33 47 98 98 cisplatin
46 43 58 88 91 Carboplatin 42 50 56 87 97 floxuridine 38 38 58 92
91 methotrexate 42 43 68 94 98 oxaliplatin 23 24 41 95 98
Bevacizumab 21 27 40 88 87
[0120] Other drugs tested produced similar results, shown in the
above table, including Crizotinib, Docetaxel, Erlotinib, Etoposide,
Gemcitabine, Irinotecan, Paclitaxel, Pemetrexed Vinorelbine.
Example XVIII: Treatment of Patients with Various Cancers and Lung
Cancer
[0121] To date most patients with cancer that are treated with
radiation or cancer drugs show a partial reduction of tumor sizes,
but in most cases the cancer remains and life expectances increases
for a short period of time. This is the case for lung cancer. Five
patients with various cancers including including lung cancers,
were treated with 3-Bromopyruvate, an alkylating agent and a
well-known inhibitor of energy metabolism. Results to date have
been mixed. The problem with most cancer drugs is not only their
toxicity to noncancerous tissue, but is their inability to
completely eradicate the cancer. Cancer drugs cause hypoxia in
normal noncancerous cells and they destroy lung tissue and their
ability to synthesize lung surfactants, thus cause damage to
surrounding tissue. In mice studies conducted by others, they
investigated the chemo preventive activity of 3-bromopyruvate. For
the aerosol treatment the mice were treated with 10-30 mg/5 ml
daily and treated for 8 weeks. Aerosolized 3-bromopyruvate
significantly decreased tumor multiplicity and tumor load by 40%
and 60%, respectively, at a dose of 10 mg/5 mL by inhalation.
Interestingly, the efficacy of aerosolized 3-bromopyruvate did not
accompany any liver toxicity indicating that it is a safer safer
route of administering this compound. Treatment with
3-bromopyruvate in tissue cultures of lung cancer cells showed an
increased immune histo chemical staining for cleaved caspase-3,
suggesting that the lung tumor inhibitory effects of
3-bromopyruvate were through induction of apoptosis.
[0122] 3-Bromopyruvate also dissociated hexokinase II from
mitochondria, reduced hexokinase activity, and blocked energy
metabolism in cancer cells, finally triggered cancer cell death and
induced apoptosis through caspase-3, and PARP in human lung cancer
cell line. The problem with 3-bromopyruvate was its toxicity to
normal lung cells. The formula needed to protect noncancerous cells
from 3-bromopyruvate and to enhance its effect on tumors, was the
addition of inhaled 20 mM solution of sodium pyruvate, calcium,
phosphate, magnesium formula inhaled 1-2 hours prior to the
inhalation of the 10 mg of 3-bromopyruvate. The investigators were
given the sodium pyruvate with calcium, phosphate and magnesium
formula and instructed to have the rats inhale the formula 1-2
hours prior the inhalation of the cancer drug. 25 This approach
reduced tumor sizes by 90% compared the 60% reduction with
3bromopyruvate by itself. The addition of dichloroacetate with
3-bromopyruvate to the sodium pyruvate with calcium, phosphate and
magnesium formula was the best formula decreasing tumor loads by
95%, especially with the addition of magnesium bicarbonate that
increased the PH to 7.9 to neutralize the lactic acid produced in
tumors that enhance tumorigenesis. Similar effects were seen with
the inhalation of the sodium pyruvate, calcium, phosphate, and
magnesium formula followed in two hours by oral or inhalation
administration of the 3-bromopyruvate or doxorubicin.
Example XIX: Tumor Volume Decrease at 8 Weeks is Associated with
Longer Survival in EGFR-Mutant Advanced Non-Small-Cell Lung Cancer
Patients Treated with EGFR TKI
[0123] Departments of *Imaging, .sup..dagger.Biostatistics and
Computational Biology, Dana-Farber Cancer Institute, Boston, Mass.;
.sup..dagger-dbl.Department of Medical Oncology and Medicine,
Dana-Farber Cancer Institute and Brigham and Women's Hospital,
Boston Mass.; and Department of Radiology, Brigham and Women's
Hospital, Boston Mass. Background: The study investigated whether
tumor volume changes at 8 weeks of therapy is associated with
outcomes in advanced non-small-cell lung cancer (NSCLC) patients
harboring sensitizing epidermal growth factor receptor (EGFR)
mutations treated with EGFR tyrosine kinase inhibitors (TKIs).
Methods: In 56 advanced NSCLC patients with sensitizing EGFR
mutations treated with first-line erlotinib or gefitinib, tumor
volumes of dominant lung lesions were measured on baseline and
follow-up computed tomography, and were analyzed for association
with survival. Results: Among 56 eligible patients, the median
tumor volume was 17.8 cm.sup.3 (range, 1.3-172.7 cm.sup.3) on the
baseline scans. Forty-nine patients had follow-up computed
tomography at approximately 8 weeks; the median tumor volume at 8
weeks was 7.1 cm.sup.3 (range, 0.4-62.3 cm.sup.3), with the median
proportional volume change of -59% (range, -90% to +91%) from
baseline. The proportional volume change at 8 weeks was associated
with survival (p=0.02). Using the cutoff value of 38% volume
decrease (75th percentile) at 8 weeks, patients with volume
decrease more than 38% (n=37) had a median overall survival of 43.5
months compared with 16.3 months among those with volume decrease
of 38% or less (n=12; p 0.01). The median progression-free survival
for patients with more than 38% volume decrease was 12.6 months,
compared with 5.5 months for those with 38% or lesser volume
decrease (p=0.2). The 12 patients with 8-week volume decrease of
38% or lesser had significantly shorter survival. The present study
demonstrated that proportional tumor volume decrease at 8 weeks of
therapy was associated with prolonged survival in advanced NSCLC
patients, with sensitizing EGFR mutation treated with first-line
gefitinib or erlotinib.
Example XX: Cancer Trial Pilot Study
[0124] In eleven patients with various cancers and chronic
Hypoxemia, five with lung cancer, including three with non small
cell lung cancer and six with various other cancers, were given the
formula containing the sodium pyruvate with calcium, phosphate and
magnesium by inhalation, which increased .sub.SaO2 levels in these
patients to enhance the effect of the chemotherapy or radiation,
and increased the synthesis of lung surfactants in lung alveoli
cells to protect normal cells and help reduce hypoxia in cancer
cells. These patients inhaled the formula one to two hours before
they were treated with cancer drugs or radiation, given by current
standard methods, and continued to inhale the surfactant enhancer
formula twice a day for the eight weeks following the chemo therapy
treatment. Because these patients are older, they often lack good
nutritional eating habits, which effects their immune system. Thus,
the patients were also given a proprietary diet high in a unique
blend of antioxidants, and nutrients, that they consumed every day
before and after chemo or radiation. Good nutrition is always a
plus when patients undergo chemo or radiation as sited in numerous
published articles. The diet specifically designed for patients
with cancer and hypoxemia included calcium pyruvate, dicalcium
phosphate and magnesium in their components. The diet included
Lecithin which contains Phosphatidylcholine one table spoon daily
needed for phospholipid synthesis in cells and mitochondria and to
protect them from chemo, calcium pyruvate 6 grams daily, Magnesium
pyruvate 1 gram with 350 mg of magnesium needed by mitochondrial
enzymes, calcium phosphate or dicalcium phosphate 1 gram needed by
cellular enzymes to maintain hemostasis, Baker's yeast one oz.
scoop daily to provide other pre cancer nutrients and vitamin E 400
units or more.
[0125] In patients with severe Hypoxemia, Oxygen therapy was
continued and the patient also inhaled the surfactant enhancer
formula prior to and after chemotherapy for eight weeks. These
patients continued chemo therapy beyond the eight weeks and ten
patients are still alive six to 10 years later, beating the
national survival rate by 4 years. Other drugs tested given by IV
or oral standard treatments reduces tumor sizes or loads by an
average 29.2% as sited in the literature. These drugs were
Crizotinib, Docetaxel, Erlotinib, Etoposide, Gemcitabine,
Irinotecan, Paclitaxel, Pemetrexed, Vinorelbine. The inhalation of
the surfactant enhancer decreased tumor loads and sizes, that was
averaged among the eleven patients was 54.5%, a statistically and
clinically significant result. This clearly showed that decreasing
hypoxemia and increasing oxygen levels at hypoxia tumor sites
increased the efficacy of chemotherapy or radiation and enhanced
the reduction of tumor loads and sizes which increases survival
rates significantly. One patient with lung cancer and pulmonary
hypertension and COPD was treated with various cancer drugs
including Gefitinib, erlotinib or doxorubicin over a year period.
His lung cancer did not respond well to any of the treatments and
his tumors shrank by only 15%. Pulmonary arterial hypertension
causes the arteries that carry blood from the heart to the lungs to
narrow, resulting in decreased oxygen flow to the blood vessels.
When the body is deprived of vital oxygen, the blood pressure in
the pulmonary arteries spikes above the normal range compressing
the heart's right ventricle. The pressure on this area will
eventually cause the right side of the heart to swell, gradually
weaken, and restrict blood flow to the lungs. If left untreated,
pulmonary hypertension can end in heart failure. The current
treatment is the inhalation of Nitric oxide gas. As stated in table
III the addition of the N-acetylcysteine to the phospholipid
membrane enhancer formula increased Nitric oxide dramatically over
any other pyruvate salt formulas. We had the patent pre and post
inhale the sodium pyruvate with calcium, phosphate and magnesium
formula with the addition of the N-acetylcysteine during the next
round of chemotherapy. His .sub.SaO2 levels rose by 5% and his
nitric oxide levels increased by over 225% compared to the standard
sodium pyruvate formula in saline, without the addition of calcium,
phosphate and magnesium, that raises nitric oxide by 19% an 11
times greater increase. His tumor load and size shrank by 78% in
eight weeks and in his next round of treatment the tumors
disappeared. His pulmonary hypertension also disappeared. He is
still alive four years later, beating the odds-on survival.
Aeroshot Inc sells a caffeine inhaled product that delivers 100 mg
of caffeine. One of the patients with lung cancer that was treated
with cisplatin used the Aeroshot product along with the surfactant
enhancer and decreased tumor sizes by 60% in eight weeks. Caffeine
is thought to increase the antitumor effect of cisplatin or
DNA-damaging agents because it is known that caffeine inhibits DNA
repair. It appears from the results in this patient that the
addition of caffeine to the surfactant enhancer (sodium pyruvate
with calcium, phosphate and magnesium) enhanced the effect of the
cisplatin.
Example XXI: Immunotherapy's Especially for Non-Small Cell Lung
Cancer
[0126] Keytruda (pembrolizumab), Yervoy (ipilimumab), Opdivo
(nivolumab), Tecentriq (atezolizumab) are medicines that may treat
your lung cancer by working with your immune system. They can cause
your immune system to attack normal organs and tissues in many
areas of your body and can affect the way they work. These problems
can sometimes become serious or life-threatening and can lead to
death. These problems may happen anytime during treatment or even
after your treatment has ended. Serious side effects may include
lung problems (pneumonitis). Symptoms of pneumonitis may include:
new or worsening cough; chest pain; and shortness of breath. In all
these cases these drugs increase hypoxemia by inhibiting the
synthesis of lung surfactants. Several patients that reported lung
problems with the use of these medications (new or worsening cough;
chest pain; and shortness of breath) were given our inhaled formula
containing the sodium pyruvate, with calcium, phosphate and
magnesium. They reported that their lung problems were eliminated,
after using the inhaled formula.
Example XXII: Four-Week Use of Oxymetazoline Nasal Spray Once Daily
at Night Induces Rebound Swelling and Nasal Hyperreactivity that
can be Reversed with the Addition of the Sodium Pyruvate, Dicalcium
Phosphate Magnesium Formula. Ohio State University Medical Center
2001
[0127] A randomized double-blind parallel study with 90 healthy
volunteers was performed to examine the effect of oxymetazoline
nasal spray on the development of rhinitis medicamentosa. For 30
days, 45 subjects were given oxymetazoline nasal spray once daily
at night and placebo in the morning and at noon, The other 45
patients were given oxymetazoline nasal spray with 20 mM sodium
pyruvate with calcium, phosphate and magnesium by inhalation, which
increased .sub.SaO2 levels in these patients once daily at night
and placebo in the morning and at noon, before and after the course
of treatment, the mucosal surface positions were determined with
rhinostereometry, followed by histamine challenge tests. In the
morning and the evening just before use of the nasal spray,
symptoms of nasal stuffiness were evaluated on visual analogue
scales (0-100). After 30 days, rebound swelling and nasal
stuffiness occurred only in the oxymetazoline group without the
addition of the pyruvate formula. In the group receiving
oxymetazoline nasal spray once daily at night, the mean rebound
swelling was 1.1 mm (p<0.01) and the estimated mean symptom
score for nasal stuffiness in the evening was 43 (p<0.05). In
the group receiving oxymetazoline with the pyruvate formula, nasal
spray once daily at night, the mean rebound swelling was 0.1 mm
(p<0.01) and the estimated mean symptom score for nasal
stuffiness in the evening was 3 (p<0.05). The finding of an
increase in histamine sensitivity in the oxymetazoline without the
pyruvate formula, was taken to indicate nasal hyperreactivity. It
is concluded that the risk of developing rebound swelling and nasal
hyperreactivity remains, with oxymetazoline nasal spray when used
once a day for 30 days, but not when Oxymetazoline contained the
sodium pyruvate formula with calcium, phosphate and magnesium.
Example XXIII: Concussions
[0128] The secondary effects of cranial trauma that may further
compromise brain function are edema, hypoxia, hemorrhage, infection
and oxygen radicals. Other important components of posttraumatic
cerebral pathophysiology include, but are not limited to,
generation of lactic acid, decreased intracellular magnesium, free
radical production, inflammatory responses, and altered
neurotransmission. Concussions also cause impaired mitochondrial
oxidative metabolism that worsens the energy crisis in the brain.
Edema may be the result of diffuse shearing of capillary, glial,
and neuronal membranes or may be secondary to local contusion or
laceration. Edema can generate local pressure that can compromise
both arterial and venous cerebral blood flow, causing ischemia and
more edema. This may precipitate a vicious cycle sometimes
impossible to reverse. The mass effect of edema, focal or diffuse,
can cause rostro caudal brain stem deterioration (possibly with
herniation), a major cause of delayed death from head trauma. Brain
dysfunction and destruction are aggravated by hypoxia, the result
of compromised respiratory function caused by the following: (1)
injury to the chest, (2) aspiration pneumonia in the unconscious
patient, (3) respiratory center depression from rostro caudal
deterioration or direct damage to the medulla, (4) pulmonary edema
secondary to hypothalamic-septal damage, or (5) status epilepticus.
Blood loss from multiple injuries and, as mentioned, brain edema
further compromise delivery of oxygen to the brain. We gave several
football players the 20 mM sodium pyruvate with calcium, phosphate
and magnesium by inhalation, which increased .sub.SaO2 levels in
these patients, to reduce brain damage and hypoxia. Measurement of
reaction times can be measured by the speed of the mouse clicks to
common questions. Someone with a concussion will react slowly to
these questions. The inhalation of the 20 mM sodium pyruvate with
calcium, phosphate and magnesium formula, increased reaction times
by 42% over the baseline measurements. In the treatments of
patients with concussions or Alzheimer's, the inhalation formulas
were delivered by inhalation using a breathing mask.
[0129] Smoke Inhalation Damage and Treatment.
[0130] The same approach can be applied to smoke inhalation damage.
The results indicate that the current pathophysiologic concept is
of a disease process that leads to immediate and delayed pulmonary
injury. The lung injury process is activated by toxins in the
smoke's gas and particle component and by a resulting in lung
inflammation. This inflammatory process becomes self-perpetuating
through the activation of a large number of inflammatory cytokines
and oxygen radicals, which reduce the ability of the lungs to
synthesize phospholipids. Several patients with smoke inhalation
damage used the mask and testing showed an increase in .sub.SaO2
after the inhalation of the sodium pyruvate, calcium, phosphate and
magnesium formula and reduced coughing.
TABLE-US-00009 TABLE IX Comparison of various salts of pyruvate
against a 20 mM sodium pyruvate nasal sprays in patients with sinus
& lung diseases including IPF and COPD. Overall rating was 1-10
with 1 being the most negative and 10 being having the best rating.
All nasal sprays contained 0.22% of each salt of pyruvate per liter
of 0.9% sodium chloride. When the various salts of pyruvate were
mixed the percentages always equaled 0.22% or as an example 0.11%
of sodium pyruvate and 0.11% of calcium pyruvate to equal a 20 mM
solution or 0.22%. Relief of Percentage congestion, Percentage
increase of coughing Increase in Overall Various Salts of Increased
Nitric Oxide and lung SaO2 over Rating pyruvate in saline in FEV-1%
over baseline Irritation tightness baseline 1-10 Sodium 12.0 19.0
none 6 2 7 Calcium 7.0 17.0 None 5 1 7 Potassium 6.1 10.0 None 5 no
6 Magnesium 4.0 5.1 slight 6 no 4 Zinc 1.0 2.0 Yes 4 No 3 Manganese
0.0 2.0 Yes 4 No 3 Lithium 0.0 00.0 Yes 2 No 2 Aluminum 0.0 00.0
Yes 1 No 1 Ammonium 0.0 00.0 Yes 1 No 1 Potassium Phosphate 0.0 0
Slight 4 No 3 sodium & calcium 12.0 16 None 5 2 7 pyruvates
sodium & magnesium 8.4 15 None 6 No 6 pyruvates sodium &
calcium & 8.0 19 None 5 2 6 magnesium pyruvates sodium &
calcium & 7.0 18 None 5 2 7 pyruvate &potassium phosphate
sodium & magnesium 8.0 20 None 4 2 6 pyruvates & potassium
phosphate Sodium & calcium & 10.0 19 None 7 2% 7 Magnesium
pyruvates &Potassium phosphate Sodium pyruvate 25 57.0 0 9 6%
10 & calcium chloride & magnesium chloride and potassium
phosphate
[0131] Katz and Martin (current inventor) suggested the use of
other salts of pyruvate to inhale and treat nasal and lung
diseases. They never tested the individual salts for their ability
to reduce inflammation or increase lung functions. This table
demonstrated that not all salts of pyruvate produced clinically
significant results and that many were irritating. The salts of
pyruvate, Zinc, manganese, lithium, magnesium, ammonium and
aluminum were irritating and were much higher than blood levels and
produced a metal taste. The combination of sodium, calcium and
magnesium pyruvates with potassium phosphate did not product the
clinically significant results achieved with the formula that
contained 0.22% Sodium pyruvate 0.90% sodium chloride, 0.01%
Calcium chloride, 0.01% magnesium chloride and 0.001% potassium
phosphate by weight per liter of water.
TABLE-US-00010 TABLE X Comparison of various nasal sprays of a 20
mM sodium pyruvate solution in patients with sinus & lung
diseases including IPF and COPD. Overall rating was 1-10 with 1
being the most negative and 10 being the best result. Percentages
of ingredients in one liter of water 0.22% sodium pyruvate, 0.90%
sodium chloride, 0.01% Calcium chloride, 0.01% magnesium chloride
and 0.001% potassium phosphate by weight added individually or in
combination as listed below. Formula for the sodium pyruvate with
the membrane enhancer: to one liter of purified water add 2.2 gm of
sodium pyruvate, 9.0 gm of sodium chloride, 0.1 gm of calcium
chloride, 0.1 gm of magnesium chloride, and 0.01 gram of potassium
phosphate. Sodium pyruvate in saline with various ions of Relief of
calcium chloride, Percentage congestion, Percentage magnesium
increase of coughing and Increase in chloride and Increased Nitric
Oxide lung SaO2 over Overall Potassium phosphate in FEV-1% over
baseline Irritation tightness baseline Rating 1-10 Sodium pyruvate
12.0 20.0 None 6 2 7 in saline Calcium chloride 12.0 19.0 none 5 2
7 Magnesium chloride 12.0 19.0 None 5 1 7 K phosphate 10.1 10.0
None 5 no 6 Calcium chloride& 11.0 5.1 None 6 no 5 Magnesium
chloride Calcium chloride& 10.0 8.0 Yes 4 1 6 Potassium
phosphate Magnesium chloride & 11.4 16 None 5 2 7 potassium
phosphate Sodium pyruvate 28 57.0 none 9 6% 10 & calcium
chloride & magnesium chloride and potassium phosphate Gennero
culture 00 -10.0 very Increased -2% 1 medium 20090181007 coughing
and congestion
[0132] Table X demonstrated unexpected synergistic combination of
0.22% Sodium pyruvate 0.9% sodium chloride, 0.01% Calcium chloride,
0.01% magnesium chloride and 0.001% potassium phosphate by weight
per liter of water. Each individual component did not produce
higher clinical results. The culture medium of Gennero listed
above, patent application 20090181007 produces very bad results
compared to the other formulas. This patent combined dozens of
ingredients, including the use of enzyme, growth factors, sugars,
nucleotide and vitamins, amino acids and sodium pyruvate, other
nutrients and calcium chloride, magnesium chloride and calcium
phosphate other ingredients to stimulate the growth of cartilage
and collagen for knees and joints. When inhaled it performed very
poorly even though it contained the ingredients in the surfactant
enhancer the sodium pyruvate, calcium chloride, magnesium chloride
and calcium phosphate. The other ingredients produced irritation.
Mucus increased as did coughing and did not increase lung
functions. The Gennero formula also decreased the synthesis of
nitric oxide which is critical to increasing lung functions, and
bronchodilation and reducing nasal and lung infections. The
concentrations of the ingredients in the 0.22% sodium pyruvate with
0.9% sodium chloride, with 0.01% calcium chloride, 0.01% magnesium
chloride and 0.001% potassium phosphate by weight per liter of
water was determined form blood levels of these ingredients that
are known to work and not induce toxicity if higher levels were
used. It produced the most clinically significant results in all
categories.
Example XXIV: Inhibiting Lung Fibrosis and Increasing the Lung
Functions of FEV-1, FVC, PEF, SaO2, Nitric Oxide and (% FEV1/FVC
Ratios). An Open Label Placebo Controlled Comparison of a 20 mM
Sodium Pyruvate Nasal Spray with the Surfactant Enhancer
Ingredients in Patients with Pulmonary Fibrosis, COPD, Diabetics,
and Hypertension
[0133] There have been over 56,381 patient complaints to the FDA
from patients with Idiopathic Pulmonary Fibrosis (IPF) without
COPD, and Pulmonary Fibrosis with COPD, Diabetics, and patients
with hypertension, stating that Rx, OTC, and steroid-based
inhalation products, have failed to provide relief from nasal or
lung inflammation nor have the ability to increase lung functions,
FEV-1, FVC, PEF, SaO2, especially FEV-1/FVC ratios. This study was
designed to determine the effect of inhaled 20 mM sodium pyruvate
saline nasal spray with the addition of calcium chloride, magnesium
chloride and potassium phosphate (surfactant enhancer ingredients)
to determine if this formula would have a positive effect in these
patients, while on or off their medications and to determine if the
nasal inhalation solutions would have any added benefit to current
therapies on nasal inflammation; lung functions, including FVC,
FEV.sub.1, PEF; and FEV-1/FVC ratios; SaO.sub.2; expired NO, and
frequency of coughing. Nasal steroids and other OTC nasal
treatments shut down the synthesis of nasal nitric oxide, which
then leads to a decrease in lung functions and a 34% increase in
infections, mouth breathing and coughing.
[0134] The FEV1/FVC ratio, also called Tiffeneau-Pinelli index, is
a calculated ratio used in the diagnosis of obstructive and
restrictive lung disease. It represents the proportion of a
person's vital capacity that they are able to expire in the first
second of forced expiration (FEV1) to the full, forced vital
capacity (FVC). The result of this ratio is expressed as % FEV1/FVC
ratio. Normal values are approximately 75%. In restrictive lung
disease, the FEV1 and FVC are equally reduced due to fibrosis or
other lung pathology like pulmonary fibrosis, which occurs in
pulmonary fibrosis, and in patients with diabetes, and
hypertension.
[0135] Methods:
[0136] An initial twenty-one-day sub-chronic clinical trial was
conducted that included patients with Pulmonary Fibrosis with COPD
and with Idiopathic Pulmonary Fibrosis without COPD, that remained
on their normal medications (steroids), but were also administered
the 20 mM sodium pyruvate saline nasal spray with the surfactant
enhancer ingredients (0.22% Sodium pyruvate 0.90% sodium chloride,
0.01% Calcium chloride, 0.01% magnesium chloride and 0.001%
potassium phosphate by weight per liter of water). If the patients
were also on nasal sprays as part of their normal therapy, that
nasal spray was eliminated. In all patients the test results were
compared to their previous three-week screening and baseline data
(there current therapies) as the placebo control for each variable
including all their lung functions, FEV-1, FVC, PEF, FEV-1/FVC
ratios, SaO2, Nitric oxide, coughing rates, nasal inflammation.
[0137] Results: Treatment with the 20 mM Sodium Pyruvate Saline
Nasal Spray with Calcium Chloride, Magnesium Chloride, and
Potassium Phosphate.
[0138] The patients that had both diseases, Pulmonary Fibrosis and
COPD, showed a clinically significant improvement in lung functions
as determined by changes in FEV-1, FVC, or PEF or FEV-1/FVC ratios
on the testing days compared to baseline for the 21 day clinical
trial while on their medications. The 20 mM sodium pyruvate saline
nasal spray with the surfactant enhancers ingredients did enhance
the effect of any medication used to treat patients with both
pulmonary fibrosis and COPD. This group of patients showed very
little responses to medications because of the double nature of the
two diseases they have.
[0139] Results: Treatment with the 20 mM Sodium Pyruvate Nasal
Spray with Calcium Chloride, Magnesium Chloride, and Potassium
Phosphate (Surfactant Enhancer Ingredients), in Patients with Both
Pulmonary Fibrosis and COPD and Patients with Idiopathic Pulmonary
Fibrosis without COPD.
[0140] When patients that had both Pulmonary Fibrosis and COPD were
administered the 20 mM sodium pyruvate formula with the correct
concentrations of calcium chloride, magnesium chloride, and
potassium phosphate, (surfactant enhancer), a significant
improvement was demonstrated in FEV-1, FVC, or PEF and FEV-1/FVC
ratio, which increased from 67% to 87% while on or off their
medications. This same result was also observed in all patients
with Idiopathic Pulmonary Fibrosis without COPD as determined by
improvements in FEV-1, FVC, or PEF or FEV-1/FVC and FEV-1/FVC
ratios from 51% to 87%, while on or off their medications. This
formula produced clinically significant results that was superior
to other formulas tested and showed that current therapies have no
effect on patients with pulmonary fibrosis. The data for both
groups, from this study also showed that coughing was significantly
(p=0.005) reduced in all patients by day 14; a significant
(p=0.011) improvement in nasal irritation/erythema with most
patients being free of irritation by day 12 (p=0.000) and a
significant (p=0.010) increase in the group average expelled-NO by
day 6.
[0141] The Sodium Pyruvate with the Surfactant Enhancer Increased
Nitric Oxide in the Nasal Cavity that Inhibits Coughing, Post Nasal
Drip and Mouth Breathing.
[0142] The upper and lower airways form one contiguous and
functionally related organ that is critical to normal lung
functions. The nasal cavity produces 900-1,100 parts per billion of
nitric oxide, which is used to kill invading bacteria, fungi, and
viruses compared to the lungs which produce 4-48 parts per billion
nitric oxide. Nasal nitric oxide also produces clinically useful
bronchodilation and has been shown to reduce pulmonary fibrosis.
Blockage of nasal nitric oxide by inflammation reduces the amount
of nitric oxide reaching the lungs, which reduces critical lung
functions, leading to increased lung and nasal infections, a
reduced SaO.sub.2 level, reduced FEV-1 levels also leading to mouth
breathing and coughing. Nasal steroids and other OTC nasal
treatments shut down the synthesis of nasal nitric oxide, which
then leads to decreased lung functions and a 34% increase in
infections.
Example XXV: Tissue Culture Studies that Demonstrate that Lung
Fibrosis can be Reversed Using Sodium Pyruvate with the Surfactant
Enhancer Ingredients to Target Myofibroblasts
[0143] In experiments using lung tissues from patients with
pulmonary fibrosis and/or IPF, it was demonstrated that the
reversal of lung fibrosis and the underlying cellular mechanisms
were affected by the use of the 20 mM sodium pyruvate saline
formula with the addition of calcium chloride, magnesium chloride
and potassium phosphate (surfactant enhancer ingredients).
[0144] Cellular activity was lower in myofibroblast cells within
fibrotic regions of human lung tissue from pulmonary fibrosis
and/or IPF patients. Myofibroblasts deposit extracellular collagen
fiber as part of the fibrosis process. Structural changes to the
airway are believed to contribute to an irreversible decrement in
lung function in these individuals. Subepithelial deposition of
collagen (types I, III, and V) and other extracellular proteins,
fibroblast proliferation, mucus hypersecretion, and smooth muscle
thickening are all evident in airway remodeling in pulmonary
Fibrosis. Other cellular components may not only stimulate
differentiation of fibroblasts to myofibroblasts, but also inhibit
apoptosis of the myofibroblasts in the lung parenchyma causing
extended survival of this population and excessive collagen
deposition, which causes fibrosis.
[0145] Activation of myofibroblasts apoptosis from lungs of humans
with pulmonary Fibrosis, using the 20 mM sodium pyruvate saline
nasal spray with the addition of calcium chloride, magnesium
chloride and potassium phosphate (surfactant enhancer ingredients)
led to lower fibrotic activity also enhanced the production of new
mitochondria, the organelles in cells that produce energy in the
myofibroblasts, and it normalized the cells' sensitivity to
apoptosis.
[0146] The combination of sodium pyruvate and calcium chloride,
potassium phosphate and magnesium chloride were synergistic in its
ability to increase the incorporation of pyruvate into in
myofibroblast cells It enhanced cellular activity and decreased
collagen deposition that inhibited fibrosis, specifically measured
by changes in sub-epithelial matrix deposition, using histochemical
and immunohistochemical staining. In previous studies with rat
lungs previously treated with bleomycin, using [2-(14)C] labeled
pyruvate; cellular activity and analysis clearly showed that the
sodium pyruvate, calcium chloride, potassium phosphate and
magnesium chloride formula decreased fibrosis by inhibiting
cellular enzymes that increase fibrosis.
[0147] Gennero Culture Medium Patent Application. 20090181007.
[0148] This patent combined dozens of ingredients, including the
use of enzyme, growth factors, sugars, nucleotide and vitamins,
amino acids and sodium pyruvate, other nutrients and calcium
chloride, magnesium chloride and calcium phosphate other
ingredients to stimulate the growth of cartilage and collagen for
knees and joints. We assessed this formula and discovered it did
stimulate the synthesis of cartilage and collagen, when placed in
lung tissue cultures with fibroblasts, that differentiated into
myofibroblasts that produced a huge amount to collagen, which in
patients with pulmonary fibrosis would be fatal. Activation of
myofibroblasts to increase the synthesis of collagen from lungs of
humans with pulmonary Fibrosis, with the Gennero culture medium led
to more fibrotic activity that did not cause the myofibroblasts to
normalize to undergo apoptosis. Even though this formula contained
sodium pyruvate, calcium chloride, magnesium chloride and calcium
phosphate it acted in the opposite manner when these ingredients
were tested with the other ingredients listed in the culture
medium. One cannot assume you can achieve clinically significant
results because a culture medium contained some of the ingredients
listed in the membrane surfactant enhancer. The addition of the
other ingredients when inhaled did produce the opposite effect by
increasing fibrosis instead of stopping it. This prior art
reference teaches away from the present invention methods.
TABLE-US-00011 TABLE XI Percentage measurements in patients with
pulmonary fibrosis, permanent hypoxemia, IPF and in patients with
un meet needs that cannot use steroids, Diabetics, and Hypertensive
patients with FEV-1/FVC ratios around 50%. Comparison of various
pyruvate nasal spray formula against the 20 mM sodium pyruvate
formula with calcium chloride, potassium phosphate and magnesium
chloride. Percentages of ingredients in one liter of water 0.22%
sodium pyruvate, 0.9% sodium chloride 0.01% Calcium chloride, 0.01%
magnesium chloride and 0.001% potassium phosphate by weight
(surfactant enhancer), demonstrated clinical superiority over all
other formulas listed. Nasal formula with 0.9% Katz Pat. Nos.
sodium chloride 5,798,388 With 20 mM 5,939,459 Katz formula Nasal
formula Nasal formula Nasal formula sodium pyruvate 5,952,384 Katz
formula 0.90% Sodium 0.45% sodium with 0.9% with 1.0% and calcium
6,482,856 0.90% sodium chloride With chloride with sodium chloride
sodium chloride chloride, magnesium application chloride 0.5 5.0 mM
20 mM sodium with 20 mM with 20 mM chloride and 200220006961 mM
pyruvate pyruvate pyruvate sodium pyruvate sodium pyruvate
potassium phosphate Percentage 10% 11% 20% 26% 28% 72% decrease in
coughing Percentage 5% 4% 9% 11% 14% 36% increase in FEV-/ FVC
ratios over baseline of 50% Percentage 6% 7% 13% 15% 18% 67%
decrease in fibrosis Percentage increase 2% 4% 7% 14% 22% 77% in
apoptosis in myofibroblasts Cell death
[0149] Nasal Inhalation Sodium Pyruvate with the Membrane Enhancer
Decrease Mouth Breathing to Increase Serotonin Levels Back to
Normal Levels.
[0150] Nasal inhalation of sodium pyruvate with the membrane
enhancers, not only decreases nasal inflammatory agents, it reduces
mouth breathing to increase the synthesis of nitric oxide to normal
levels which maintains normal levels of serotonin. With the
reduction of nasal nitric oxide due to congestion, inflammation and
mouth breathing, normal levels of serotonin drop. Serotonin is one
of the most widely recognized of all neurotransmitters. It is
intricately involved in numerous core physical processes such as
the regulation of sleep, appetite and aggression. Serotonin is also
a key player in mood, anxiety, fear, and general sense of
well-being. Imbalances in serotonin, particularly relative to
norepinephrine and dopamine, are common causes of certain types of
depression. Antidepressants that block serotonin's re-uptake back
into serotonin neurons are among the most common of all classes of
medications prescribed. Serotonin deficiency is a common
contributor to mood problems, sleep and is common with patients
that have a lung or sinus disease that mouth breath. Nitric oxide
is needed to maintain normal levels of serotonin to maintain normal
health.
Serotonin Urine Tests.
[0151] Eleven patients with various lung and sinus diseases
including COPD, allergic rhinitis, chronic rhinosinusitis and
pulmonary fibrosis were instructed to use the 20 mM sodium pyruvate
nasal spray (0.22% Sodium pyruvate, 0.9% sodium chloride, 0.01%
Calcium chloride, 0.01% magnesium chloride and 0.001% potassium
phosphate by weight per liter of water) for two weeks. Urine
samples were collected from these patients prior to using the nasal
spray and two weeks later and compared. All patients had below
normal levels of serotonin when compared to normal individuals. The
5-hydroxyindoleacetic acid (5-HIAA) urine test is used to help
diagnose and monitor serotonin levels. It may be ordered by itself
or along with a blood serotonin and/or chromogranin A level. 5-HIAA
is the primary metabolite of serotonin that is excreted in the
urine. The formula tested and listed above increased serotonin
levels over 62% above base line measurements to bring the serotonin
back to normal levels. Mouth breathing disappeared as did coughing,
all lung functions increased and anxiety, fear disappeared and
general sense of well-being occurred.
[0152] Nitric Oxide is Elicited and Inhibits Viral Replication in
Pigs Infected with Porcine Respiratory Coronavirus
[0153] We examined NO levels by Greiss assay in bronchoalveolar
lavage (BAL) of pigs infected with either porcine respiratory
coronavirus (PRCV). The antiviral effects of NO on this virus was
tested in an in vitro system using a NO donor, S-nitroso-N-acetyl
penicillamine (SNAP). We detected a large increase in NO levels in
BAL fluids of PRCV-infected pigs. Pulmonary epithelial cell
necrosis induced by PRCV coincided with increased NO. Moreover, NO
levels in cell culture medium of PRRSV-infected alveolar
macrophages (AMs) did not differ from that of mock-infected AMs.
Antiviral assays showed that NO significantly inhibited PRCV
replication in swine testicular (ST) cells. NO plays a role in
innate immunity to respiratory CoV infections by inhibiting viral
replication.
[0154] Although particular embodiments of the invention have been
described in detail herein with reference to the accompanying
drawings, it is to be understood that the invention is not limited
to those particular embodiments, and that various changes and
modifications may be effected therein by one skilled in the art
without departing from the scope or spirit of the invention as
defined in the appended claims.
CONCLUSIONS
[0155] Comparison of the various sodium pyruvate formulations
including any 20 mM sodium pyruvate saline nasal spray to the 20 mM
sodium pyruvate nasal spray with calcium chloride, magnesium
chloride, and potassium phosphate (surfactant enhancer ingredients)
in patients with Pulmonary Fibrosis with and without COPD,
diabetics and patients with hypertension, demonstrated superiority
in increasing lung functions, and the FEV-1/FVC ratios from 51% to
87% and achieving relief in the patients over the other sodium
pyruvate saline nasal spray by itself, without the surfactant
enhancer ingredients, especially in patients with both Pulmonary
Fibrosis and COPD. All formulation decreased inflammation but not
all formulas decreased fibrosis or collagen deposition
significantly or increased apoptosis in myofibroblasts. The use of
the 20 mM sodium pyruvate nasal spray with calcium chloride,
magnesium chloride, and potassium phosphate (surfactant enhancer
ingredients) resulted in: [0156] 1. A significant unexpected
improvement in lung function (breathing) in all patients with
pulmonary Fibrosis with or without COPD) compared to baseline, as
determined by changes in FVC, FEV.sub.1, PEF, and FEV-1/FVC ratios
while on their medications. [0157] 2. Coughing and mouth breathing
was significantly reduced with the 20 mM sodium pyruvate nasal
spray with the surfactant enhancer ingredients, and continued to
decrease over the course of the daily treatment. [0158] 3. A
significant increase in the group average expelled-NO (nitric
oxide), with the 20 mM sodium pyruvate nasal spray with the
surfactant enhancer ingredients in all patients showing an increase
during the study. [0159] 4. Improvement in endurance and exercise
was reported with the 20 mM sodium pyruvate nasal spray with the
surfactant enhancer ingredients in all patients [0160] 5. A
significant (p=0.011) improvement in nasal irritation/erythema with
the 20 mM sodium pyruvate nasal spray with the surfactant enhancer
ingredients with most patients being free of irritation by day 12
(p=0.000) [0161] 6. Serotonin came back to normal levels. Mouth
breathing disappeared as did coughing, all lung functions
increased, anxiety and fear disappeared and general sense of
well-being occurred with the 20 mM sodium pyruvate nasal spray with
the surfactant enhancer ingredients. [0162] 7. Increasing cellular
protection and deactivation of myofibroblasts collagen deposition
from lungs of humans with pulmonary Fibrosis and IPF to repair and
reverse lung fibrosis, with the 20 mM sodium pyruvate nasal spray
with the surfactant enhancer ingredients [0163] 8. Increase in
apoptosis in myofibroblasts with the sodium pyruvate formula that
contained the surfactant enhancer ingredients. [0164] 9. Inhibits
replication of the coronavirus with the 20 mM sodium pyruvate nasal
spray with the surfactant enhancer ingredients.
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