WO1994022306A1 - Nitric oxide combination therapy - Google Patents

Nitric oxide combination therapy Download PDF

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Publication number
WO1994022306A1
WO1994022306A1 PCT/US1994/003562 US9403562W WO9422306A1 WO 1994022306 A1 WO1994022306 A1 WO 1994022306A1 US 9403562 W US9403562 W US 9403562W WO 9422306 A1 WO9422306 A1 WO 9422306A1
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WO
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Prior art keywords
nitric oxide
compound
administered
neutralizing compound
composition
Prior art date
Application number
PCT/US1994/003562
Other languages
French (fr)
Inventor
Jonathan S. Stamler
Original Assignee
Brigham And Womens Hospital
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Brigham And Womens Hospital filed Critical Brigham And Womens Hospital
Priority to AU65284/94A priority Critical patent/AU6528494A/en
Publication of WO1994022306A1 publication Critical patent/WO1994022306A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors

Definitions

  • nitric oxide is exceedingly unstable, reacting essentially instantaneously with oxygen, superoxide anion, and redox metals (Lancaster et al., Proc. Natl. Acad. Sci. USA. 87:1223-1227 (1990); Ignarro et al., Circ. Res. 5_:1-21 (1989); and Gryjglewski et al., Nature 320:454-456 (1986)).
  • NO production in the lung is not known. However, it has been believed that potential beneficial bronchodilation effects of NO may be counterbalanced by generation of toxic nitrogen oxides that form readily under the high ambient concentration of oxygen and other reactive oxygen species.
  • Introduction of NO into the lungs has been associated by some with adverse effects, which occur as a direct result of the particular chemical reactivity of the uncharged NO radical (NO").
  • NO uncharged NO radical
  • These adverse effects create impediments to NO therapy which generally involves administration of NO' .
  • the reaction between NO", and 0- or reactive O, species which are present in high concentrations in the lung generates highly toxic products, such as NO, and peroxynitrite. These reactions also result in the rapid inactivation of NO, thus allegedly eliminating any beneficial pharmacological effect.
  • Zapol and Frostell PCT Publication No. WO 92/10228 discloses a method for treating or preventing bronchoconstriction, e.g., asthma or reversible pulmonary vasoconstriction, e.g., pulmonary hypertension, by inhalation of gaseous nitric oxide or nitric oxide-releasing compounds. Many such compounds are known. These investigators characterize the mammalian circulatory system as consisting of two separate circuits, the systemic circuit and the pulmonary circuit which are controlled by opposite sides of the heart.
  • bronchodilating and pulmonary vasodilating methods are important advantages of their bronchodilating and pulmonary vasodilating methods.
  • the rapid binding of NO to hemoglobin ensures that any vasodilatory action of inhaled NO is solely a local or selective effect in the blood vessels of the lung, with no concomitant vasodilation downstream in the systemic circulation.
  • a method of treating an individual in need of treatment with nitric oxide which comprises (i) administering by the inhalation route a therapeutically effective amount of nitric oxide and (ii) administering a compound that neutralizes toxic species to which nitric oxide spontaneously oxidizes.
  • the neutralizing compound is preferably administered concurrently with nitric oxide administration, preferably by the inhalation route, e.g., in mixture with the nitric oxide, or intravenously, and is preferably a thiol.
  • the invention is based on the discovery by the inventor that thiols, e.g. N-acetylcyteine, or precursors of glulathione synthesis react with NO (where x is 2 or more) to prevent toxicity thereof to the lung.
  • thiols e.g. N-acetylcyteine
  • NO where x is 2 or more
  • compounds can be administered in accordance with the invention that upregulate the body's production of thiols, e.g. glutathione.
  • thiol refers to a compound which is selected from the group consisting of N-acetylcysteine, glutathione, cysteine, homocysteine, pantathoeine derivatives, penicillamine and captopril.
  • thiol refers to particular long carbon-chain lipophilic thiols.
  • the invention relates to a method for treatment of an individual in need thereof with nitric oxide which comprises (i) administering by the inhalation route a therapeutically effective amount of nitric oxide and (ii) administering a compound that neutralizes toxic species to which nitric oxide spontaneously oxidizes.
  • the invention in another aspect, relates to a composition for treating an individual in need of treatment with nitric oxide which comprises (i) an inhalable preparation of a therapeutically effective amount of nitric oxide and (ii) a compound that neutralizes toxic species to which nitric oxide spontaneously oxides.
  • the neutralizing compound is preferably in an inhalable preparation, e.g. in mixture with the nitric oxide, or is in an intravenous preparation.
  • the neutralizing compound is preferably a thiol.
  • the thiol is selected from the group consisting of N-acetylcysteine, glutathione, cysteine, homocysteine, pantathoeine derivatives, penicillamine, captopril and long carbon-chain lipophilic thiols.
  • Modes of administration include but are not limited to intravenous, intranasal, and oral routes.
  • the compounds may be administered by, for example, by infusion or bolus injection and may be administered together with other biologically active agents.
  • compositions comprise a therapeutically effective amount of a therapeutic, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable carrier includes but is not limited to physiologically acceptable gases and mixtures thereof and liquid carriers such as saline, buffered saline, dextrose, water, and combinations thereof.
  • the formulation should suit the mode of administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic to ameliorate any pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • the amount of the neutralizing compound which will be effective in combination with the nitric oxide will depend on the level and duration of the nitric oxide administered, and can be determined by standard clinical techniques without undue experimentation.
  • the precise dose of the neutralizing compound to be employed in the formulation will also depend on the route of administration, and should be decided according to the judgment of the practitioner and each patient's circumstances.
  • suitable dosage ranges for intravenous or nebulized inhalation administration are generally about up to about 200 milligrams of neutralizing compound per kilogram body weight. Alternatively, doses of up to about 50 mg/kg can be administered up to about 6 times per day.
  • Suitable dosage ranges for inhalation administration of nitric oxide include at least those disclosed in Zapol and Frostell, PCT Publication No. WO 92/10228.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

Abstract

Deleterious effects of nitrous oxide and other higher oxidation states of nitric oxide are diminished even at high levels of nitric oxide administered by the inhalation route by treating an individual with nitric oxide by the inhalation route and administering a compound that neutralizes toxic species to which nitric oxide spontaneously oxidizes. The neutralizing compound is preferably administered concurrently with nitric oxide administration, preferably by the inhalation route, e.g., in mixture with the nitric oxide or intravenously, and is preferably a thiol.

Description

NITRIC OXIDE COMBINATION THERAPY
Background of the Invention
Under physiologic conditions, nitric oxide (NO) is exceedingly unstable, reacting essentially instantaneously with oxygen, superoxide anion, and redox metals (Lancaster et al., Proc. Natl. Acad. Sci. USA. 87:1223-1227 (1990); Ignarro et al., Circ. Res. 5_:1-21 (1989); and Gryjglewski et al., Nature 320:454-456 (1986)).
The consequences of NO production in the lung are not known. However, it has been believed that potential beneficial bronchodilation effects of NO may be counterbalanced by generation of toxic nitrogen oxides that form readily under the high ambient concentration of oxygen and other reactive oxygen species. Introduction of NO into the lungs has been associated by some with adverse effects, which occur as a direct result of the particular chemical reactivity of the uncharged NO radical (NO"). These adverse effects create impediments to NO therapy which generally involves administration of NO' . For example, the reaction between NO", and 0- or reactive O, species which are present in high concentrations in the lung, generates highly toxic products, such as NO, and peroxynitrite. These reactions also result in the rapid inactivation of NO, thus allegedly eliminating any beneficial pharmacological effect. (Furchgott R.F. et al., I. Endothelium-Derived Relaxing Factors and Nitric Oxide; eds. Rubanyi G.M. , pp. (1990); Gryglewski, R.J. et al., Nature 320:454-456 (1986)). Furthermore, NO' reacts with the redox metal site on hemoglobin to form methemoglobin, which inhibits oxygen-hemoglobin binding, thereby significantly reducing the oxygen-carrying capacity of the blood.
Nonetheless, some workers have convincingly demonstrated the value of NO therapy in bronchoconstriction and reversible pulmonary vasoconstriction. For example, Zapol and Frostell, PCT Publication No. WO 92/10228 discloses a method for treating or preventing bronchoconstriction, e.g., asthma or reversible pulmonary vasoconstriction, e.g., pulmonary hypertension, by inhalation of gaseous nitric oxide or nitric oxide-releasing compounds. Many such compounds are known. These investigators characterize the mammalian circulatory system as consisting of two separate circuits, the systemic circuit and the pulmonary circuit which are controlled by opposite sides of the heart. They report that (since NO gas which enters the bloodstream is rapidly inactivated by combination with hemoglobin) the bronchodilatory effects of inhaled NO are limited to the ventilated bronchi and the vasodilatory effects of inhaled NO are limited to those blood vessels near the site of NO passage into the blood stream: i.e., pulmonary microvessels. They conclude from this that an important advantage of their bronchodilating and pulmonary vasodilating methods is that one can selectively prevent or treat bronchospasm and/or pulmonary hypertension without producing a concomitant lowering of the systemic blood pressure to potentially dangerous levels and that, therefore, their method allows for effective reversal of pulmonary hypertension without the risk of underperfusion of vital organs, venous pooling, ischemia, and heart failure that may accompany systemic vasodilation. More specifically, they report that the rapid binding of NO to hemoglobin ensures that any vasodilatory action of inhaled NO is solely a local or selective effect in the blood vessels of the lung, with no concomitant vasodilation downstream in the systemic circulation.
Summary of the Invention
In accordance with the present invention, it has been discovered for the first time that the deleterious effects of nitrous oxide and other higher oxidation states of nitric oxide can be prevented or ameliorated even at high levels of nitric oxide administered by the inhalation route by a method of treating an individual in need of treatment with nitric oxide which comprises (i) administering by the inhalation route a therapeutically effective amount of nitric oxide and (ii) administering a compound that neutralizes toxic species to which nitric oxide spontaneously oxidizes.
The neutralizing compound is preferably administered concurrently with nitric oxide administration, preferably by the inhalation route, e.g., in mixture with the nitric oxide, or intravenously, and is preferably a thiol.
Detailed Description
The invention is based on the discovery by the inventor that thiols, e.g. N-acetylcyteine, or precursors of glulathione synthesis react with NO (where x is 2 or more) to prevent toxicity thereof to the lung. Likewise, compounds can be administered in accordance with the invention that upregulate the body's production of thiols, e.g. glutathione.
In one preferred embodiment, the term "thiol" refers to a compound which is selected from the group consisting of N-acetylcysteine, glutathione, cysteine, homocysteine, pantathoeine derivatives, penicillamine and captopril. In another preferred embodiment the term "thiol" refers to particular long carbon-chain lipophilic thiols.
Thus, in one aspect the invention relates to a method for treatment of an individual in need thereof with nitric oxide which comprises (i) administering by the inhalation route a therapeutically effective amount of nitric oxide and (ii) administering a compound that neutralizes toxic species to which nitric oxide spontaneously oxidizes.
In another aspect, the invention relates to a composition for treating an individual in need of treatment with nitric oxide which comprises (i) an inhalable preparation of a therapeutically effective amount of nitric oxide and (ii) a compound that neutralizes toxic species to which nitric oxide spontaneously oxides. The neutralizing compound is preferably in an inhalable preparation, e.g. in mixture with the nitric oxide, or is in an intravenous preparation. As noted above with respect to the method, the neutralizing compound is preferably a thiol. Most preferably, the thiol is selected from the group consisting of N-acetylcysteine, glutathione, cysteine, homocysteine, pantathoeine derivatives, penicillamine, captopril and long carbon-chain lipophilic thiols.
Therapeutic Administration and Compositions
Modes of administration include but are not limited to intravenous, intranasal, and oral routes. The compounds may be administered by, for example, by infusion or bolus injection and may be administered together with other biologically active agents.
The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of a therapeutic, and a pharmaceutically acceptable carrier or excipient. Such a carrier includes but is not limited to physiologically acceptable gases and mixtures thereof and liquid carriers such as saline, buffered saline, dextrose, water, and combinations thereof. The formulation should suit the mode of administration.
In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic to ameliorate any pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
The amount of the neutralizing compound which will be effective in combination with the nitric oxide will depend on the level and duration of the nitric oxide administered, and can be determined by standard clinical techniques without undue experimentation. The precise dose of the neutralizing compound to be employed in the formulation will also depend on the route of administration, and should be decided according to the judgment of the practitioner and each patient's circumstances. However, suitable dosage ranges for intravenous or nebulized inhalation administration are generally about up to about 200 milligrams of neutralizing compound per kilogram body weight. Alternatively, doses of up to about 50 mg/kg can be administered up to about 6 times per day. Suitable dosage ranges for inhalation administration of nitric oxide include at least those disclosed in Zapol and Frostell, PCT Publication No. WO 92/10228.
The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

Claims

What Is Claimed Is:
1. A method for treating an individual in need of treatment with nitric oxide which comprises (i) administering by the inhalation route a therapeutically effective amount of a compound selected from nitric oxide and a compound that delivers nitric oxide in a therapeutically effective amount upon such administration and (ii) administering a compound that neutralizes toxic species to which NO spontaneously oxidizes.
2. The method of claim 1 wherein the neutralizing compound is administered concurrently with nitric oxide administration.
3. The method of claim 1 wherein the neutralizing compound is administered by the inhalation route.
4. The method of claim 3 wherein the neutralizing compound is administered in mixture with the nitric oxide.
5. The method of claim 1 wherein the neutralizing compound is administered intravenously.
6. The method of claim 1 wherein the neutralizing compound is a thiol.
7. The method of claim 6 wherein the thiol is selected from the group consisting of N-acetylcysteine, glutathione, cysteine, homocysteine, pantathoeine derivatives, penicillamine, captopril and long carbon-chain lipophilic thiols.
8. The method of claim 1 wherein the neutralizing compound is administered in a dose range of up to about 200 mg/kg body weight.
9. The method of claim 1 wherein the neutralizing compound is administered in doses of up to about 50 mg/kg up to about 6 times per day.
10. A composition for treating an individual in need of treatment with nitric oxide which comprises (i) aninhalable preparation of a therapeutically effective amount of nitric oxide and (ii) a compound that neutralizes toxic species to which nitric oxide spontaneously oxidizes.
11. The composition of claim 10 wherein the neutralizing compound is an inhalable preparation.
12. The composition of claim 11 wherein the_ neutralizing compound is administered in mixture with the nitric oxide.
13. The composition of claim 10 wherein the neutralizing compound is an intravenous preparation.
14. The composition of claim 10 wherein the neutralizing compound is a thiol.
15. The composition of claim 14 wherein the thiol is selected from the group consisting of N-acetylcysteine, glutathione, cysteine, homocysteine, pantathoeine derivatives, penicillamine, captopril and long carbon-chain lipophilic thiols.
PCT/US1994/003562 1993-04-06 1994-03-31 Nitric oxide combination therapy WO1994022306A1 (en)

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US4436793A 1993-04-06 1993-04-06
US08/044,367 1993-04-06

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1018984A1 (en) * 1997-06-26 2000-07-19 Cordis Corporation MEDICAL DEVICE FOR $i(IN VIVO) NITRIC OXIDE RELEASE
US6153186A (en) * 1995-09-15 2000-11-28 Duke University Medical Center Red blood cells loaded with S-nitrosothiol and uses therefor
US6197745B1 (en) 1995-09-15 2001-03-06 Duke University Methods for producing nitrosated hemoglobins and therapeutic uses therefor
US6232434B1 (en) 1996-08-02 2001-05-15 Duke University Medical Center Polymers for delivering nitric oxide in vivo
EP1301076A2 (en) * 2000-06-28 2003-04-16 The General Hospital Corporation Enhancing therapeutic effectiveness of nitric oxide inhalation
US6627738B2 (en) 1995-09-15 2003-09-30 Duke University No-modified hemoglobins and uses therefor
US6855691B1 (en) 1995-09-15 2005-02-15 Duke University Methods for producing and using S-nitrosohemoglobins
US6911427B1 (en) 1995-09-15 2005-06-28 Duke University No-modified hemoglobins and uses therefore
US6916471B2 (en) 1995-09-15 2005-07-12 Duke University Red blood cells loaded with S-nitrosothiol and uses therefor
WO2018053397A1 (en) * 2016-09-16 2018-03-22 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Methods for treating or preventing organophosphate poisoning
WO2023173141A3 (en) * 2022-03-11 2023-11-16 Loma Linda University Compositions and methods of treatment of disease using combination of a nitrodilator and a nitrogen oxide compound

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MEDLINE, Abstract, Vol. 90, No. 2, issued August 1992, DUPY et al., "Bronchodilator Action of Inhaled Nitrix Oxide", see abstract no. 92355776; & J. CLIN. INVEST., (Aug 1992), 90(12). *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6855691B1 (en) 1995-09-15 2005-02-15 Duke University Methods for producing and using S-nitrosohemoglobins
US6153186A (en) * 1995-09-15 2000-11-28 Duke University Medical Center Red blood cells loaded with S-nitrosothiol and uses therefor
US6197745B1 (en) 1995-09-15 2001-03-06 Duke University Methods for producing nitrosated hemoglobins and therapeutic uses therefor
US6203789B1 (en) 1995-09-15 2001-03-20 Duke University Red blood cells loaded with S-nitrosothiol and uses therefor
US7538193B2 (en) 1995-09-15 2009-05-26 Duke University NO-modified hemoglobins and uses therefor
US7202340B2 (en) 1995-09-15 2007-04-10 Duke University No-modified hemoglobins and uses therefor
US6916471B2 (en) 1995-09-15 2005-07-12 Duke University Red blood cells loaded with S-nitrosothiol and uses therefor
US6911427B1 (en) 1995-09-15 2005-06-28 Duke University No-modified hemoglobins and uses therefore
US6627738B2 (en) 1995-09-15 2003-09-30 Duke University No-modified hemoglobins and uses therefor
US6884773B1 (en) 1995-09-15 2005-04-26 Duke University Modified hemoglobins, including nitrosylhemoglobins, and uses thereof
US6875840B2 (en) 1996-08-02 2005-04-05 Duke University Polymers for delivering nitric oxide in vivo
US6403759B2 (en) 1996-08-02 2002-06-11 Duke University Polymers for delivering nitric oxide in vivo
US6673891B2 (en) 1996-08-02 2004-01-06 Duke University Polymers for delivering nitric oxide in vivo
US6232434B1 (en) 1996-08-02 2001-05-15 Duke University Medical Center Polymers for delivering nitric oxide in vivo
US7417109B2 (en) 1996-08-02 2008-08-26 Duke University Polymers for delivering nitric oxide in vivo
US7087709B2 (en) 1996-08-02 2006-08-08 Duke University Polymers for delivering nitric oxide in vivo
EP1018984A1 (en) * 1997-06-26 2000-07-19 Cordis Corporation MEDICAL DEVICE FOR $i(IN VIVO) NITRIC OXIDE RELEASE
EP1018984A4 (en) * 1997-06-26 2003-03-12 Cordis Corp MEDICAL DEVICE FOR $i(IN VIVO) NITRIC OXIDE RELEASE
EP1301076A2 (en) * 2000-06-28 2003-04-16 The General Hospital Corporation Enhancing therapeutic effectiveness of nitric oxide inhalation
AU2001273622B2 (en) * 2000-06-28 2007-05-10 The General Hospital Corporation Enhancing therapeutic effectiveness of nitric oxide inhalation
KR100849103B1 (en) * 2000-06-28 2008-07-30 더 제너럴 하스피탈 코포레이션 Enhancing therapeutic effectiveness of nitric oxide inhalation
US6935334B2 (en) 2000-06-28 2005-08-30 The General Hospital Corporation Enhancing therapeutic effectiveness of nitric oxide inhalation
EP1301076A4 (en) * 2000-06-28 2004-09-22 Gen Hospital Corp Enhancing therapeutic effectiveness of nitric oxide inhalation
WO2018053397A1 (en) * 2016-09-16 2018-03-22 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Methods for treating or preventing organophosphate poisoning
US11291637B2 (en) 2016-09-16 2022-04-05 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Methods for treating or preventing organophosphate poisoning
WO2023173141A3 (en) * 2022-03-11 2023-11-16 Loma Linda University Compositions and methods of treatment of disease using combination of a nitrodilator and a nitrogen oxide compound

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