U.S. patent application number 10/833182 was filed with the patent office on 2004-10-07 for methods and apparatus for therapeutic treatment of respiratory, cardiac and other pathologies.
Invention is credited to Fein, Harry, Zhang, Xueji.
Application Number | 20040197274 10/833182 |
Document ID | / |
Family ID | 32993261 |
Filed Date | 2004-10-07 |
United States Patent
Application |
20040197274 |
Kind Code |
A1 |
Fein, Harry ; et
al. |
October 7, 2004 |
Methods and apparatus for therapeutic treatment of respiratory,
cardiac and other pathologies
Abstract
A storage and delivery system for directly applying nitric oxide
to a user includes a portable and disposable capsule and a source
of nitric oxide gas disposed within the cavity. Gas flow control
apparatus controls the flow of nitric oxide gas from the cavity.
Gas flow initiation apparatus allows the user to initiate the flow
of nitric oxide gas. The encapsulated nitric oxide gas is applied
by positioning the capsule proximate to the objective site of the
user and initiating flow of the nitric oxide gas.
Inventors: |
Fein, Harry; (Nokomis,
FL) ; Zhang, Xueji; (Sarasota, FL) |
Correspondence
Address: |
Alix, Yale & Ristas, LLP
750 Main Street
Hartford
CT
06103
US
|
Family ID: |
32993261 |
Appl. No.: |
10/833182 |
Filed: |
April 27, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10833182 |
Apr 27, 2004 |
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09884786 |
Jun 19, 2001 |
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6749834 |
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Current U.S.
Class: |
424/45 ;
128/200.23; 424/718 |
Current CPC
Class: |
A61M 2202/0275 20130101;
A61M 15/08 20130101; A61M 2205/8225 20130101; Y10S 514/958
20130101; A61M 15/0025 20140204 |
Class at
Publication: |
424/045 ;
424/718; 128/200.23 |
International
Class: |
A61L 009/04; A61M
011/00; A61K 033/00 |
Claims
What is claimed:
1. A method of storing pressurized gas for subsequent therapeutic
application comprising encapsulating the pressurized gas in a
portable, light-weight gas impermeable capsule.
2. The method of claim 1 wherein the capsule includes means for
controlling the concentration of gas delivered from the
capsule.
3. The method of claim 2 further comprising the step of maintaining
delivered nitric oxide gas at safe concentration levels to avoid
toxic effects when applied to body cavities of subjects.
4. A method of providing therapeutic application of a gas as
required comprising: encapsulating chemical reagents which form the
gas when mixed and mixing the chemical reagents when required.
5. The method of claim 3 wherein said gas is nitric oxide.
6. A method of directly applying nitric oxide gas for therapeutic
use by humans and animals using a portable nitric oxide gas
source.
7. The method of claim 5 wherein the gas source is disposable
gas.
8. The method of claim 7 further comprising positioning the nitric
oxide gas source for application proximal to or within a nostril of
a subject human or animal.
9. The method of claim 7 further comprising positioning elements of
said nitric oxide gas source proximal to an objective site so as to
provide optimal therapeutic effect.
10. The method of claim 7 further comprising diluting inhaled gas
by the respiratory tidal volume of a user.
11. The method of claim 7 further comprising positioning the nitric
oxide gas source for application proximal to or within any passage
of a subject human or animal.
12. A portable gas storage device for storing pressurized gas
comprising: a gas impermeable capsule; means for controlling the
flow rate of gas when released from the capsule; and means for user
initiation of gas outflow from said capsule.
13. The device of claim 12 wherein the pressurized stored gas is
nitric oxide.
14. The device of claim 12 further comprising pressure control
means for maintaining a constant gas venting pressure.
15. The device of claim 12 further comprising a porous filter
adapted for restricting the rate of gas outflow.
16. The device of claim 15 further comprising means for filtering
undesired impurities from the delivered gas stream.
17. The device of claim 15 wherein the porous filter includes
chemical reagents for removing nitrogen dioxide gas from the
delivered gas stream.
18. The device of claim 12 wherein the device is disposable.
19. A gas generator comprising: a capsule; a plurality of chemical
reagents disposed within the capsule, the chemical reagents
generating a gas when activated; and means for controlling the rate
at which generated gas is vented from the capsule.
20. The gas generator of claim 19 wherein the generated gas is
nitric oxide.
21. The gas generator of claim 19 further comprising pressure
regulator means for providing a constant gas venting pressure.
22. The gas generator of claim 19 further comprising a porous plug
for restricting the rate of gas outflow.
23. The gas generator of claim 22 wherein the porous plug includes
reagents for filtering nitrogen dioxide gas from the gas
outflow.
24. The gas generator of claim 19 further comprising a porous plug
for preventing water vapor from leaving the capsule.
25. The gas generator of claim 19 further comprising a gas
permeable tube.
26. The gas generator of claim 19 wherein the capsule is completely
enclosed by a gas permeable polymer jacket.
27. The gas generator of claim 26 wherein the polymer jacket is
impermeable to water and chemical reagents.
28. The gas generator of claim 19 wherein the chemical reagents are
selected from the group consisting of water, sodium nitrite,
potassium nitrite, sodium iodide, potassium iodide, ascorbic acid,
hydrochloric acid, nitric acid and sulfuric acid, cupric chloride,
cuprous chloride, and vanadium.
29. The gas generator of claim 19 wherein the chemical reagents are
selected from the group of S-Nitrosothiols (RSNO) consisting of
S-nitroso-N-acetyl-D-, -dimethylcysteine (SNAP),
S-nitroso-L-glutathione (GSNO), S-Nitrosocysteine, S-nitrosated
amino acid, S-nitrosated peptides, and S-nitrosated protein.
30. The gas generator of claim 19 further comprising breakable
vessel means, disposed within the capsule a first of the chemical
reagents being stored within the vessel and a second of the
chemical regents being stored between the vessel and the capsule,
for allowing the first chemical reagent to mix with the second
chemical reagent when broken.
31. The gas generator of claim 19 wherein the chemical reagents
include NONOate.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a division of application Ser. No. 09/884,786, filed
Jun. 19, 2001 to which this application claims benefit under 35
U.S.C. .sctn.120.
BACKGROUND OF THE INVENTION
[0002] The perception that nitric oxide (NO), a chemically active
gas, plays an essential role in human and animal physiology was
first demonstrated in 1987 with the publication of Nitric Oxide
Accounts for the Biological Activity of Endothelium Derived
Relaxing Factor; Palmer, R. M., Ferridge, A. G., Moncada, S; Nature
1987; 327:524-526. The authors demonstrated that the
endothelial-derived relaxation factor (EDRF) was indeed nitric
oxide. Many research publications have since defined more clearly
the multiple and complex roles of NO in human, animal and plant
physiology. Synthesized endogenously in humans, animals and plants,
NO plays many very important physiological roles. For example,
research reports have shown that NO may be effective in the
treatment of sickle cell anemia.
[0003] Nitric oxide, in conjunction with ventilatory support and
other appropriate agents, is used for the treatment of term and
near-term (greater than 34 weeks) neonates with hypoxic respiratory
failure associated with clinical or echocardiographic evidence of
pulmonary hypertension, where it improves oxygenation and reduces
the need for extracorporeal membrane oxygenation. It has also been
reported to be useful as a selective pulmonary vasodilator in
patients with adult respiratory distress syndrome. Lack of systemic
vasodilatory effects with nitric oxide is an advantage over other
vasodilators (e.g., epoprostenol (prostacyclin),
nitroprusside).
[0004] Among the increasing range of pathologies which can be
successfully treated with gaseous NO is anal disease. Anal fissure
(or fissure-in-ano), anal ulcer, acute hemorrhoidal disease, and
levator spasm (proctalgia fugax) are common, benign conditions of
the anal canal which affect men and women. An anal fissure or ulcer
is a tear or ulcer of the mucosa or lining tissue of the distal
anal canal. An anal fissure/ulcer can be associated with other
systemic or local diseases, but it is more frequently present as an
isolated finding. The typical, idiopathic fissure or ulcer is
confined to the anal mucosa, and usually lies in the posterior
midline, distal to the dentate line. The person with an anal
fissure or ulcer suffers from anal pain and bleeding, more
pronounced during and after bowel movements.
[0005] Hemorrhoids are specialized vascular areas lying subjacent
to the anal mucosa. Symptomatic hemorrhoidal disease is manifest by
bleeding, thrombosis or prolapse of the hemorrhoidal tissues. Men
and women are affected. Most commonly, internal hemorrhoidal tissue
bulges into the anal canal during defecation causing bleeding. As
the tissue enlarges, prolapse pain, thrombosis, and bleeding can
ensue. Thrombosis of internal or external hemorrhoids is another
cause of pain and bleeding.
[0006] Levator spasm (or proctalgia fugax) is a condition of
unknown etiology affecting women more frequently than men. This
syndrome is characterized by spasticity of the levator ani muscle,
a portion of the anal sphincter complex. The patient suffering from
levator spasm complains of severe, episodic rectal pain. Physical
exam may reveal spasm of the puborectalis muscle. Pain may be
reproduced by direct pressure on this muscle. Bleeding is not
associated with this condition.
[0007] The underlying causes of these problems are poorly
understood. However, all of these disorders are associated with a
relative or absolute degree of anal sphincter hypertonicity. In the
case of anal fissure/ulcer the abnormality appears to be an as yet
unidentified problem of the internal and sphincter muscle. The
internal sphincter is a specialized, involuntary muscle arising
from the inner circular muscular layer of the rectum. Intra-anal
pressure measurements obtained from people suffering from typical
anal fissure/ulcer disease show an exaggerated pressure response to
a variety of stimuli. The abnormally high intra-anal pressure is
generated by the internal sphincter muscle. The abnormally elevated
intra-anal pressure is responsible for non-healing of the
fissure/ulcer and the associated pain. U.S. Pat. No. 5,504,117
teaches methods to treat anal pathologies by the topical
application of preparations that stimulate the production of
endogenous nitric oxide synthase (NOS) which, in turn, causes NO to
be generated in endothelial tissue and in the nervous system, by
the catalytic action of NOS upon L-Argenine.
[0008] Although safe NO dosage values are at present still
evolving, the Occupational Safety and Health Administration (OSHA)
has set the time-weighted average inhalation limit for NO at 25 ppm
for 10 hours and NOsub2 not to exceed 5 ppm. NIOSH Recommendations
for Occupational Safety and Health Standards: Morbidity and
Mortality Weekly Report, Vol. 37, No. S-7, p. 21 (1988). The
Environmental Protection Agency (EPA) has stated that a
health-based national (maximum ambient) air quality standard for
NOsub2 is 0.053 ppm (measured as an annual average).
[0009] When exposed to oxygen, NO gas will, depending on
environmental conditions, undergo oxidation to NOsub2, also to
higher oxides of nitrogen. Gaseous nitrogen dioxide, if inhaled in
sufficient concentration (for example, as little as 10 ppm for ten
minutes), is toxic to lung tissue and can produce pulmonary edema
and this concentration and exposure time, or more, could result in
death. Standards with regard to nitrogen dioxide toxicity have not
been firmly established. Nitrogen dioxide is a deep lung irritant
that can produce pulmonary edema and death if inhaled at high
concentrations. The effects of NOsub2 depend on the level and
duration of exposure. Exposure to moderate NOsub2 levels, 50 ppm
for example, may produce cough, hemoptysis, dyspnea, and chest
pain. Exposure to higher concentrations of NOsub2 (greater than 100
ppm) can produce pulmonary edema, that may be fatal or may lead to
bronchiolitis obliterans. Some studies suggest that chronic
exposure to nitrogen dioxide may predispose to the development of
chronic lung diseases, including infection and chronic obstructive
pulmonary diseases.
[0010] It is common practice in therapeutic NO inhalation
procedures both to monitor and also to remove NOsub2 before it can
be inhaled by a subject to whom NO is being applied. For example,
the NO respiratory gas mixture may be transported through a soda
lime mixture to scavenge nitrogen dioxide. However, NO gas in the
therapeutic concentration range (i.e. 1 ppm to as much as 100 ppm)
can be administered safely, for short time periods, in dry normal
air (21% oxygen) without the formation of toxic concentrations of
NOsub2. Moreover, the present invention may include intra-capsular
means to adsorb NOsub2.
[0011] Historically, NO gas is commercially manufactured using the
Ostwald process (U.S. Pat. No. 4,774,069, U.S. Pat. No. 5,478,549)
in which ammonia is catalytically converted to NO and Nitrous Oxide
at a temperature above 800 degrees centigrade. This process thus
involves the mass production of NO at high temperatures in an
industrial setting. The therapeutic advantages of NO over other
pulmonary and cardiovascular drugs have led researchers to attempt
the design of an instrument that can deliver variable
concentrations of NO accurately. For example, U.S. Pat. No.
5,396,882 describes a process for generating NO in an electric arc
discharge in air where the electrodes are separated by an air gap
in an arc chamber. The application of a high voltage across the air
gap produces a localized plasma that breaks down oxygen and
nitrogen molecules and generates a mixture of NO, ozone, and other
NOx species. The concentration of NO in this system can be varied
by adjusting the operating current. The gas mixture is then
purified and mixed with air in order to obtain therapeutically
significant concentrations of NO prior to administration to a
patient. However, the quantification of generated NO by this system
is purely empirical making the instrument extremely susceptible to
the slightest fluctuations in the internal and external parameters
such as ambient humidity and the surface area of the electrodes in
the arc chamber.
[0012] Although inhalation of nitric oxide gas has been shown to be
effective for treatment of pulmonary hypertension, there are
several drawbacks and limitations of this particular mode of
therapy. For example, current art therapy requires large and heavy
gas tanks, expensive monitoring equipment, and a trained
anesthesiologist to operate the tanks and equipment so as to
deliver NO gas to a patient with safety. Therefore, NO inhalation
therapy is at present limited to hospitals or similar clinical
facilities. Thus there is a great needed for a more flexible,
portable and less expensive means with which NO may be delivered
safely in an organ specific manner without causing systemic
vasodilation.
[0013] For over a century, nitroglycerin has been used as a
vasodilating agent in the treatment of cardiovascular disease.
Nitroglycerin, or glyceryl trinitrate, is an organic nitrate ester
which when administered to a subject is converted biologically to
nitric oxide by stimulating an enzyme, nitric oxide synthase (NOS),
which in turn, catalyzes the production of endogenous NO from
L-argenine. However, the effectiveness of nitroglycerin is greatly
diminished because the recipient of therapeutic administration of
nitroglycerin rapidly develops a tolerance to the beneficial
effects of nitroglycerin. Therefore, onset of nitroglycerin
tolerance significantly limits the therapeutic value of
nitroglycerin because increased nitroglycerin dosages have little
or no effect on vasorelaxation or vasodilatation. A further
limitation may result from the fact that nitroglycerin is
physiologically non specific. That is, vascular response to the
drug will be generally distributed over the entire circulatory
system.
SUMMARY OF THE INVENTION
[0014] The present invention teaches new and novel methods and
means with which NO can be rapidly delivered to alveolar vascular
tissue so as to bring about a rapid increase in the concentration
of NO in lung and heart vascular epithelia. The effect is to cause
rapid dilation of blood vessels in the lung and heart and to a
considerably lesser degree, in more distal blood vessels through
which blood circulates owing to the rapid absorption of NO by red
blood cells.
[0015] The present invention features methods for prevention and
treatment of asthma attacks and other forms of bronchial
constriction, acute respiratory failure, or reversible pulmonary
vasoconstriction (i.e., acute or chronic pulmonary vasoconstriction
which has a reversible component). An affected subject may be
identified, for example, by acute physical distress symptoms or by
traditional diagnostic procedures. The subject will then inhale a
therapeutically-effective concentration of gaseous nitric oxide so
as to achieve therapeutic relief.
[0016] The present invention teaches methods and devices that
produce NO from the inside of portable and disposable capsules
containing NO under pressure and from chemical reagents which, when
appropriately combined or activated, generate a controlled outflow
of pure NO gas to the capsule exterior in free air. It is essential
that the concentration of gas inhaled from the above mentioned
capsular NO source be large enough to effect therapeutically
beneficial results and at the same time not exceed a safe NO
concentration maximum for gas inhalation. Both exposure time and
gas concentration values together dictate what safe dosage may
be.
[0017] The present invention teaches the principles of new devices
and new procedures that will provide effective therapeutic
application of inhaled NO during coronary and respiratory
emergencies such as angina, thrombosis in heart and lung blood
vessels; also hypertension in lung vasculature, as well as
reversible asthma attacks.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] The present invention may be better understood and its
numerous objects and advantages will become apparent to those
skilled in the art by reference to the accompanying drawings in
which:
[0019] FIG. 1 is a schematic, cross-sectional view of a first
embodiment of a NO storage and delivery system in accordance with
the invention;
[0020] FIG. 2 is a schematic, cross-sectional view of a second
embodiment of a NO storage and delivery system in accordance with
the invention;
[0021] FIG. 3 is a schematic, cross-sectional view of a third
embodiment of a NO storage and delivery system in accordance with
the invention; and
[0022] FIG. 4 is a schematic, cross-sectional view of a fourth
embodiment of a NO storage and delivery system in accordance with
the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0023] A number of compounds have been developed that are capable
of delivering nitric oxide in a pharmacologically useful way. Such
compounds include compounds that release nitric oxide after being
metabolized and compounds that release nitric oxide spontaneously
in aqueous solutions. Compounds capable of releasing NO upon being
metabolized include the widely used nitrovasodilators glyceryl
trinitrate (nitroglycerin) and sodium nitroprusside (SNP). These
compounds are relatively stable but they release or cause the
release of NO upon activation.
[0024] Many nitric oxide-nucleophile complexes also have been
described. Some of these compounds, known as NONOates, evolve
nitric oxide upon heating or hydrolysis. These compounds, unlike
nitroglycerin or SNP, release NO without requiring activation.
NONOates have reproducible half-lives ranging from 2 seconds to 20
hours. Nitricoxide/nucleophile complexes (NONOates) that release
nitric oxide in aqueous solution are disclosed in U.S. Pat. No.
5,389,675, U.S. Pat. No. 5,366,977, and U.S. Pat. No. 5,250,550.
The nitric oxide-releasing functional group is R--[NONO], where R
is an organic or inorganic moiety bonded to the [NONO].
[0025] NO may be generated from S-nitrosothiols (RSNO) in presence
of catalyst Cu(I), as outlined in the reaction below:
2RSNO.fwdarw.2 NO+RS-SR (1)
[0026] The concentration of generated NO is equal to the original
RSNO concentration after, the addition of the catalyst Cu(I).
[0027] NO may be generated chemically. In a first example, based on
the reaction of nitrite with iodide in an acidic medium as in the
reaction:
2 KNO.sub.2+2 KI+2 H.sub.2SO.sub.4.fwdarw.2 NO+I.sub.2+2 H.sub.2O+2
K.sub.2SO.sub.4 (2)
[0028] The concentration of NO is determined by the nitrite and
iodide concentrations. Ascorbic acid may be used above to replace
KI as a reductant.
[0029] In a second example, at room temperature, vanadium (III)
rapidly reduces nitrite to nitric oxide in an acidic solution.
Vanadium (III), as a reductant is oxidized to vanadium (IV):
NO.sub.2-+2H.sup.++e.fwdarw.NO+H.sub.2O (3)
[0030] The NO storage and delivery system 10 shown in FIG. 1
employs a gas impermeable capsule 12 as the storage vessel for a
gas source 14 composed of compressed NO gas. NO gas is injected
into the capsule 12 under pressure in an anaerobic environment. The
internal gas-filled cavity 16 has preferably a 1 to 5 ml inner
volume. Internal NO gas pressure is typically 15 to 30 psi. The
capsule casing is impermeable to gas leakage.
[0031] Gas is released from the capsule 12 via an opening 18
extending through the capsule wall and an applicator sleeve 20
enclosing the opening 18 and extending outwardly from the capsule
12. Gas release can be effected, for example, by removal of a
gas-tight cap 22 from the neck 24 of the applicator sleeve 20.
Alternative capsule sealing methods can be easily implemented by
conventional art means.
[0032] A miniature pressure controller 26 within the sleeve 20
limits the exit pressure of the stored gas so as to release NO gas
at a constant pressure which is less than that of the initial
internal capsule gas pressure. An outlet filter 28 downstream of
the pressure controller 26 restricts the rate of gas outflow. For
example, gas release pressure regulated at 5 psi would be adequate
to assure constant gas outflow for periods of time which can be
made to range from a few seconds to hours. The flow rate of exiting
gas can be limited to a few micro liters per minute. Prior to use,
the capsule 12 is stored in a sterile bag that is gas and moisture
impermeable to prevent environmental and bacterial
infiltration.
[0033] As an alternative to charging the capsule 12 from an
external pressurized NO gas source, the NO gas source 14 can be a
NO bearing polymer. The polymer material is sealed within the
capsule cavity 16 and slowly decomposes to release the NO gas
stored therein, and thus constitutes the intra capsular NO gas
supply 14. The polymer material, is initially loaded into the
capsule 12 in an oxygen-free environment. If NONOate is to be the
NO source 14, de-aerated water must be applied to initiate NO
release.
[0034] FIG. 2 illustrates a second embodiment of the system 10'
having a NO gas source 30 in which NO gas is created by activation
of stored chemical reagents 32, 34. Capsule 36 is flexible and gas
impermeable. The gas source 30 comprises stored reagents 32 and 34,
which are physically isolated by a breakable divider 38, for
example a glass tube, containing reagent 32. Bending capsule 38
breaks reagent vessel 38 causing chemical reagents 32 and 34 to
mix, resulting in the rapid formation of NO gas within the capsule
36. The known stoichiometry of the chemical reaction and the volume
of the capsule interior allows accurate prediction of the resulting
intra capsular NO gas pressure. A single example of several
feasible chemical reactions is illustrated in equation (1) above.
In this example, reagent 32 is a solution of potassium nitrite and
reagent 34 is a mixture of potassium iodide and sufric acid.
[0035] Compressed NO gas flows out of the capsule 36 via a check
valve 40 comprised, for example, by a ball 42 and spring 44. The
outflow filter 46 controls the gas outflow rate and also filters
water vapor from the fluid reagents in the capsule 36. The filter
46 may be treated with a nitrogen dioxide adsorbent so as to insure
that, if present, virtually no nitrogen dioxide will be present in
the generated gas. Prior to use, the capsule 36 is stored in a
sterile bag that is gas and moisture impermeable to prevent
environmental and bacterial infiltration.
[0036] The embodiment 10" shown in FIG. 3 is similar in form and
function to the embodiment 10' of FIG. 2 except that outlet filter
46 of FIG. 2 is replaced by a NO gas permeable capped tube 48 which
delivers a diffuse gentle flow of NO into the nostrils or,
alternatively, other body cavities of subject humans or animals for
therapeutic effect. Internal tubular gas pressure and the gas
permeability of the capped tube 48 both determine the rate of the
resulting NO gas outflow. Prior to use, the capsule 36 is stored in
a sterile bag that is gas and moisture impermeable to prevent
environmental and bacterial infiltration.
[0037] The embodiment 10'" illustrated in FIG. 4 has an ovoid or
lozenge shaped capsule 50. The capsule 50 is impermeable to acid or
water or other interior reagents 32, 34 employed therein. The
capsule 50 is also NO gas permeable and flexible. Active chemical
reagents 32' and 34' are similar in function to reagents 32 and 34
of FIG. 2. Reagent 32' is contained in a breakable compartment 38'
or tube as in FIG. 2. In use, the capsule 50 is activated by
applying sufficient force to break the reagents tube 38' which
initiates a NO gas producing reaction as discussed above. After
activation, the capsule 50 may be lubricated with a gas permeable
fluid 52 such as silicone and gently inserted into the appropriate
body cavity of a subject requiring NO gas therapy as discussed
above. Upon completion of the NO treatment, the capsule 50 may be
withdrawn by using the attached cord 54. For respiratory therapy,
the capsule 50 may be held under the nostrils for the duration of
the treatment. Prior to use, the capsule 50 is stored in sterile
bags that are gas and moisture impermeable to prevent environmental
or bacterial infiltration and possible contamination.
[0038] It should be appreciated that by using a system 10, 10',
10", 10'" in accordance with the invention, pure NO gas is
generated for inhalation proximal to or within the nostrils of the
subject and transported to the lungs by the tidal action of the
subject's respiration.
[0039] The concentration of nitric oxide gas is diluted by the
respiratory tidal volume of the user. Consequently, the user's own
respiration performs the dual function of transporting and diluting
the NO gas. Moreover, negligible nitrogen dioxide formation occurs
within the time interval in which NO gas is transported by the
respiratory tidal volume to the lung alveoli. Theoretical analysis
and experimental results indicate the NO.sub.2 concentration is
much less than 1 ppm for the time periods used by the inventive
methods of the present invention. It should also be appreciated
that the subject system 10, 10', 10", 10'" does not require an
expensive and complex gas mixing and delivery system because the
subject's own respiration safely delivers NO gas at low ppm
concentration levels to the subject's lungs. It should further be
appreciated that the subject system 10, 10', 10", 10'" does not
utilize industrial NO gas tanks, which are expensive, heavy and
potentially dangerous.
[0040] The above disclosed embodiments are generally single use
systems with the amount of pressurized NO gas or reagents sized
accordingly. It should be appreciated that once the reagents of
embodiments 10', 10", and 10'" are mixed together, the resulting
reaction will continue to completion. Further, the absence of a
gas-tight cap 22 on the applicator sleeve of the second embodiment
10' and the permeable nature of the capped tube 48 of the third
embodiment 10", and the capsule 50 of the fourth embodiment 10'",
preclude retention of the NO gas within the capsule 36, 36', 50
after the reagents 32, 32', 34, 34' have been mixed. While it is
possible that the gas-tight cap 22 of the first embodiment 10 may
be replaced before all of the pressurized NO gas is dispensed
through the applicator sleeve 20, the escaping NO gas will
interfere with such replacement and there is no way of assuring
that the remaining amount of NO gas will be therapeutically
useful.
[0041] While preferred embodiments have been shown and described,
various modifications and substitutions may be made thereto without
departing from the spirit and scope of the invention. Accordingly,
it is to be understood that the present invention has been
described by way of illustration and not limitation.
* * * * *