Source: http://www.google.com/patents/US7955294?dq=5,815,794
Timestamp: 2014-07-23 14:21:23
Document Index: 490499205

Matched Legal Cases: ['Application No. 60', 'art 2', 'art 2', 'art 2', 'art 2', 'art 2']

Patent US7955294 - Intermittent dosing of nitric oxide gas - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsA method and corresponding device are described for combating microbes and infections by delivering intermittent high doses of nitric oxide to a mammal for a period of time and which cycles between high and low concentration of nitric oxide gas. The high concentration of nitric oxide is preferably delivered...http://www.google.com/patents/US7955294?utm_source=gb-gplus-sharePatent US7955294 - Intermittent dosing of nitric oxide gasAdvanced Patent SearchPublication numberUS7955294 B2Publication typeGrantApplication numberUS 11/598,221Publication dateJun 7, 2011Filing dateNov 10, 2006Priority dateMay 11, 2004Also published asCA2563493A1, CN1950120A, CN1950120B, EP1755715A2, EP1755715A4, US20070144515, US20080029093, US20110226241, US20120199123, WO2005110441A2, WO2005110441A3Publication number11598221, 598221, US 7955294 B2, US 7955294B2, US-B2-7955294, US7955294 B2, US7955294B2InventorsAlex Stenzler, Christopher C. Miller, Bevin B. McMullinOriginal AssigneeSensormedics Corporation, Pulmonox Technologies CorporationExport CitationBiBTeX, EndNote, RefManPatent Citations (114), Non-Patent Citations (158), Referenced by (1), Classifications (22), Legal Events (1) External Links: USPTO, USPTO Assignment, EspacenetIntermittent dosing of nitric oxide gasUS 7955294 B2Abstract A method and corresponding device are described for combating microbes and infections by delivering intermittent high doses of nitric oxide to a mammal for a period of time and which cycles between high and low concentration of nitric oxide gas. The high concentration of nitric oxide is preferably delivered intermittently for brief periods of time that are interspersed with periods of time with either no nitric oxide delivery or lower concentrations of nitric oxide. The method is advantageous because at higher concentration, nitric oxide gas overwhelms the defense mechanism of pathogens that use the mammalian body to replenish their thiol defense system. A lower dose or concentration of nitric oxide gas delivered in between the bursts of high concentration nitric oxide maintains nitrosative stress pressure on the pathogens and also reduces the risk of toxicity of nitric oxide gas.
1. A method of topically delivering nitric oxide gas to a mammal to kill or inhibit the growth of microbes, the method comprising alternately administering at least a first concentration of nitric oxide gas and a second concentration of nitric oxide gas for a number of cycles, the first concentration applied topically for a first period of time sufficient to overwhelm the microbes' thiol defense mechanisms and kill or inhibit the growth of at least a portion of the microbes, and the second concentration lower than the first concentration and applied topically for a second period of time sufficient to maintain nitrosative stress on the microbes and interfere with replenishing the level of the microbes' thiol defense mechanisms, whereby the cycling of the first and second concentrations provides a cumulative killing of the microbes.
2. The method of claim 1 wherein the second period of time is longer than the first period of time.
3. The method of claim 1 wherein the first concentration of nitric oxide gas ranges from about 160 ppm to about 400 ppm.
4. The method of claim 3 wherein the second concentration of nitric oxide gas is less than about 80 ppm.
5. The method of claim 2 wherein the first period of time is about 30 minutes and the second period of time is about 3.5 hours.
6. A method of topically delivering nitric oxide gas to a mammal to kill or inhibit the growth of microbes, the method comprising topically administering to the mammal a first concentration of nitric oxide gas for a number of time periods that are interspersed with intervals in between wherein a second concentration of nitric oxide gas lower than the first concentration is topically administered during the intervals, wherein the first concentration of nitric oxide gas is sufficient to overwhelm the microbes' thiol defense mechanisms and kill or inhibit the growth of at least a portion of the microbes and the second concentration of nitric oxide gas is sufficient to maintain nitrosative stress on the microbes and interfere with replenishing the level of the microbes' thiol defense mechanisms, and whereby the topical administration of the first concentration and second concentration for a number of cycles provides a cumulative killing of the microbes.
7. The method of claim 6 wherein the first concentration of nitric oxide gas ranges from about 160 ppm to about 400 ppm.
8. The method of claim 7 wherein the second concentration of nitric oxide gas is less than about 80 ppm.
9. The method of claim 6 wherein the microbes are selected from a group consisting of bacteria, mycobacteria, viruses and fungi.
10. A device for delivery of nitric oxide gas to kill or inhibit the growth of microbes comprising:
a delivery interface adaptable for topical delivery of the gases to a mammal;
a gas mixer downstream of the sources of nitric oxide gas and diluent gas and upstream of the delivery interface for mixing the nitric oxide gas with the diluent gas;
a controller that communicates with the gas mixer wherein the controller comprises logic for setting a nitric oxide gas delivery profile comprising at least a first concentration of nitric oxide gas sufficient to overwhelm the microbes' thiol defense mechanisms and kill or inhibit the growth of at least a portion of the microbes and a second concentration of nitric oxide gas sufficient to maintain nitrosative stress on the microbes and interfere with replenishing the level of the microbes' thiol defense mechanisms, and for automatically switching between the at least first and second concentrations of nitric oxide gas on a timed basis for a number of cycles, whereby the cycling of the first and second concentrations provides a cumulative killing of the microbes.
11. The device of claim 10 wherein each cycle comprises at least first and second time periods corresponding respectively to delivery of the first and second concentrations of nitric oxide gas.
12. The device of claim 11 wherein, in each cycle, the first time period is shorter than the second time period.
13. The device of claim 10 wherein the gas mixer comprises a T or Y shaped tubing connection and a flow control valve.
14. The device of claim 10 wherein the gas mixer comprises a gas blender.
15. The device of claim 10 wherein the delivery interface comprises a bathing unit for topical delivery of nitric oxide gas to a surface of the body.
16. The device of claim 10 further comprising a nitric oxide gas analyzer for measuring the concentration of nitric oxide gas flowing to the delivery interface, wherein the nitric oxide gas analyzer sends signals to the controller.
17. A device for delivery of nitric oxide gas to kill or inhibit the growth of microbes comprising:
a first source of gas;
a second source of gas;
a switch valve downstream of the first and second sources of gas and upstream of the delivery interface, said switch valve for directing the flow of the gases from their sources to the delivery interface; and
a controller controlling the switch valve and which commands the switch valve to switch between the first and second sources of gas on a timed basis for a number of cycles;
wherein the first source of gas has a higher concentration of nitric oxide gas than the second source of gas and the controller causes the gases to be administered according to a delivery profile that provides sufficient nitric oxide gas to affect a cumulative killing of microbes;
wherein the concentration of nitric oxide gas in the first source of gas is sufficient to overwhelm the microbes' thiol defense mechanisms and to kill or inhibit the growth of at least a portion of the microbes and the concentration of nitric oxide gas in the second source of gas is sufficient to maintain nitrosative stress on the microbes and interfere with replenishing the level of the microbes' thiol defense mechanisms; and
wherein cycling between the first and second sources of gas provides a cumulative killing of the microbes.
18. The device of claim 17 wherein each cycle comprises at least first and second time periods corresponding respectively to delivery of the first and second gases.
19. The device of claim 18 wherein, in each cycle, the first time period is shorter than the second time period.
20. The device of claim 17 wherein the delivery interface comprises a bathing unit for topical delivery of the gases to a surface of the body.
21. The device of claim 17 further comprising a nitric oxide gas analyzer for measuring the concentration of nitric oxide gas flowing to the delivery interface, wherein the nitric oxide gas analyzer sends signals to the controller.
This application is a continuation of PCT Application No. PCT/US05/016427, filed May 11, 2005, which claims priority to U.S. Provisional Application No. 60/570,429, filed May 11, 2004.
BACKGROUND OF THE INVENTION NO is an environmental pollutant produced as a byproduct of combustion. At extremely high concentrations (generally at or above 1000 ppm), NO is toxic. NO also is a naturally occurring gas that is produced by the endothelium tissue of the respiratory system. In the 1980's, it was discovered by researchers that the endothelium tissue of the human body produced NO, and that NO is an endogenous vasodilator, namely, an agent that widens the internal diameter of blood vessels.
With this discovery, numerous researchers have investigated the use of low concentrations of exogenously inhaled NO to treat various pulmonary diseases in human patients. See e.g., Higenbottam et al., Am. Rev. Resp. Dis. Suppl. 137:107, 1988. It was determined, for example, that primary pulmonary hypertension (PPH) can be treated by inhalation of low concentrations of NO. With respect to pulmonary hypertension, inhaled NO has been found to decrease pulmonary artery pressure (PAP) as well as pulmonary vascular resistance (PVR). The use of inhaled NO for PPH patients was followed by the use of inhaled NO for other respiratory diseases. For example, NO has been investigated for the treatment of patients with increased airway resistance as a result of emphysema, chronic bronchitis, asthma, adult respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease, (COPD). In 1999, the FDA approved the marketing of nitric oxide gas for use with persistent pulmonary hypertension in term and near term newborns. Because the withdrawal of inhaled nitric oxide from the breathing gas of patients with pulmonary hypertension is known to cause a severe and dangerous increase in PVR, referred to as a �rebound effect�, nitric oxide must be delivered to these patients on a continuous basis.
In addition to its effects on pulmonary vasculature, NO may also be introduced as a anti-microbial agent against pathogens via inhalation or by topical application. See e.g., WO 00/30659, U.S. Pat. No. 6,432,077, which are hereby incorporate by reference in their entirety. The application of gaseous nitric oxide to inhibit or kill pathogens is thought to be beneficial given the rise of numerous antibiotic resistant bacteria. For example, patients with pneumonia or tuberculosis may not respond to antibiotics given the rise of antibiotic resistant strains associated with these conditions.
SUMMARY OF THE INVENTION It is envisioned that a method and device delivering intermittent high doses of nitric oxide for a period of time and which cycles between high and low concentration of nitric oxide is desirable, useful, and overcomes the problems of toxicity. The high concentration of nitric oxide is preferably delivered intermittently for brief periods of time that are interspersed with periods of time with either no nitric oxide delivery or lower concentrations of nitric oxide. This keeps the exposure to the high concentrations of nitric oxide required to overwhelm the nitric oxide defense mechanisms of the pathogens to an average level that is safe for humans to inhale.
Devices for the delivery of nitric oxide are commercially available and may include continuous flow devices, flow matching devices, or pulse dose devices. For example, the FDA has already approved three different nitric oxide delivery systems in the United States: AeroNOx� Delivery System and the ViaNOx DS System (Pulmonox, Canada) and the INOvent� Delivery System (Datex-Ohmeda, Wis.). Other devices have also been described in literature and various publications and patents (e.g., U.S. Pat. No. 6,581,599, which is incorporated here by reference in its entirety).
In another aspect of the invention, the device for use to deliver intermittent high doses of nitric oxide may include a source of nitric oxide gas (e.g., nitric oxide gas in compressed gas cylinders), controller (e.g. an electronic controller or microprocessor), nitric oxide analyzer, and timer in which the concentration of nitric oxide delivered is automatically changed on a timed basis to a concentration set by the operator and for a set period of time defined by the operator. The device would include logic (e.g. software or firmware) that allows for setting of two different nitric oxide concentrations and with separate time settings for the delivery of each concentration. The device may also include gas mixers (such as gas blenders or combinations of flow control valves and T or Y shaped tube connections), tubings, a source of diluent gas (e.g. room air, oxygen, or inert gas), and electronically regulated needle valves or other valve mechanism for controlling the release of nitric oxide gas, or the diluent gas, or both.
BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1-3 illustrate schematic representations of various embodiments of a nitric oxide delivery device according to one aspect of the present invention.
FIG. 4 illustrates the logic for setting the alternating delivery profile for high and low concentrations of nitric oxide gas.
FIG. 5 illustrates the logic for delivering alternating high and low concentrations of nitric oxide gas.
FIG. 6 shows the effect on survival of S. aureus (ATCC#25923) when alternately exposed to NO gas (gNO) exposure at 160 ppm nitric oxide gas for 30 minutes and 20 ppm for 3.5 hours for a total exposure time of 24 hours.
FIG. 7 shows the effect on survival of P. aeruginosa (ATCC#27853) when alternately exposed to NO gas (gNO) exposure at 160 ppm nitric oxide gas for 30 minutes and 20 ppm for 3.5 hours for a total exposure time of 24 hours.
FIG. 8 shows the effect on survival of P. aeruginosa (clinical strain from Cystic Fibrosis) when alternately exposed to NO gas (gNO) exposure at 160 ppm nitric oxide gas for 30 minutes and 20 ppm for 3.5 hours for a total exposure time of 24 hours.
FIG. 9 shows the effect on survival of E. coli when alternately exposed to NO gas (gNO) at 160 ppm nitric oxide gas for 30 minutes and 20 ppm for 3.5 hours for a total exposure time of 24 hours.
FIG. 10 shows the effect on survival of a MshA mycothiol deficient mutant Mycobacterium smegmatis and its wild type counterpart when exposed to 200 ppm NO gas (gNO).
FIG. 11 shows the level of mycothiol in wild type Mycobacterium smegmatis when exposed to 400 ppm NO gas (gNO) compared to exposure to air.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS It is currently believed that at higher concentration, nitric oxide gas overwhelms the defense mechanism of pathogens that use the mammalian body to replenish their thiol defense system. The 20 thiol defense system may include for example, the mycothiol for mycobacterium or glutathione for other bacteria. Once this defense mechanism is depleted, the pathogen is defenseless against the killing effects of nitric oxide. A lower dose or concentration of nitric oxide gas delivered in between the bursts of high concentration nitric oxide maintains nitrosative stress pressure on the pathogens to prevent them from rebuilding their defense system to an adequate level. Thus, a preferred therapeutic or delivery profile for combating pathogens may comprise the delivery of a first concentration of nitric oxide gas for a number of time periods interspersed with intervals in between wherein a second concentration of nitric oxide is administered during the intervals. The first concentration is preferably at a high concentration sufficient to kill or inhibit microbial growth. For example, the first concentration may range from about 80 ppm to 400 ppm, more preferably between 150 to 250 ppm and most preferably between 160 ppm to 200 ppm.
The second concentration is preferably at low concentration of nitric oxide gas such as ranging from 20 to 80 ppm. Alternatively, it should also be understood that the second concentration can also be zero ppm or close to trace amount of nitric oxide gas.
Turning now to the figures, FIGS. 1-3 illustrate various embodiments of a nitric oxide delivery device for use with the present invention. FIG. 1 shows, in its most general sense, a NO delivery device 2 that includes a source of nitric oxide gas 8 adapted for delivery of the NO gas to a mammal through a delivery interface 6. FIG. 1 illustrates one preferred embodiment of the invention.
In FIG. 1, the NO gas source 8 is a pressurized cylinder containing NO gas. While the use of a pressurized cylinder is the preferred method of storing the NO-containing gas source 8, other storage and delivery means, such as a dedicated feed line (wall supply) can also be used. Typically, the NO gas source 8 is a mixture of N2 and NO. While N2 is typically used to dilute the concentration of NO within the pressurized cylinder, any inert gas can also be used. When the NO gas source 8 is stored in a pressurized cylinder, it is preferable that the concentration of NO in the pressurized cylinder fall within the range of about 800 ppm to about 10,000 ppm. Commercial nitric oxide manufacturers typically produce nitric oxide mixtures for medical use at around the 1000 ppm range. Pressurized cylinders containing low concentrations of NO (e.g., less than 100 ppm NO) can also be used in accordance with the device and method disclosed herein. Of course, the lower the concentration of NO used, the more often the pressurized cylinders will need replacement.
FIG. 1 also shows a source of diluent gas 14 as part of the NO delivery device 2 that is used to dilute the concentration of NO. The source of diluent gas 14 can contain N2, O2, Air, an inert gas, or a mixture of these gases. It is preferable to use a gas such as N2 or an inert gas to dilute the NO concentration at lower concentration since these gases will not oxidize the NO into NO2 as would O2 or air. Nevertheless, for inhalation applications for delivery of high concentration of NO where higher concentration of nitrogen may already be present, the NO flow may be supplemented or diluted with oxygen to prevent the displacement of oxygen by nitrogen that may lead to asphyxiation. It is preferred, especially when delivering higher concentration of NO gas that delivery line downstream of the injection site or gas blender be minimized to reduce the risk of formation of NO2.
The source of diluent gas 14 is shown as being stored within a pressurized cylinder. While the use of a pressurized cylinder is shown in FIG. 1 as the means for storing the source of diluent gas 14, other storage and delivery means, such as a dedicated feed line (wall supply) can also be used. The source of diluent gas can also be a ventilator, air pump, blower, or other mechanical device that moves breathable air.
Still referring to FIG. 1, the delivery device 2 preferably includes a controller 36 that is capable of controlling the flow control valve 22 and the gas blender 20. The controller 36 is preferably a microprocessor-based controller 36 that is connected to an input device (not shown). The input device may be used by an operator to adjust various parameters of the delivery device such as NO concentration and therapy/exposure time periods. An optional display can also be connected with the controller 36 to display measured parameters and settings such as the set-point NO concentration, the concentration of NO flowing to the delivery interface 6, the concentration of NO2, the flow rate of gas into the delivery interface 6, the total time of therapy/delivery, and/or the number of cycles for alternating between high and low concentrations of NO gas.
The controller preferably includes a timer for counting down the time periods of the NO gas delivery at the different concentrations. Moreover, the controller preferably includes logic such as firmware or software programs for executing the alternate delivery of high and low concentration of NO gas at pre-set or user programmable time periods. The processes for execution by such logic are illustrated in FIGS. 4 and 5.
FIG. 2 shows an alternative embodiment of a nitric oxide delivery device 52 in which the desired concentration of NO gas is achieved by mixing with a T or Y shaped connection 70 based on the flow rates of the NO gas flowing from the NO gas source 8 and the diluent gas flowing from the diluent gas source 74. The respective flow rates are controlled via the flow control valves 72 and 75. Mixing of the gases starts at the T or Y shaped connection point 70 and continues through the delivery line 78. An NO analyzer 80 samples the gas mixture at a juncture close to the delivery interface to determine the NO concentration of the gas mixture flowing to the delivery interface 76. The measured NO concentration is then fed back through signal line 88 to the controller 86, which in turn processes the information by comparing the measured NO concentration with the set desired NO gas concentration. The controller 86 then adjusts the flow control valves 72 and 75, if appropriate, by sending control signals through lines 82 and 84 such that the flow rate(s) may be adjusted in order to achieve the desired concentration of NO gas flowing to the delivery interface 76. It should be understood that the controller 86 may similarly include all the features discussed above in connection with controller 36 in FIG. 1. Likewise, the delivery interface 76 may be adapted similarly to the delivery interface 6, as described in connection with FIG. 1.
FIG. 3 illustrates yet another embodiment of a nitric oxide delivery device in accordance to one aspect of the present invention. In this delivery device 102, instead of having gas mixers (e.g., gas blender or T or Y-shaped connection), the delivery device 102 utilizes a switch valve 104 to switch between a high concentration NO gas source 106 and a low concentration NO gas source 108. The switch valve 104 is controlled by the controller 116 that at the appropriate time switches between the high and low concentration of NO gas according to the present invention. It should be understood that the low concentration NO gas source 108 can also be replaced with non-NO gas source such as air, if the desired period of low NO concentration is zero ppm of NO gas.
Referring now to FIGS. 4 and 5, process flows are exemplified that may be executed by logic (firmware or software) programmed into the controllers 36, 86, and 116. FIG. 4 illustrates a process flow for setting up the desired concentrations and time periods for NO gas delivery starting from Step 400 �START.� At Step 405, the logic enters the setup subroutine for setting the desired NO concentrations and time periods. At Step 410, the logic verifies if there are concentration values set for the NO delivery profile. If values are already set, then the process proceeds to Step 415 to verify the values set for the time periods of delivery. If no values have yet been set for the NO concentrations, then the logic calls a subprocess comprising of steps 412 and 414 is called to set the 1st and 2nd NO concentration for the therapeutic profile to be delivered. For example, the 1st NO concentration may be set for about 160 ppm to 300 ppm of NO gas to be delivered and the 2nd concentration may be set for 0 ppm to 80 ppm of NO gas to be delivered. The values of the NO concentrations set are then used by the controller to set the gas blender or the flow control valves in the process illustrated in FIG. 5.
FIG. 5 illustrates a process flow for execution by the logic in controller 36, 56, and 116, for the alternating delivery of high and low concentration of NO gas.
The START THERAPY in step 500 can be started once the NO gas delivery values in FIG. 4 has been entered. At Step 505, the controller 36 (FIG. 1) may then send a control signal through line 42 to the gas blender to set the appropriate gas blender settings to achieve the 1st concentration of NO gas, the value of which was set in the setup process of FIG. 4. This process may also include feedback control from the NO analyzer 40 (FIG. 1) to the controller 36 such that the control of the gas blender may be fine tuned in that the actual NO gas concentration being delivered to the delivery interface 6 matches the set NO gas concentration.
Alternatively, the controller at Step 505 may send control signals to the flow control valves 72 and 75 (FIG. 2) to set the appropriate flow rates for the mixing of the gases to achieve the 1st concentration set in the setup process of FIG. 4. This process may similarly include feedback control from the NO analyzer 80 (FIG. 2) to the controller 56. In yet another embodiment, the controller at Step 505 may set the switch valve 104 (FIG. 3) to select for delivery the NO gas from a source corresponding to the 1st concentration of NO gas set in the setup process of FIG. 4.
Delivery of NO gas proceeds in accordance with the settings in Step 505. At step 510, the timer comprised in the controller 36, 56, or 116 compares the value of the 1st time period set in FIG. 4 with the actual countdown in time. If the time period has not elapsed, then the gas blender, flow control valves, or switch valve settings remain the same in Step 512. If the 1st time period has elapsed, then step 515 sets the gas blender, flow rates, or switch valve settings to that corresponding to the 2nd concentration of NO gas, the value of which was set in the process of FIG. 4. Delivery of NO gas then proceeds on the 2nd concentration until the 2nd time period elapsed.
Further Examples of Delivery Methods
The implementation of the intermittent delivery of high doses of NO gas can be by many means. For example, delivery by inhalation or to the respiratory airway can be made to spontaneously breathing mammals or those managed with mechanical ventilation. With respect to spontaneously breathing mammals, delivery can be achieved via many of previously described gas delivery systems such as masks or nasal cannulas. The device for these mammals may include flowmeter or flow sensor to detect the onset of breathing (e.g., inhalation vs. exhalation) such that the nitric oxide gas would be delivered only when the mammal inhales. Mechanically ventilated mammals would have the nitric oxide delivered into the inspiratory limb of the ventilator circuit and may similarly be triggered only when the ventilator cycled a breath into the mammal.
In both of these implementations, the pattern of nitric oxide delivery may vary depending on the targeted location of the infection within the mammal's lungs and the desire to have the least concentration of nitric oxide residual in the delivery circuit. For example, if the infection were in the air sacs of the lungs, the nitric oxide could be turned off towards the end of the breath when the gas was going to be delivered only to the airways. As an alternative, if the infection were only in the airways, then the starting gas might have a lower concentration of nitric oxide.
Furthermore, it is preferred that the injection site for NO gas delivery be close to the patient's airway when using higher concentrations of NO gas so as to reduce the time for conversion to NO2. This minimizes the dwell time of the NO gas in the delivery line before inhalation. Alternaively, the delivery system may utilize a bolus injection of a high concentration at a time point within the breath and allow the dilution of the NO to occur within the lungs.
The effectiveness of the intermittent high dose delivery of nitric oxide gas in combating microorganisms was tested and verified. Briefly, the experimental methods were as follows. Inoculums of varying bacteria was prepared to a suspension of 2.5�108 cfu/ml, and diluted 1:1000 in sterile normal saline. Three milliliters of the inoculums were used per well in a sterile culture place. Exposure of the inoculums were performed in an exposure chamber, which has been described for example, in Ghafarri, A. et al., �A direct nitric oxide gas delivery system for bacterial and mammalian cell cultures,� Nitric Oxide. 12(3):129-40 (May 2005), which is hereby incorporated by reference as if fully set forth herein. The inoculums were exposed to 160 ppm of NO gas at a flow rate of 2.5 liters per minute for 30 minutes followed by exposure to 20 ppm of NO gas for 3.5 hours. The exposure to high and low concentrations of NO gas was repeatedly cycled every 4 hours for 24 hours. At various times (e.g., 0, 4, 8, and 12 hours), samples were taken and plated to determine the survivability of the bacteria as determined by counting cfu/ml.
FIGS. 6-9 show the survival of various bacteria used in the experiment with NO gas compared to exposure to air as control. As seen in these figures, cycling exposure to high and low concentrations of nitric oxide is an effective method of killing the bacteria. While it was observed that the effectiveness of cycling exposure to high and low concentrations over a longer period of time, was similar to that of continuous exposure to high concentration, cycling exposure provides a better safety profile in minimizing the risk of methemoglobin formation.
Additional studies were performed to test the hypothesis that the effect of NO gas in killing microorganisms is related to thiol function. Based on studies with various microorganisms, it was observed that Mycobacteria are less sensitive to NO gas damage. This may be due to Mycobacteria having an exceptional thiol, mycothiol, that maintains the redox balance in the cell and protects the cell from nitrosative and oxidative stress. In order to test this hypothesis, sensitivities to NO gas was compared between mycothiol-deficient Mycobacterium smegmatis Mutant MshA to its wild type counterpart, mc2 155 by exposing both strains to 200 ppm of NO gas. MshA is an enzyme needed in mycothiol biosynthesis.
FIG. 10 shows that the mycothiol-deficient MshA mutant was more sensitive to NO gas than its wild type counterpart and was killed in less time than its wild type counterpart.
Further experiments were conducted to assay and measure the mycothiol level using HPLC in wild type M. smegmatis after exposure to 400 ppm NO gas and were compared to mycothiol level after exposure to air. FIG. 11 shows that upon exposure to 400 ppm of NO gas, the level of mycothiol in the mycobacterium was reduced compared to exposure to air.
Thus, these results show the NO gas may likely act to deplete mycothiol, which is the mechanism by which the mycobacterium protects itself against oxidative stress.
In other bacteria, it is believed that the analogous molecule to mycothiol in mycobacteria is glutathione. The glutathione pool may normally act to protect the bacteria from endogenous NO and H2O2, which are released by macrophages against pathogens. Delivery of exogenous NO gas may thus act to overwhelm the glutathione pool, eliminating bacterial protection from H2O2, and binding iron based enzymes causing O2 consumption cessation and electron transport center disruption and freeing metal ions into the bacterial cytosol. The free oxygen, metal ions, NO, and hydrogen peroxide further produce reactive nitrogen and oxygen species as well as metal ions that damage the bacteria's DNA by deamination. Thus, it is believed that cycling or alternating delivery of concentration of NO gas sufficient to overwhelm the glutathione defense mechanism for a period of time and a lower concentration of NO gas may be effective in combating microbes such as bacteria, mycobacteria, and fungi while at the same time exhibit a better safety profile.
Microbes may also include viruses. While viruses do not by themselves have thiol based detoxification pathways, they may still be inherently more susceptible to nitrosative stress. NO may inhibit viral ribonucleotide reductase, a necessary constituent enzyme of viral DNA synthesis and therefore inhibit viral replication. Nitric oxide may also inhibit the replication of viruses early during the replication cycle, involving the synthesis of vRNA and mRNA encoding viral proteins. With viruses also depending on host cells for detoxification of the body's defense pathways, the direct cytotoxic mechanisms of NO entering the host cells and the intracellular changes it produces, could also account for the viricidal effects through viral DNA deamination. Thus, it is believed that the cycling or alternating delivery of NO gas at high and low concentrations may also be effective against viruses.
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D., "A Universal Nitric Oxide Delivery System," British Journal of Anaesthesia, vol. 73, No. 4, pp. 700-702 (Oct. 1994).Referenced byCiting PatentFiling datePublication dateApplicantTitleUS20100040703 *Aug 12, 2009Feb 18, 2010Chris MillerUse of nitric oxide* Cited by examinerClassifications U.S. Classification604/23, 128/203.12, 604/290, 604/305International ClassificationA61M16/20, A61M16/12, A61H33/14, A61M16/00, A61M16/10, A61K33/00, A61M35/00Cooperative ClassificationA61M16/204, A61M16/0051, A61M16/202, A61M2016/102, A61M2202/0275, A61M16/12, A61H33/14, A61K33/00European ClassificationA61K33/00, A61M16/12, A61M16/00KLegal EventsDateCodeEventDescriptionFeb 11, 2008ASAssignmentOwner name: PULMONOX TECHNOLOGIES CORPORATION, CANADAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MILLER, CHRISTOPHER;MCMULLIN, BEVIN;REEL/FRAME:020578/0817;SIGNING DATES FROM 20060111 TO 20060203Owner name: SENSORMEDICS CORPORATION, CALIFORNIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:STENZLER, ALEX;REEL/FRAME:020515/0814Effective date: 20060106Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MILLER, CHRISTOPHER;MCMULLIN, BEVIN;SIGNING DATES FROM 20060111 TO 20060203;REEL/FRAME:020578/0817RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google