EARLY MANAGEMENT, MITIGATION and PREVENTION OF SEPSIS and SEPSIS-LIKE SYNDROMES, INCLUDING NEO-NATAL ARDS DUE TO INFECTION, INJURY or IATROGENESIS
20220370411 · 2022-11-24
Inventors
Cpc classification
A61P29/00
HUMAN NECESSITIES
A61P31/00
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
A61P17/02
HUMAN NECESSITIES
A61K31/541
HUMAN NECESSITIES
A61K31/541
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
A61K31/166
HUMAN NECESSITIES
International classification
A61K31/405
HUMAN NECESSITIES
A61K31/166
HUMAN NECESSITIES
A61K31/541
HUMAN NECESSITIES
A61P17/02
HUMAN NECESSITIES
Abstract
The present invention relates to the early treatment, including pre-diagnosis treatment, of sepsis and acute inflammatory syndromes such as systemic inflammatory response syndrome (SIRS) by PLA2 and metalloprotease inhibitors to improve the performance of antibiotics and outcomes prior to and after confirmation of the diagnosis of sepsis and/or SIRS in a patient or subject. Additional embodiments include methods of treating sepsis, anthrax and severe acute respiratory syndrome coronavirus (SARS and SARS-CoV2) and related inflammatory syndromes and compositions, including pharmaceutical compositions and blood sample compositions. In further embodiments, the present invention is directed to embodiments which evidence that LY315920, LY333013 and related sPLA2 inhibitors are particularly effective COVID-19/cytokine release syndrome therapeutics-prophylactics. In embodiments, the PLA2 inhibitor is varespladib (LY315920), methyl varespladib (LY333013), AZD2716-(R)-3-(5′-benzyl-2′-carbamoyl-[1,1′-biphenyl-3-yl)-2-methylpropanoic acid—as a racemic mixture or separately, as the “R” enantiomer), AZD Compound 4 (3-(5′-Benzyl-2′-carbamoylbiphenyl-3-yl)propanoic acid) and LY433771 ((9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl) oxyacetic acid), a pharmaceutically acceptable salt thereof or a mixture thereof. In embodiments, the metalloprotease inhibitor is Prinomastat, Batimastat, marimastat or vorinostat dosed alone or in combination with preferred sPLA2 inhibitors for the treatment of infection, inflammatory and wound conditions arising from various causes. Methods and compositions for achieving accelerated. treatment of wounds and burns, anthrax metalloprotease toxin (lethal factor) driven complications, ARDS, neo-natal and pediatric acute respiratory distress syndrome (neo-natal/pediatric ARDS), including, meconium aspiration syndrome are also disclosed.
Claims
1. A method of reducing the likelihood that an injured patient or subject at risk of an inflammatory syndrome will produce one or more of sepsis, septic shock, an acute inflammatory syndrome (whether iatrogenic or not) or acute respiratory distress syndrome, comprising administering to said patient or subject an effective amount of at least one PLA2 inhibitor and/or at least one metalloprotease inhibitor alone or in combination with at least one antibiotic.
2. The method according to claim 1 wherein said PLA2 inhibitor is varespladib (LY315920), methyl varespladib (LY333013), AZD2716 (R)-3-(5′-benzyl-2′-carbamoyl-[1,1′-biphenyl]-3-yl)-2-methylpropanoic acid -—as the racemic mixture or enantiomer thereof), AZD compound 4 (3-(5′-Benzyl-2′-carbamoylbiphenyl-3-yl)propanoic acid and LY433771 ((9[(phenyl)methyl]-5-carbamoylearbazol-4-yl}oxyacetic acid), a pharmaceutically acceptable salt thereof or a mixture thereof.
3. The method according to claim 1 or 2 wherein said metalloprotease inhibitor is prinomastat, BB-94 (marimastat), BB-2516 (batimastat), vorinostat, cefixime and doxycycline, a pharmaceutically acceptable salt thereof or a mixture thereof.
4. The method according to any of claims 1-3 wherein said PLA2 inhibitor and/or said metalloprotease inhibitor is combined with at least one antibiotic.
5. The method according to claim 4 wherein said antibiotic is selected from the group consisting of a penam, a carboxylpenicillin, a cephalosporin, a monobactam, a carbapenem, a fluoroqunoline, a macrolide or a mixture thereof.
6. A method of treating an injured or burned patient or subject to improve wound healing and/or to inhibit, ameliorate or reduce the likelihood of one or more of sepsis, septic shock, acute inflammatory syndrome, including inflammatory response syndrome (SIRS) and/or acute respiratory distress syndrome (ARDS) in said patient or subject, comprising administering to said patient or subject an effective amount of at least one PLA2 inhibitor and/or a metalloprotease inhibitor in combination with an effective amount of at least one antibiotic.
7. The method according to claim 6 comprising administering to said patient or subject at least two antibiotics.
8. The method according to claim 6 or 7 wherein said antibiotic(s) is co-administered with at least one PLA2 inhibitor.
9. The method according to any of claims 6-8 wherein said antibiotic(s) is co-administered with at least one metalloprotease inhibitor.
10. The method according to any of claims 6-9 wherein said PLA2 inhibitor is varespladib (LY315920), methyl varespladib (LY333013), AZD2716-(R)-3-(5′-benzyl-2′-carbamoyl1,1′-biphenyl]-3-yl)- 2-methylpropanoic acid—as a racemic mixture or enantiomer thereof), AZD compound 4(3-(5′-Benzyl-2′-carbamoylbiphenyl-3-yl)propanoic acid and LY433771 ((9-[phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid), darapladib, a pharmaceutically acceptable salt thereof or a mixture thereof.
11. The method according to any of claims 6-10 wherein said metalloprotease inhibitor is prinomastat, BB-94 (marimastat), BB-2516 (batimastat), vorinostat, cefixime and doxycycline, a pharmaceutically acceptable salt thereof or a mixture thereof.
12. A method of treating a patient or subject with sepsis, including early sepsis, comprising administering to said patient or subject in need, an effective amount of at least one antibiotic and an effective amount of at least one PLA2 inhibitor and/or a metalloprotease inhibitor.
13. The method according to claim 12 comprising administering to said patient or subject at least two antibiotics.
14. The method according to claim 12 or 13 wherein said antibiotic(s) is co-administered with at least one PLA2 inhibitor.
15. The method according to any of claims 12-14 wherein said antibiotic(s) is co-administered with at least one metalloprotease inhibitor.
16. The method according to any of claims 12-15 wherein said PLA2 inhibitor is varespladib (LY315920), methyl varespladib (LY333013), AZD2716-(R)-3-(5′-benzyl-2′-carbamoyl1,1′-biphenyl]-3-yl)-2-methylpropanoic acid —as a racemic mixture or enantiomer thereof), AZD compound 4 (3-(5′-Benzyl-2′-carbamoylbiphenyl-3-yl)propanoic acid and LY433771 ((94(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid), darapladib, a pharmaceutically acceptable salt thereof or a mixture thereof
17. The method according to any of claims 12-16 wherein said metalloprotease inhibitor is prinomastat, BB-94 (marimastat), BB-2516 (batimastat), vorinostat, cefixime and doxycycline, a pharmaceutically acceptable salt thereof or a mixture thereof.
18. A method for preserving a blood sample(s) taken from a patient or subject who has injuries or burns which place the patient or subject at risk for one or more of sepsis, septic shock, acute inflammatory syndrome, including inflammatory response syndrome (SIRS) and/or acute respiratory distress syndrome (ARDS), the method comprising combining in said blood sample an effective amount of at least one PLA2 inhibitor and/or at least one metalloprotease each alone, together or in combination with an effective amount of at least one antibiotic.
19. The method according to claim 18 wherein said blood sample is combined with at least one PLA2 inhibitor.
20. The method according to claim 18 or 19 wherein said antibiotic(s) is combined with at least one metalloprotease inhibitor.
21. The method according to any of claims 18-20 wherein said PLA2 inhibitor is varespladib (LY315920), methyl varespladib (LY333013), AZD2716-(R)-3-(5′-benzyl-2′-carbamoyl[1,1′-biphenyl]-3-yl)-2-methylpropanoic acid —as a racemic mixture or enantiomer thereof), AZD compound 4 (3-(5′-Benzyl-2′-carbamoylbiphenyl-3-yl)propanoic acid and LY433771 ((9-[(phenyl)methyl]-5-carbamoylcarbazol-4-ylloxyacetic acid), a pharmaceutically acceptable salt thereof or a mixture thereof.
22. The method according to any of claims 18-21 wherein said metalloprotease inhibitor is prinomastat, BB-94 (marimastat), BB-2516 (batimastat), vorinostat, cefixime and doxycycline, a pharmaceutically acceptable salt thereof or a mixture thereof.
23. A composition comprising a blood sample(s) taken from a patient or subject who has injuries or burns which place the patient or subject at risk for one or more of sepsis, septic shock, acute inflammatory syndrome, including inflammatory response syndrome (SIRS) and/or acute respiratory distress syndrome (ARDS), in combination with an effective amount of at least one PLA2 inhibitor and/or at least one metalloprotease each alone, together or in combination with an effective amount of at least one antibiotic.
24. The composition according to claim 23 wherein said blood sample is combined with at least one PLA2 inhibitor.
25. The composition according to claim 23 or 24 wherein said composition comprises at least one antibiotic and at least one metalloprotease inhibitor.
26. The composition according to any of claims 23-25 wherein said PLA2 inhibitor is varespladib (LY315920), methyl varespladib (LY333013), AZD2716-(R)-3-(5′-benzyl-2′-carbamoyl41,1′-biphenyl]-3-yl)-2-methylpropanoic acid as a racemic mixture or enantiomer thereof), AZD compound 4 (3-(5′-Benzyl-2′-carbamoylbiphenyl-3-yl)propanoic acid and LY433771 ((9-[(phenyl)methyl]-5-carbamoylcarbazol-4-ylloxyacetic acid), darapladib a pharmaceutically acceptable salt thereof or a mixture thereof.
27. The composition according to any of claims 23-26 wherein said metalloprotease inhibitor is prinomastat, BB-94 (marimastat), BB-2516 (batimastat), vorinostat, cefixime and doxycycline, a pharmaceutically acceptable salt thereof or a mixture thereof.
28. A pharmaceutical composition for use in treating a patient at risk for or afflicted with one or more of sepsis, septic shock, acute inflammatory syndrome, including inflammatory response syndrome (SIRS) and/or acute respiratory distress syndrome (ARDS), comprising an effective amount of at least one antibiotic in combination with at least one PLA2 inhibitor and/or at least one metalloprotease inhibitor.
29. The composition according to claim 28 comprising at least one PLA2 inhibitor.
30. The composition according to claim 28 or 29 comprising at least one metalloprotease inhibitor.
31. The composition according to any of claims 28-30 wherein said PLA2 inhibitor is varespladib (LY315920), methyl varespladib (LY333013), AZD2716-(R)-3-(5′-benzyl-2′-carbamoyl-[1,1′-biphenyl]-3-yl)-2-methylpropanoic acid—as a racemic mixture or enantiomer thereof), AZD compound 4 (3-(5′-Benzyl-2′-carbamoylbiphenyl-3-yl)propanoic acid and LY433771 ((9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid), darapladib, a pharmaceutically acceptable salt thereof or a mixture thereof.
32. The composition according to any of claims 28-31 wherein said metalloprotease inhibitor is prinomastat, BB-94 (marimastat), BB-2516 (batimastat), vorinostat, cefixime and doxycycline, a pharmaceutically acceptable salt thereof or a mixture thereof.
33. A method of inhibiting or reducing the likelihood of a COVID-19/cytokine release syndrome in a patient at risk of same comprising administering to said patient at risk at least one PLA2 inhibitor and/or at least one metalloprotease inhibitor.
34. The method according to claim 33 wherein said PLA2 inhibitor is is varespladib (LY315920), methyl varespladib (LY333013), AZD2716- (R)-3-(5′-benzyl-2′ -carbamoyl[1,1-biphenyl]-3-yl)-2-methylpropanoic acid—as a racemic mixture), AZD compound 4 (3-(5′-Benzyl-2′-carbamoylbiphenyl-3-yl)propanoic acid and LY433771 ((9-[(phen)tnethyl]-5-carbamoylcarbazol-4-ylloxyacetic acid), a pharmaceutically acceptable salt thereof or a mixture thereof.
35. The method according to claim 33 or 34 wherein said metalloprotease inhibitor is prinomastat, BB-94 (marimastat), BB-2516 (batimastat), vorinostat, cefixime and doxycycline, a pharmaceutically acceptable salt thereof or a mixture thereof.
36. The method according to any of claims 1-3 wherein said PLA2 inhibitor and/or said metalloprotease inhibitor are combined.
37. A method of treating neo-natal acute respiratory distress syndrome (neo-natal ARDS), including meconium aspiration syndrome in a patient in need comprising administering to said patient at least one PLA2 inhibitor.
38. The method according to claim 37 wherein said PLA2 inhibitor is LY315920, LY333013, AZD2716, as an enantiomerically enriched species or as a racemic mixture or mixtures thereof.
39. The method according to either of claim 37 or 38 wherein said neo-natal ARDS is meconium aspiration syndrome (MAS).
40. A method of treating a patient or subject in need at risk for or afflicted with anthrax or severe acute respiratory syndrome coronavirus infection (SARS or SARS-CoV2), comprising administering to said patient or subject an effective amount of at least one PLA2 inhibitor and/or a metalloprotease inhibitor and optionally at least one antibiotic to provide an unexpected inhibition, amelioration and/or avoidance of sepsis, septic shock, acute inflammatory syndrome, including inflammatory response syndrome (SIRS) and/or acute respiratory distress syndrome (ARDS) in the patient or subject.
41. The method according to claim 40 comprising administering to said patient or subject at least two antibiotics in combination with said PLA2 inhibitor(s) and/or said metalloprotease inhibitor(s).
42. The method according to 40 or 41 wherein at least one PLA2 inhibitor is administered to said patient.
43. The method according to any of claims 40-42 wherein at least one metalloprotease inhibitor is administered to said patient or subject.
44. The method according to any of claims 40-43 wherein said PLA2 inhibitor is varespladib (LY315920), methyl varespladib (LY333013), AZD2716-(R)-3-(5′-benzyl-2′-carbamoyl[1,1′-biphenyl]-3-yl)-2-methylpropanoic acid —as a racemic mixture or enantiomer thereof), AZD compound 4 (3-(5′-Benzyl-2′-carbamoylbiphenyl-3-yl)propanoic acid and LY433771 ((9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yloxyacetic acid), darapladib, a pharmaceutically acceptable salt thereof or a mixture thereof.
45. The method according to any of claims 40-44 wherein said metalloprotease inhibitor is prinomastat, BB-94 (marimastat), BB-2516 (batimastat), vorinostat, cefixime and doxycycline, a pharmaceutically acceptable salt thereof or a mixture thereof.
46. The method according to any of claims 1-17 and 33-45 wherein said PLA2 inhibitor and said metalloprotease inhibitor are co-administered.
47. The method according to any of claims 18-22 wherein said PLA2 inhibitor and said metalloprotease inhibitor(s) are used together.
48. The composition according to any of claims 23-32 comprising at least one PLA2 inhibitor and at least one metalloprotease inhibitor.
49. The method according to any of claims 1-22 and 33-45 wherein said metalloprotease inhibitor is prinomastat.
50. The composition according to any of claims 23-32 wherein said PLA2 inhibitor is varespladib, methylvarespladib, AZD2716 (as a racemic mixture or as the “R” enantiomer), a pharmaceutically acceptable salt thereof or a mixture thereof.
51. The method according to any of claims 1-22 and 33-45 wherein said PLA2 inhibitor is varespladib, methylvarespladib, AZD2716 (as a racemic mixture or as the “R” enantiomer), a pharmaceutically acceptable salt thereof or a mixture thereof.
52. The composition according to any of claims 23-32 wherein said PLA2 inhibitor is varespladib, methylvarespladib, AZD2716 (as a racemic mixture or as the “R” enantiomer), a pharmaceutically acceptable salt thereof or a mixture thereof.
53. A pharmaceutical composition comprising a therapeutically effective amount of at least one PLA2 inhibitor, at least one metalloprotease inhibitor or a mixture thereof in combination with an antibiotic.
54. The composition according to claim 53 wherein said antibiotic is a penam, a carboxylpenicillin, a cephalosporin, a monobactam, a carbapenem, a fluoroqunoline, a macrolide or a mixture thereof.
55. The composition according to claim 53 wherein said antibiotic is ciprofloxacin, levofloxacin, moxifloxacin, penicillin g, doxycycline, chloramphenicol, ofloxacin or mixtures thereof
56. The composition according to any of claims 53-55 wherein said PLA2 inhibitor is varespladib (LY315920), methyl varespladib (LY333013), AZD2716 (R)-3-(5′-benzyl-2′-carbamoyl-[1,1′-biphenyl]-3-yl)-2-methylpropanoic acid—as a racemic mixture or enantiomer thereof) , AZD compound 4 (3-(5′-Benzyl-2′-carbamoylbiphenyl-3-yl)propanoic acid and LY433771 ((9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid), darapladib, a pharmaceutically acceptable salt thereof or a mixture thereof.
57. The method according to any of claims 53-56 wherein said metalloprotease inhibitor is prinomastat, BB-94 (marimastat), BB-2516 (batimastat), vorinostat, cefixime and doxycycline, a pharmaceutically acceptable salt thereof or a mixture thereof.
Description
BRIEF DESCRIPTION OF THE FIGURES
[0072]
[0073]
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[0075]
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[0077] XX
—NE X X H General motif for zinc binding metalloproteases [0079]
FG
—Conserved zinc binding site in anthrax lethal factor [0080]
MG
—In zinc binding rattlesnake venom metalloproteases
Prinomastat was chosen for mouse lung-injury and ARDS study as well as in subsequent ECIS studies for this reason and to be combined with an sPLA2 inhibitor. There is no known explanation for why Prinomastat is more potent than these other inhibitors for these embodiments and it has not been contemplated as a therapeutic to combat toxin damage as seen caused by anthrax lethal factor, a toxic metalloprolease. Prinomastat has not been previously reported to be more potent than anthrax lethal factor inhibitor, but demonstrably more potent as seen in Table 2, Sistrurus venom was used as surrogate for anthrax lethal factor inhibitor because of the lethal factor inhibitor's high potency against Sistrurus venom metalloprotease activity (Table 2) which is similar to that of native anthrax lethal factor, which has also been termed “zincin” class metalloproteases (
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DETAILED DESCRIPTION OF THE INVENTION
[0089] The following terms shall be used throughout the specification to describe the present invention. Where a term is not specifically defined herein, that term shall be understood to be used in a manner consistent with its use by those of ordinary skill in the art.
[0090] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention. In instances where a substituent is a possibility in one or more Markush groups, it is understood that only those substituents which form stable bonds are to be used.
[0091] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described.
[0092] It must be noted that as used herein and in the appended claims, the singular forms “a,”“and” and “the” include plural references unless the context clearly dictates otherwise.
[0093] Furthermore, the following terms shall have the defintions set out below.
[0094] The term “patient” or “subject” is used throughout the specification within context to describe an animal, generally a mammal, especially including a domesticated animal and preferably a human, to whom a treatment, including prophylactic treatment (prophylaxis) is provided. For treatment of those infections, conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal. In most instances, the patient or subject is a human patient of either or both genders.
[0095] The term “compound” is used herein to describe any specific compound or bioactive agent disclosed herein, including any and all stereoisomers (including diastereomers), individual optical isomers (enantiomers, including with respect to compound AZD2716) or racemic mixtures, pharmaceutically acceptable salts and prodrug forms. The term compound herein refers to stable compounds. Within its use in context, the term compound may refer to a single compound or a mixture of compounds as otherwise described herein.
[0096] The term “effective” is used herein, unless otherwise indicated, to describe an amount of a compound or component which, when used within the context of its use, produces or effects an intended result, whether that result relates to the prophylaxis and/or therapy of an infection and/or disease state or as otherwise described herein. The term effective subsumes all other effective amount or effective concentration terms (including the term “therapeutically effective”) which are otherwise described or used in the present application.
[0097] The term “pharmaceutically acceptable” as used herein means that the compound, composition, including a salt form, is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.
[0098] The terms “treat”, “treating”, and “treatment”, etc., as used herein within context, also refers to any action providing a benefit to a patient at risk for any of the disease states or conditions (which can be treated pursuant to the present invention (e.g., ameliorate, inhibit, reduce the severity, cure, etc.). Treatment, as used herein, principally encompasses therapeutic treatment, but may also encompass both prophylactic and therapeutic treatment, depending on the context of the treatment. The term “prophylactic” when used in context, means to reduce the likelihood of an occurrence or in some cases, reduce the severity of an occurrence within the context of the treatment of a disease state or condition otherwise described herein.
[0099] The term “coadministration” shall mean that at least two compounds or compositions are administered to the patient at the same time, such that effective amounts or concentrations of each of the two or more compounds may be found in the patient at a given point in time. Although compounds according to the present invention may be co-administered to a patient at the same time, the term embraces both administration of two or more agents at the same time or at different times, provided that effective concentrations of all coadministered compounds or compositions are found in the subject at a given time. Compounds according to the present invention may be administered with one or more additional bioactive agents to address specific disease conditions in a treated patient or subject.
[0100] The term “prevention” is used within context to mean “reducing the likelihood” of a condition or disease state from occurring as a consequence of administration or concurrent administration of one or more compounds or compositions according to the present invention, alone or in combination with another agent. Thus, the term prevention is used within the context of a qualitative measure and it is understood that the use of a compound according to the present invention to reduce the likelihood of an occurrence of a condition or disease state as otherwise described herein will not be absolute, but will reflect the ability of the compound to reduce the likelihood of the occurrence within a population of patients or subjects in need of such prevention.
[0101] The term “sepsis” is used to describe a clinical syndrome that complicates infection. It is characterized by signs of inflammation (vasodilation, leukocyte accumulation, increased microvascular permeability) occurring in tissues that are remote from the infection. Systemic inflammatory response syndrome (SIRS) is also a clinical syndrome that complicates a noninfectious insult (e.g., acute pancreatitis, pulmonary contusion). Theories about the onset and progression of sepsis and SIRS are focused on dysregulation of the inflammatory response, including the possibility that a massive and uncontrolled release of proinfiammatory mediators initiates a chain of events that lead to widespread tissue injury. This response can lead to multiple organ dysfunction syndrome (MODS), which is the cause of the high mortality associated with these syndromes.
[0102] Sepsis is typically associated with a bacterial infection and is characterized by a whole-body inflammatory state (SIRS) and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to bacteria presence in the blood, urine, lungs, skin, or other tissues. Sepsis is also referred to as “blood poisoning” or septicemia. Severe sepsis is the systemic inflammatory response, plus infection, plus the presence of at least one organ dysfunction. Septicemia (also sometimes referred to as bacteremia) refers to the presence of pathogenic organisms in the bloodstream, leading to sepsis.
[0103] Sepsis is a life-threatening condition in which the body is fighting a severe infection that has spread via the bloodstream. If a patient becomes “septic,” he or she will likely have low blood pressure leading to poor circulation and lack of blood perfusion of vital tissues and organs, resulting in shock. This condition of shock is often referred to as septic shock when an infection is the cause of shock to distinguish it from shock due to blood loss or from other causes. Sepsis and septic shock can develop either as a result of the body's own defense system or from toxic substances made by the infecting agent. Survival rates for sepsis depend on the patient's underlying medical conditions, how quickly the diagnosis is made, the organism that causes the infection, and the patient's age.
[0104] In the United States, sepsis is the second-leading cause of death in non-coronary ICU patients, and the tenth-most-common cause of death overall according to data from the Centers for Disease Control and Prevention (the first being heart disease). Sepsis is common and also. more dangerous in elderly, inummocompmmised, and critically ill patients. It occurs in 1-2% of all hospitalizations and accounts for as much as 25% of intensive-care unit (ICU) bed utilization. It is a major cause of death in intensive-care units worldwide, with mortality rates that range from 20% for sepsis to 40% for severe sepsis to >60% for septic shock.
[0105] Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysftinction syndrome (formerly known as multiple organ failure) and death. Its most common victims are children, immunocompromised individuals, and the elderly, as their immune systems cannot deal with the infection as effectively as those of healthy adults. Frequently, patients suffering from septic shock are cared for in intensive care units. The mortality rate from septic shock is approximately 25%-50% (See United States Patent Application Document No. 20140162978). Many details of optimal EGDT remain unresolved and controversial. The current invention resolves or mitigates several key elements of EGDT timing and protocol flexibility making a novel and critical. advance to patient care for this long-unmet need of complex and critically ill and injured patients.
[0106] Adequate management of septic patients is often complicated by delay in administering therapy after sepsis has been recognized. Every hour delay in the administration of appropriate antibiotic therapy there is associated with a significant rise in mortality.
[0107] “Sepsis” as used herein and within context includes all of the aforementioned septic states, conditions and clinical symptoms, e.g. “sepsis” includes but is not limited to systemic inflammatory response syndrome (SIRS), septicemia and septic shock.
[0108] The term “early sepsis” is used to describe the initial stages of sepsis before a full septic state occurs. It is important to recognize the signs of early sepsis and immediately seek treatment if treatment has not yet been initiated because the infection can spread rapidly—often in a matter of hours. Sepsis occurs when an infection in the body enters the bloodstream and spreads throughout the body; this can lead to septic shock, a potentially fatal condition. Some of the earliest signs of sepsis include a high fever, a feeling of fatigue, an increased heart rate, rapid breathing or breathing difficulty. Experts generally look for at least two symptoms to suspect and diagnose sepsis. A diagnosed infection is also one of these symptoms.
[0109] If the original source of the infection is on the surface of the body, one of the best indicators of early sepsis is the presence of red streaks coming off the area and moving up the infected limb. Not all infections are superficial however, which is why the other signs of early sepsis are also important to recognize.
[0110] Infections will often present with a fever that steadily increases, but may not be evident without core temperature measurements. As the fever increases, muscle pain and weakmess may become present, and some people may experience pain in the joints as well. This fever may also cause chills, and some people notice that they become dizzy and shaky, with a corresponding drop in blood pressure.
[0111] Accompanied by the chills and fever, the signs of early sepsis also often include a rapid heartbeat and quick breathing. People may find that they cannot slow the breathing or the heart rate down no matter how much they try to relax and take deep breaths. These symptoms will also worsen as the infection progresses through the body. The signs of early sepsis typically only last for a short time; if they are not addressed with emergency treatment with antibiotics, other, more serious symptoms will quickly become apparent.
[0112] Some individuals will develop a rash on the skin in addition to the red streaks. This rash can show up anywhere on the body. In addition, urine output will generally decrease significantly, which is a symptom that the organs are slowing function, which is extremely dangerous. Mental state may change as well; some people become confused and agitated. Rather than wait and see if these early symptoms of sepsis get better, it is important to receive emergency treatment as soon as possible, in this case at least one antibiotic in combination with at least one PLA2 inhibitor and or metalloprotease inhibitor. This is another reason to be certain to care for any injuries or infections in the body, to clean cuts and scrapes well, and to take an entire course of antibiotics when prescribed, to be sure all infections are killed before they can spread.
[0113] The term “likelihood of sepsis” is used to describe a patient or subject who has extensive burns andlor a severe injury including an injury associated with an infection which likely will result in sepsis and includes any patient or subject with a several burn and/or injury which will likely result in an infection.
[0114] The term “severe bunts” or “extensive burns” is used to describe a patient or subject who. will likely have an infection or will result in an infection Which can cause sepsis or an acute inflammatory spidromes such as systemic inflammatory response syndrome (SIRS) or related inflammatory syndrome. The severity of a burn, along with the type of burn, is important to assess before planning a burn treatment regimen and providing treatment pursuant to the present invention. Burn severity often indicates the recovery time needed and whether or not the burn patient will experience permanent effects, such as scarring or an interference or change in physiological function. More importantly, the severity, of a burn may indicate that the patient or subject will become infected, thus substantially increasing the likelihood of sepsis or an acute inflammatory syndromes such as systemic inflammatory response syndronie (SIRS). Severe burns are typically classified by measuring the total body surface area (TBSA) of the burn injury.
[0115] This system measures the percentage of burned skin in comparison to the rest of the victim's body. A burn injury of the same size will result in a higher TBSA for a child than for an adult, due to the child's smaller body size. The American Burn Association has set forth guidelines for measuring TBSA and diagnosing severe burns.
[0116] Burn injuries are typically placed into three major categories. In adults, burns with a TBSA of 10 percent or less are classified as minor burns. In children, minor burns measure five percent TBSA or less. Moderate bums may cover roughly ten-to-twenty percent of adults. In children, moderate burns cover roughly five-to-10 percent. Minor and moderate burns often do not produce infection consistent with eventual sepsis and/or acute inflammatory syndrome, but the patient or subject must be monitored carefully and treated pursuant to the present invention when there is evidence for risk of infection. Major, or severe bums, measure more than 20 percent TBSA in adults and more than 10 percent in children. Major or severe burns in a patient or subject are a prima facie indication that the patient or subject should be treated pursuant to the present invention.
[0117] Severe bums may be caused by a number of sources, including, but not limited to thermal, e.g. hot liquids or gases, open flames and hot surfaces; chemical, e.g. strong acids Or bases, such as sulfuric acid and bleach; electrical: high voltage exposure, electric arcs, and lighting; radiation: ultraviolet light, microwaves, ionizing radiation such as from x-rays or nuclear fallout. Severe burns may be accidental or intentional (especially with children and/or elders).
[0118] The term “traumatic injury” or “wound” is used to describe any injury of a severe or sufficient nature that has an identifiable risk of becoming infected or fail to heal for other reasons. Traumatic injury may refer to physical injuries of sudden onset and severity which require immediate medical attention. Initially small insults (e.g. a scratch or abrasion) as well as immediate and severe insults (e.g. motor vehicle collision or blast injury) may cause systemic shock called “shock trauma” and may require resuscitation and interventions to save life and limb. Traumatic injuries are the result of a wide variety of blunt, penetrating and burn mechanisms. They include motor vehicle collisions, sports injuries, falls, natural disasters and a multitude of other physical injuries which can occur at home, on the street, or while at work. Microscopic injuries lead to serious injury or illness if not treated (e.g. tetanus)
[0119] With respect to major trauma, many accidents resulting in traumatic injury can be treated appropriately in hospital emergency departments. More severe and multiple traumatic injuries may be triaged by emergency responders as a Trauma Alert. A Level One Trauma Alert is a determination based on a rapid physical assessment of the victim's immediate medical needs. Based on trauma alert criteria, first responders deliver the patient to the most appropriate hospital.
[0120] Trauma guidelines in the U.S. were first established in 1976, and an efficient sophisticated trauma network now serves us all wherever we live, work or travel. Hospitals are accredited and designated as Level I, II, III or IV Trauma Centers based on the care they are able to provide, as well as the volumes they serve, urban and paral. The trauma system is designed to accommodate mass casualties and disaster situations. Level I Centers provide the highest level of care with optimal resources and capabilities, staff and specialties around-the-clock, and are continuously monitored to assure that they meet or exceed national standards. Trauma centers work closely with their respective EMS systems so that care begins pre-hospital.
[0121] Typically, critically injured patients deemed a Trauma Alert are delivered to a resuscitation area which may look more like an operating room than a traditional emergency department. In this environment, a highly-skilled professional trauma team is ready to provide immediate life-saving procedures in state-of-the-art trauma hays. Research shows that getting to the right place at the right time, commonly known as the “Golden Hour” or within the first 60 minutes after the occurrence of a major multi-system trauma, is critical. Adult and pediatric trauma surgeons, trauma staff and resources are ready and dedicated 24/7 to provide this unique level of response so that critically injured patients will have the best possible chance of survival and the least residual disability from their injuries.
[0122] Following care in the trauma resuscitation area at a Level One facility, patients may proceed to surgery, an intensive care unit or the trauma nursing floor, with all the resources and services of the hospital available in a true multi-disciplinary fashion. Patients brought to Level II-IV centers may remain at that hospital or be transferred to a higher level of care as appropriate.
[0123] Sonic common types of traumatic injuries include, but are not limited to traumatic brain injury, spinal cord injury, spinal fractures, amputations, facial trauma, acoustic trauma, concussions, crush injuries, broken bone injury, broken jaw, skull fracture, cuts, puncture wounds, lacerations, collapsed lung, burns, myocardial contusions, electrical injuries, hypovolemic shock, subarachnoid hemorrhage and subdural hematoma, among others.
[0124] The Injury Severity Score (ISS) is an established medical score to assess trauma severity. It correlates with mortality, morbidity and hospitalization time after trauma. It is used to define the teen major trauma. The ISS classifies each injury in every body region according to its relative severity on a six point ordinal scale, e.g. minor, moderate, serious, severe, critical, Maximal in six body regions, e.g. head/neck, face, thorax, abdomen/pelvis, external.
[0125] The term “systemic inflammatory response syndrome” or “SIRS” is used to describe an inflammatory syndrome which is caused by systemic response of the body due to severe inflammation or infection. This is characterized with high fever and rapid heartbeat and abuonnal level of white blood cells in blood. The symptoms of SIRS vary widely depending on the triggering factor for the response and the victim's underlying predispositions. Some of the common signs include high fever, chills and localized pain based on inflammation. Some of the criteria for diagnosing SIRS including the following: [0126] Very high or very low level of white blood cells in blood. It may go up to 12,000 per liter or below 4,000 also. [0127] High fever and chills. The temperature may shoot up to 100.4 F or can go below 96 F also. [0128] Rapid heartbeat and [0129] Fast respiratory rate.
[0130] SIRS can be caused by severe infection, ischemia or after effects of surgery. Infection can occur due to bactena., virus and other microorganisms (fungi or parasites). It can be anything ranging from sepsis, cellulitis to diabetic foot infection. SIRS can develop due to non-infectious conditions like dehydration, burns, cirrhosis, autoimmune disorders, immune therapies, acute ischemia, and myocardial infarction and due to hemorrhagic shock. In rare cases, SIRS can cause potential complications like hemolytic uremic syndrome (HUS) anemia, renal failure, respiratory failure, gastritis and abnormal levels of electrolytes.
[0131] The method of treatment for SIRS is based on symptoms and health condition of the patient. Some patients may show signs of sepsis due to severe rate of infection without having any sign of SIRS. In case of myocardial infarction or respiratory failure emergency treatment may be given on ICU, if available.
[0132] Blood pressure of the patient may be restored to normal by injecting vasopressor or similar drugs intravenously. If SIRS has developed due to surgical conditions like cholecystitis or ruptured appendix suitable surgical measures are initiated. Antibiotics are given if the root cause of infection is bacteria. Similarly antiviral medications are injected through vein if the doctor confirms the cause is viral infection. In the present invention, these agents are combined with PLA2 andlor metalloprotease inhibitors in treating SIRS. Blood glucose level is monitored carefully and if required, insulin therapy is given to stabilize the level of blond glucose.
[0133] In the present invention, the administration of at least one antibiotic in combination with at least one PLA2 inhibitor andior at least one metalloprotease inhibitor is used to reduce the likelihood that a patient suffering a severe injury or burn will contract an infection which will develop into sepsis, septic shock, acute inflammatory syndrome, including systemic inflammatory response syndrome (SIRS) and/or acute respiratory distress syndrome (ARDS), as described herein.
[0134] Antibiotics which may be used in the present invention include, for example, broad-spectrum antibiotics such as a broad spectrum β-lactam antibiotic or a broad-spectrum carbapenem or a mixture thereof, which can be used alone or combined with fluoroquinolones macrolides, or aminoglycosides. In general, a combination of antibiotics may not be recommended for the treatment of sepsis but without shock and immunocompromised persons unless the combination is used to broaden the anti-bacterial activity. The choice of antibiotics is important in controlling infection, sepsis and ultimately determining the survival of the patient. It is often recommended that antibiotics are commenced within about an hour of making the diagnosis (e.g. within 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 45 minutes, 50 minutes, 60 minutes, 75 minutes or 90 minutes), although the times can be slightly longer. In some embodiments, antibiotics and PLA2 inhibitors and/or metalloprotease inhibitors are initiated immediately or as soon as the severity of a burn or injury is assessed in a patient or subject.
[0135] For severe sepsis and septic shock a broad spectrum antibiotic (often two such antibiotics) are administered intravenously or intravenously and orally to the patient or subject in combination with the PLA2 inhibitor and or metalloprotease at the first indication that the patient or subject has sepsis, including early sepsis. The antibiotics may include, for example a β-lactam antibiotic with broad coverage such as broad spectrum penicillin derivatives (penams) amoxicillin and ampicillin, carboxylpenicillins (e.g. carbenicillin and ticarcillin), cephalosporins (cephems) such as cefixime, doxycycline, cefotaxime, cefpodoxime, ceftazidime, ceftriaxone, cefdinir, ceftaroline fosnir all of which are broad spectrum, monobactams (e.g. aztreonam, tigemonam, carumonam and nocardicin A) and carbapenems (e.g. doripenem, faropenem, imipenem, meropenem, ertapenem, panipenim, razupenem, tehipenem, thienamycin or cilastatin/imipenem), a fluorogunoline (e.g. ciprofloxacin, levofloxacin, fleroxacin, lometioxacin, nadifloxacin, norfloxacin, ofloxacin, perfloxacin, nufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, temafloxacin, garenoxacin, gatifloxacin, gemifloxacin, moxifloxacin, clinafloxacin, sitafloxacin, prulifloxacin, besifloxacin, delafloxacin and ozenoxacin, among others), a macrolide (e.g. (e.g., azithromycin, clarithromycin, erythromycin, fiaxomycin, telithromycin, carbomycin A, josamycin A, kitasamycin, midecamycin midecamycin acetate, oleandomycin, solithromycin, spiramycin, troleandomycin and roxithromycin, related ketolides inclouding telithromycin, cethromycin and solithromycin), each of which may be used alone or in combination.
[0136] In the case of anthrax, preferred antibiotics include ciprofloxacin, levofloxacin, moxifloxacin penicillin G doxycycline, chloramphenicol, ofloxacin and mixtures thereof.
[0137] “PLA2 Inhibitors” which term includes secretory Phospholipase A2 inhibitors and Phospholipase A2 (PLA2) inhibitors are inhibitors of lipase enzymes that catalyze the hydrolysis of phospholipids at the sn-2 position yielding a free fatty acid and a lysophospholipid. PLA.sub.2 contributes towards release and/or formation of at least three important lipid mediators from membrane-arachidonic acid, platelet activating factor and lysophosphatidic acid. The release of arachidonic acid from membrane phospholipids by PLA is believed to be a key step in the control of eicosanoid production within the cell. PLA, enzymes are usually grouped into cytosolic PLA.sub.2 (cPLA.sub.2), secretory PLA.sub.2 (sPLA2) and calcium independent PLA.sub.2 (iPLA.sub.2). Venom (e.g., snake venom) PLA2 are secreted (i.e., sPLA2s). Classification is based on molecular weight, calcium requirement, structural features, substrate specificity and functional role. See Ray. et al., “Phospholipase A.sub.2 in Airway Disease: Target for Drug Discovery,” Journal of Drug Discovery and Therapeutics 1 (8) 2013, 28-40.
[0138] Inhibitors of PLA2 have been identified in various sources and have been investigated as potential therapeutic agents for treatment of inflammatory diseases. See, Magrioti, Victoria, and George Kokotos. “Phospholipase A2 inhibitors as potential therapeutic agents for the treatment of inflammatory diseases.” Evert opinion on therapeutic patents 20.1 (2010): 1-18), and Dennis, Edward A., et al. “Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention.” sPLA2 inhibitors which can be used in the invention include, but are not limited to, LY315920 and S5920 (varespladib) LY333013 and S-3013, AZ D2716—(R)-3-(5′-benzyl-2′-carbamoyl-[1,1′-biphenyl]-3-yl)-2-methylpropanoic acid—as a racemic mixture or a stereoisomer thereof, often the “R” enantiomer of the racemic mixture. AZD Compound 4 (3-(5′-Benzyl-2′-carbamoylbiphenyl-3-yl)propanoic acid) and LY433:771 ((9-[(phenyl)methyl]-5-carbamoylearbazol-4-yl}oxyacetic acid), LY 311727, BMS 181162, YM 26567, Vaiiabilin, SB 203347, S-2474 (methyl indoxam) and Indoxam. In some embodiments the PLA.sub.2 inhibitor(s) is varespladib and/or methylvarespladib.
[0139] Other PLA2 inhibitors, such as but not limited to other 1H-indole-3-glyoxylamides, are also useful in treatment of envenoming. One of ordinary skill in the art guided by the present disclosure will be able to identify PLA2 inhibitors and therapeutic combinations effective against a broad spectrum of venoms and/or tailored to a particular subset of venoms (e.g., particular species of snake, or venoms from particular types of invertebrates, for example).
[0140] Additional preferred sPLA2 inhibitors includ.e those described in U.S. Pat. No. 5,654,326 (which is incorporated by reference in its entirety herein)—represented by compounds according to the chemical structure:
##STR00001##
where X is O or S, preferably
R.sub.1 is C.sub.7-C.sub.20 alkyl, C.sub.7-C.sub.20 alkenyl, a carbocyclic radical (preferably a benzyl or ethylphenyl group) or a heterocyclic radical;
R.sub.2 is hydrogen, halo (F, Cl, Br, I), C.sub.1-C.sub.3 alkyl (preferably ethyl) or C.sub.3-C.sub.4 cycloalkyl;
R.sub.4 is H or an —O—(CH.sub.2)—C(O)ORv group, wheren is 1-3(preferably 1) and Ry is H or a C.sub.1-C.sub.3 alkyl group, preferably CH.sub.3; and
R.sub.5, R.sub.6 and R.sub.7 are H, or
a pharmaceutically acceptable salt, solvate or polymorph thereof.
[0141] Certain preferred sPLA2 inhibitor compounds (varespladib and methylvarespladib) for use in the present invention are represented by the chemical structure:
##STR00002##
where Rvis H (varespladib) or methyl (methylvarespladib), or their pharmaceutically acceptable salts. The above compounds also may be used as prodrug forms C.sub.1-C.sub.6 alkyl esters, C.sub.2-C.sub.7 acyloxyalkyl esters, or C.sub.3-C.sub.9 alkyloxycarbonvloxyalkyl esters (each formed at R.sub.4. These and other related compounds for use in the present invention are described in U.S. Pat. No. 5,654,326 to Bach, et al., which is incorporated by reference in its entirety herein.
[0142] Additional PLA.sub.2 inhibitors include for example: Varespladib Mofetil N-Acetyl Cysteine, LY329722 (sodium [3-aminooxyalyl-1-benzyl-2-ethyl-6-methyl-1H-indol-4-yloxy]-acetic acid), ochnaflavone (a naturally occurring biflavonoid), BPPA (5-(4-benzyloxyphenyl)-4S-(7-phenylhepatonoylamino) pentanoic acid, and p-bromophenacylbromide (p-BPB) and other benzophenone oximes derivatized with syndone. In certain embodiments, SPLA2 inhibitors for use in the current invention are selected from the group consisting of: {9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic acid; θ-benzyl-δJ-dimethoxy-S-tetrahydrocarbazole-carboxylic acid hydrazide; 9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide; [9-benzyl-4-carbamoyl-7-methoxy-1,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid; [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl]oxyacetic acid; methyl [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl]oxyacetic acid; 9-benzyl-methoxy-5-cyanomethyloxy-S-tetrahydrocarbazole-carboxamide; 9-benzyl-7-methoxy-5-(1H-tetrazol-5-yl-methyl)oxy)-1,2,3,4-tetrahydrocarbazole-4-carboxamide; {9-[(phenyl)methyl]-5-carbamoyl-2-methyl-carbazol-4-yl}oxyacetic acid; 9-[(3- fluorophenyl)methyl]-5-carbamoyl-2-methylcarbazol-4-yl}oxyacetic acid; {9-[(3- methyiphenyl)methyl]-5-carbamoyl-2-methylcarba.zol-4-yl}oxyacetic acid; [9- Rphenyl)methyl]-5-carbamoyl-2-(4-tiitluoromethylphenyl)-carbazol-4-ylloxyacetic acid; 9-benzyl-5-(2-methanesulfonamido)ethyloxy-7-methoxy-1 ,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-4-(2-methanesulfonamido)ethyloxy-2-methoxycarbazole-5-carboxamide; 9-benzyl-4-(2-trifluoromethanesulfonamido)ethylox.y-2-methoxycarbazole- 5-carboxamide; 9-benzyl-5-methanesulfonamidovImethyloxy-7-methoxy-1 , tetrahydrocarbazole-4-carboxamide; 9-benzyl-4-methanesulfonamidoylmethyloxy- carbazole-5-carboxamide; [5-carbamoyl-2-pentyl-9-(phenyhnethyl)carbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-(1 -methylethyl)-9-(phenylmethyl)carbazol-4- ylloxyacetic acid; [5-carbamoyl-9-(phenyhnethyl)-2-[(tri(1-methylethylJsily0oxymethyllcarbazor-ylioxyacetic acid; [5-carbamoyl-2-phenyl-9- (phenylmethyl)carbazol-4-yl]oxyacetic acid; [5-carbamoyl-244-chlorophenyD-9-(phenyhnethyl)carbazol-4-yl]oxyacetic acid; [5-mbamoyl-2-(2-fitryl)-9-(phenyhnethyDcarbazol-4-ylloxyacetic acid; [5-carbamoyl-9-(phenylinethyl)-2-[(tri(-1 -methylethylJsilyOoxymethyllcarbazol-ylloxyacetic acid; {9-[(2-Fluorophenyl)methyl]-5-carbamoylcarbazol-4-ylloxyacetic acid; {9-[(2-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(2-benzylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(1-naphthyljmethyl1-δ-carbamoylcarbazol-yl}oxyacetic acid; {9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; {9-[(3,5-dimethylphenyl)methyl-5-carbannoylcarbazol-4-yl}oxyacetic acid; {9-[(3-iodophenyl)methyl-5-carbannoylcarbazol-4-yl}oxyacetic acid; {9[(2-Chlorophenyl)methyl]-5-carbannoylcarbazol-4-yl}oxyacetic acid; {9-[(2,6-[(2,3-difluorophenyl)methyl]-5-carbannoylcarbazol- 4-yl}oxyacetic acid; {942,6-difluoropheirypmethyl]-5-carbannoylcarbazol-4-ylloxyacetic acid; {9-[(2,6-dich1orophenyl)methyl]-5-carbannoylcarbazol-4- ylloxyacetic acid; {9-[(2-biphenyDmethyl]-5-carbamoylcaibazol-4-ylloxyacetic acid; {(9-[(2-BiplieriyOmethyl]-5-carbamoylcarbazol-4-ylloxyacetic acid methyl ester; [9-Benzyl-4-carbamoyl-1 tetrahydrocarbazol-5-y1]oxyacetic acid; f9-[(2-Pyridyl)methyl]-5-carbamoylearbazol-4- yllox.sub.3Tacetic acid; f9-[(3-Pyridyl)nnethyl]-5-carbamioylcarbazol-4-ylloxyacetic acid; [9- beriz;71-4-carbamoyl-8-linethyl-1. ,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid; [9-benzyl- 5-carbamoyl-1 -methylearbazol-4-yl]oxyacetic acid; [9-benzyl.-4-carbamoyl-8-fluoro- 1 2,3,4-tetrahydrocarbazol-5-yl]ox.yacetic acid; [9-benzyl-4-carbamoyl-8-chloro-1,2,3,4- tetrahydrocarbazol-5-yl]oxyacetic acid; [5-carbamoyl-9-(phenyhmethyl)-2-[[(propei1-3- ypoxy]methyl]carbazol4-.sub.311oxyacetic acid; [5-carbamoyl-9-(phenylmethyl)-2-[(propyloxyjmethylIcarbazolylloxyacetic acid; 9-benzyl-7-methoxy-5-((carboxamidonnethyloxy-tetrahydrocathazole-carboxannide; 9-benzyl -7- methoxy-S-cyanonnethyloxy-carbazole-carboxannide; 9-benzyl-7-methoxy-5-((1H-tetrazol-5-yl-methyl)oxy)-carbazole-4-carboxannide; 9-benzyl-7-methoxy-5-((carboxamidomethl)oxy)-carbazole-4-carboxamide; [9-Benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarhazole-5-yl]oxyacetic acid; {9-[(phenyl)methyl]-5-carbannoyl-2-methyl-carbazol-4-yl}oxyacetic acid; {9-[(3-fluorophenyl)methyl]-5-carbannoyl-2-methylcalbazol-4-yl}oxyacetic acid; {9-[(3-methylphenyl)methyl-5-carbannoyl-2- methylcarbazol-4-yl}oxyacetic acid; {9-[(phenyl)methyl]-5-carbannoyl-2-(4-trifluoromethylphenyl)-carbazol-4-yl}oxyacetic acid; 9-benzyl-5-(2-methanesulfonamido)ethyloxy-7-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-4-(2-methanesulfonamido)ethyloxy-2-metlioxycarbazole-5-carboxamide; carboxamide; 9-benzyl-4-(2-trifluoromethanesulfonamido)ethyloxy-2-methoxycarbazole-5-carboxamide; 9-benzyl-5-methanesulfonamidoylmethyloxy-7-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide; 9-benzyl-4-methanesulfonamidoylmethyloxy-cakbazole-5- carboxamide; [5-carbamoyl-2-pentyl-9-(phenylmethyl)carbazol-4-yl]oxyacetic acid; [5-carbamoyl-2-(1-methylethyl)-9-(phenylmethyl)carbazol-4-yl]oxyacetic acid; [5-carbamoyl-9-(phenylmethyl)-2-Prie1- methylethyllsilyOoxymethyllcarbazolyloxyacetic acid; [5-carbamoyl-2-phenyl-9-(phenylmethyl)earbazo1-4-yi]oxyacetic acid; [5-carbamoyl-2-(4-chlorophenyl)-9-(phenylmethypcarbazol-4-ylioxyacetic acid; [5-carbamoyl-2-(2-furyI)-9-(phenylmethyOcarbazol-4-yl]oxyacetic acid; [5-carbamoyl-9-(phenylmethyl)-2-[(trie1 -methylethyLTsilyOoxymethyllcarbazol-ylioxyacetic acid; {9-R3-fluorophenyllmethyli-5-carbamoylcalbazol-4-ylloxyacetic acid; [9-R3-chlorophenyl)methylj-5- carbamoylcarbazol-4-ylloxyacetic acid; {9-[(3-phelioxyphenyl)metliyl]-5- carbamoylcarba.zol-4-yl}oxyacetic acid; { 9-R2-Fluorophenypinethyli-5-carbamoylcarbazol-4- yelloxyacetic acid; {942-trifluoromethylphenyllinedryl]-5-carbamoylcarbazol-4-yl}oxyacetic acid; f9-R2-benzylphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid; {9- [ (3 -trinuoromethylpharyOmethyli-5-carbamoylcarbazol-4-ylloxyacetic acid; 9-R1 -naphthyhmethyl1-13-carbamoylcarbazol-ylIoxyacetic acid; {9-[(2-cyanophenyi)methyl]-5-carbamoylcarbazol-4-ylloxyacetic acid; {9-R3-cyanopherwl)methyl1-5-carbamoylcarbazol-4-ylloxyacetic acid; {9-R2-methylphenypimethyl]-5-calbannoyicarbazol-4-yll oxyacetic acid; {9-[(3-methylphenl)methyl]-5-carbannoylcarbazol-4-yllox.sub.7acetic acid; {9-[(3,5-dimethylphenyl)methyl]-5-carbannoylcarbazol-4-ylloxyacetic acid; f9-[(3- iodophenyOmethyl]-5-carbannoylearbazol-4-ylloxyacetic acid; {9-[(2-Chiorophenypmethyl]-5-carbaimoyicarbazol-4-ylloxyacetic acid; t9-[(2,3-difluorophenyDthyI]-5 -carbaimoylcaibazol-4-yll oxyacetic acid; {9-[(2,6- difluorophenyl)methyl]-5-carbannoylcarbazo1-4-ylloxyacetic acid; {942,6-dichlorophenyl)methyl]-5-carbaimoylcalbazol-4- ylioxyacetic acid; f9-R3-trifluoromethoxphenyllnnethyl]-5-carbannoyicarbazol-4-ylIoxyacetic acid; {9-R2-biphenyl)methylj-5-carbannoylcarbazo1-4-ylf oxyacetic acid; {9-[(2-Hiphenyl)methyl]-5-carbamoylcarbazol-4-ylloxyacetic acid methylester; [9-Benzyl-4-carbamoyl-1 .2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid; f9-[(.sup.-2-Pyridypinethyl]-5-carbamoylcarbazol-4-y1}oxyacetic acid; f9-R3-Pyridypimethyli-5-carbannoylcarbazol-4-ylloxyacetic acid; [9-benzyl-4-carbamoyl-8-tmethyl-12,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid; [9-benzyl-5-carbamoyl-1 -methylcarbazol-4-qoxyacetic acid; [8-benzyl-carbamoyl-δ-fluoro-1,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid; [0-benzyl-5-carbannoyl-i -fluorocarbazol- 4-yl]oxyacetic acid; [9-benzyl-4-carbamoyl-8-thloro-1 ,2,3,4-tetrahydrocarbazol-5- yl]oxyacetic acid; [9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl],oxyacetic acid; [9-[(Cyclohexypmethyl]-5-carbamoylcarbazol-4-yl]oxyacetic acid; [9-[(Cyclopentyl)methyl]-5-carbamoylcarbazol4-ylloxyacetic acid; [5-carbamoyl-9-(plienylmethyl)-2-(2- thienylcarbazol-4-yl]oxyacetic acid; [5-carbamoyl-9-(phenyhmethyl)-2-[[Qropen-3- ypoxy]methyl]carbazol-4-.sub.311oxyacetic acid; [5-carbamoyl-9-(plienyhmethyl)-2-[(propyloxyjniethylIcarbazol-ylioxyacetic acid; 9-benzyl-7-methoxy-5-((carboxamidomethyloxy-tetrahydrocarbazole-carboxamide; 9-benzyl-7-methoxy-8-cyanomethyloxy-carbazole-carboxamide; 9-benzyl-7-methoxy-5-((1 H- tetrazo1-5-yl-methyl)oxy)-carbazole-4-carboxamide; 9-benzyl.-7-methoxy-5-((carboxamidomethyl)oxy)-carbazole-4-cathoxamide; [9-Benzyl-4-carbamoyl-1,2,3,4- tetrahydrocarbazole-5-yl]oxyacetic acid; (R,S)-(9-benzyl-4-carbamoyl-1-oxo-3-thia- 1 ,2,3,4-tetrahydrocarbazol-5-ypoxyacetic acid; (R,S)-(9-benzyl-4-carbamoyl-3-thia- 1 ,2,3,4-tetrahydmcafbazol-5-y0oxyacetic acid; 2-(4-oxo-5-carboxamido-9-benzyl-9/-/- pyrido[3,4-ib]indolyl)acetic acid chloride; [N-benzyl-1 -carbamoyl-1-aza-1 tetrahydrocafbazol-8-yoxyacetic acid; 4-methoxy-6-methoxycarbonyl-10-phenylmethyl-6.7,8,9-tetrahydropyrido[i2-a]indole; (+carboxamido-9-phenyhnethyl-4,5-dihydrothiopyrano[3J-b]indol-5-yl)oxyacetic acid; 3,4-dihydro-4-carboxamido1-5- methoxy-9-phenylmetliylpyrano[3,4-ib]indole; 2-[(2,9 bis-benzyl-4-carbamoyl-i tetrahydro-betacarbolin-5-ypoxy]acetic acid; 244-oxo-5-carbox.amido-9-(2-methythenzyl)-9/-/-pyrido[3,4-ib]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(3-methylbenzyl)-91-1-pyrido[3,4-ib]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(4-methylbenzyl)-91-1-pyrido[3,4-ib]indolyl]acetic acid; 2-[4-oxo-5-carboxamide-9-(4-tert-butylbenzyl)-9/4-pyrido[3,4-ib]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9- pentafluorobenzyl-91-/-pyrido[3,4-ib]indolyl]acetic acid; 2-[4--oxo-5-carboxamido-9-(2-fluorobenzyl)-9/-1-pyrido[3,4-ib]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(3-fluorobenzyl)-91-1-pyrido[3,4-ib]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(4-fluorobenzy0-9/-/-pylido[3,.4-ib]indolyl]acetic acid; 244-oxo-5-calboxamido-9-(2,6- difluorobenzyl)-91-1-pyrido[3,4-ib]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9(3,4-difluorobenzyl)-9/-/-pylido[3,.4-ib]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9(2,5-difluorobenzyl)-9/-/-pylido[3,.4-jb]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(3,5-difluorobenzyD-9/-/-py7rdo[3,4-ib]indolyliacetic acid; 2-[4-oxo-5-carboxamido-9-(2,4-difittombenzyl)-9/-/-pyrido[3,4-ib]indolyflacetic acid; 2-[4-oxo-5-carboxamido-9-(2,3- ditimorobenzyl)-9/-/-pylido[3,4-ib]indolyl]acetic acid; 244-oxo-:5-carboxamido-942- arifluoromethyljbellzyl1-9/-l-pyrido[3,4-ib]indolyflacetic acid; 2-[4-oxo-5-carboxamido-9-[2-(trifitioromethyl)benzyl]-9/-/-pylido[3,4-ib]indolyflacetic acid; 2-[4-oxo-5-carboxamido- 9-[3-(trifitioromethyl)benzyl]-9/-/-prido[3,4-iNindolyliacetic acid; 2-[4-oxo-5- carboxamido-9-[4-(trifluommethyDbenzyl1-91-/-pyrido[3,4-ib]indolyflacetic acid; 2-[4-oxo- 5-carboxamido-9-[3,5-bis(trifitioromethyDbenzyli-91-1-pyrido[3,4-ib]indolyllacetic acid; 2-[4-oxo-5-carboxamido-942,4-bis(trifittoroinethyDbenzyl]-9/-/-p.sup.-yrido[3,4-ib]indolyl]acetic acid; 2-[4-oxo-5-carboxamido-9-(a-methylnaphthyl)-9/-I-pyrido[3,4-ib]indolyflacetic acid; 244-oxo-5-carboxamido-9-(b-methylnaphthyl)-91-/-mTrido[3,4-ib]indolAacetic acid; 2-[4- oxo-5-carboxamido-9-(3,5-dimethylbenzyl)-9/-1-pyrido[3,4-iNiiidolyliacetic acid; 2-[4-oxo- 5-carboxamido-9-(2,4-dimethylbenzyl)-9/-/-pyrido[3,4-iNiiidolyliacetic acid; 2-[4-oxo-5- carboxamido-9-(2-plienyiberizyl)-9/-1-pyrido[3,4-lb] indolyflacetic acid; 2-[4-oxo-5- carboxamido-9-(3-phenylbenzyl)-9/-1-pyrido[3,4-iNindolyliacetic acid; 2-[4-oxo-5- carboxamido-944-phenylbenzy0-9/-/-pyrido[3,4-ib]indolyflacetic acid; 2-[4-oxo-5- carboxamido-9-(1 -fluorenyhnetlyy)-97-/-pyrido[3,4- iNiiidolyliacetic acid; 2-[4-oxo-5- carboxamido-9-(2-fluoro-3-methylbenzyl)-9/-/-pyrido[3,4-ib]indolyflacetic acid; 2-[4-oxo-5- carboxamido-9-(3-benzoylbenzyl)-9/-1-pyrido[3,4-iNindolyliacetic acid; 2-[4-oxo-5- carboxamido-9-(2-phenoxyberizyl)-9/4-pyrido[3,4-ib]indolyflacetic acid; 2-[4-oxo-5- carboxamido-9-(3-phenoxybenzyl)-9/-i-pyrido[3,4-iNiiidolyliacetic acid; 2-[4-oxo-5- carboxamido-9-(4-plienoxybenzy0-9/-/-pyrido[3,4-iNiiidolyliacetic acid; 2-[4-oxo-5- carboxannido-94342-(fitioroplienoxy)benzylfl-9/-1-pyzdo[3,4-ib]indolyl]acetic acid; 2-[4- oxo-5-carboxamido-9-[3[4-ftluorophenox yibenzyli]-91-/-pyrido[3,4-iNindolyl]acetic acid; 244-oxo-5-carboxamido-9-[2-fluoro-3-(trifitioromethyObenzyli-91-1-pyndo[3,4- £>]indolyl]acetic acid; 244-oxo-5-carboxamido-9-[2-thoro-4-(trifluoromethyDbenzyl]-91-pyrido[3,4-iNindolyflacetic acid; 244-oxo-5-carboxamido-942-fitioro-5- (trifluoromethyrbenzyli-9H-pyrido[3,4-tb]indolyflacetic acid; 244-oxo-5-carboxamido-9- [3-fluoro-5-(trifluoromethyljbellzyl]-9/-1-pyrido[3,4-iNifidolyl]acetic acid; 2-[4-oxo-5- carboxamido-944-fluoro-2-(trifluoromethyl)benzyl]-9i-l-pyrido[3,4- ib]indolyflacetic acid; 2- [4-oxo-5-carboxamido-944-fluoro-3-(trifitioromethyObemyli-91-1-pyrido[3,4-it]indolyflacetic acid; 2-[4-oxo-5-carboxamido-942-fitioro-6-(trifluororinethyDbenzyll-9/-/- pyrido[3,44b]indolyl]acetic acid; 214-oxo-5-carboxamido-9-(2,3,6-trifluorobenzyl)-9/-1- pyrido[3,4-ib]indolyflacetic acid; 214-oxo-5-carboxamido-9-(2,3,5-trifluorobenzyl)-91-1- pyrido[3,4-th]indolyliacetic acid; 2-[4-oxo-5-carboxamido-9-(2,4,5-tritimorobenzy0-9/-/- pyrido[3,4-iNindolyllacetic acid; 214-oxo-5-carboxamido-9-(2,4,6-tritimorobenzyl)-9/-/- pyrido [3,4-tb]int dolyllacetic acid; 214-oxo-5-carboxamido-9-(2,3,4-trilluoroberizyp-9/-/- pyrido[3,4-ib]indolyl]acetic acid; 214-oxo-5-carboxamido-9-(3,4,5-trifitiorobenzyl)-9/-/- pyrido[3,4-iNindolyljacetic acid; 214-oxo-5-carboxamido-913-(trifluommetlioxyDbenzyli-9/-1-pyrido[3,4-ib]indolyliacetic acid; 2-[4-oxo-5-carboxaniido-9-[4-(trifluoromethoxyl)benzyl]-9/-/-pylido[3,4-iNindolyilacetic acid; 214-oxo-5-carboxamido-9-[4-methoxy(tetraflitom)benzyl]-9/-1-pyrido[3,4-it]indolyliacetic acid; 214-oxo-5-carboxamido-942- imethoxybeilzyl)-9/4-pyrido[3,4-iNindolyliacetic acid; 214-oxo-5-carboxamido-9-(3-nnethoxybellzyl)-91-/-pyrido[3,4-ib]indolyllacetic acid; 2-[4-oxo-5-carboxamido-9-(4-nnethoxybellzyl)-91-/-pyrido[3,4-ib]indolyllacetic acid; 2-[4-oxo-5-carboxamido-9-(4-ethylbenzy0-91-/-prudo[3,4-iNindolyliacetic acid; 2-[4-oxo-5- carboxamido-9-(4- isopropylbenzyl)-91-/-pyrido[3,4-iNindolyliacetic acid; 2-[4-oxo-5- carboxamido-9-(3,4,5-trinnethoxyberizyl)-9/-1-pyrido[3,4- iNiudolyllacetic acid; 2-[4-oxo-5- carboxamido-9-(3,4-nnethylenedioxybenzyl)-91-1-pyrido[3,4-iNindolyliacetic acid; 2-[4- oxo-5-carboxamido-9-(4-imethoxy-3-miethylbenzyl)-9/-1-pymdo[3,4-iNindolyilacetic acid; 2- [4-oxo-5-carboxamido-9-(3,5-dintiethoxybenzyl)-9/-1-pyRdo[3,4-ib]indolyila.cetic acid; 214- oxo-5-carboxainido-9-(2,5-dimethoxybenzyl)-9/-1-pyado[3,4-ib]indolyliacetic acid; 214- oxo-5-carboxamido-9-(4-ethoxybenzyl)-91-1-pyrido[3.,4-it]indoiyi]acetic acid; 2-[4-oxo-5- carboxamido-9- (cycloliexylimethyl)-9/-1-pyrido[3,4-ib]indolyliacetic acid; 2-[4-oxo-5-carboxamido-9-(cyclopentylimethyp-914-pyrido[3,4-ib]indolyljacetic acid; 2-[4-oxo-5- carboxamido-9-ethyl-9/-pyrido[3,4-ib]iiidolyl]acetic acid; 214-oxo-5-carboxamido-9-(1 - propyl)-91-/-pyrido[34-ib]indolyl]acetic acid; 214-oxo-5-carboxamido.-942-propyl)-91-/- pyrido[3,4-iNindolyllacetic acid; 214-oxo-5-carboxamido-9-(1 -butyl)-9}1-pyrido[3,4-]indolyl]acetic acid; 214-oxo-5-carboxamido-9-(2-butyl)-91-/- pyrido[3,4-iNindolyllacetic acid; 214-oxo-5-carboxamido-9-isobutyl-91-1-pyrido[3,4-ib]indolyliacetic acid; 2-[4-oxo-5- carboxamido-912-(1 -pliellyietliyi)]-9/-1-pyTido[3,4-th]indolyllacetic acid; 2-[4-oxo-5- cafboxamido-9-[3-(1 -phenylpropyl)]-9/-/-pyrido[3,4-ib]indolyliacetic acid; 2-[4-oxo-5- carbox.amido-9[4-(1 -phenyibutyl)]-91-/-pyrido[3,4-ib]indolyl]acetic acid; 2-[4-oxo-5- carboxamido-9-(1 .-perity0-91-/-pyrido[3,4-tblindolyi]acetic acid; 2-[4-oxo-5-carboxamido-9- (1 -hexyl)-91-/-pyrido[3,4-ib]indolvliacetic acid; 4-[(9-benzyl-4-carbamoyl-1 ,23,4-tetrahydrocarbazol-6-ypoxylbutyric acid; 31(9-benzyl-4-carbamoyl-1 ,2,3,4- tetrahydrocarbazol-0-y0oxylpropylphosphonic acid; 21(9-benzyl-4-carbamoyl-1 ,2,3,4-tetrahydrocarbazol-6-yDoxylmethylbenzoic acid; 31(9-benzyl-4-carbamoyl-7-n-octyl-1,234-tetrahydrocarbazol-6-ypoxylpropylphosphonic acid; 41(9-benzyl-4-carbamoyl-7-ethyl-1,2,3,4-tetrahydrocarbazol-6-yDoxylbutvric acid; 31(9-benzyl-4-carbamoyl-7-ethyl-1,2,34-tetrahydrocarbazol-6-yl)oxy]propylphosphonic acid; 3-[(9-benzyl-4-carbamoyl-ethyl-1 2,3,4-tetrahydrocarbazol-6-yDoxylpropylphosphonic acid; (S)-(±)-4-[(9-benzyl-4carbamoyl-7-ethyl-1 ,2,3,4-tetrahydrocarbazol-6-ypoxy]butyric acid; 4-[9-benzyl-4- carbamoyl-6-(2-cyaimethyl)-1,2,3,4-tetrahydrocarbazol-6-Aoxybutyric acid; 4-[9-benzyl-4-carboxamido-7-(2-phenylethyl)-1,2,3,4-tetrahydrocarbazol-6-yl]oxybutyric acid; 449-benzyl-4-carboxamidocarbazol-6-yl]oxybutyric acid; methyl 21(9-benzyl-4-carbamoyl- 1,2,3,4-tetrahydrocarbazol-6-yDoxy methylbenzoate; 4[9-benzyl-4-carbamoyl-7-(2- cyanoethyl)-1 ,23,4-tetrahydrocalbazol-6-ylloxybutyric acid; 9-benzyl-7-methoxy-5- cyanomethyloxy-tetraliyd:rocarbazole-carboxamide; [9-benzyl-4-carbamoyl-8-methyl-carbazole-5-yl]oxyacetic acid; and [9-benzyM-carbamoyl-carbazole-6-yl]oxyacetic acid, or pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof
[0143] Direct and indirect PLA.sub.2 inhibitors also include N,N-dimethylcarbamovhnethyl,4-4-guanidinobenzoyloxy-phenylacetate (Camostat, cainostate) or ethyl-p[6-guanidinohexanoyloxy]-benzoate methansulfonate (gahexate) and leukotriene synthesis inhibitor selected from the group consisting of methyl arachidonyl fluorophosphonate (MAFP), pyrrox)phene, ONO-RS-082, 1- [3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid, 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-6-carboxylic acid, arachidonyl trifluoromethyl ketone. D609, 4-{315-chloro-2-(2-f([(3,4-dichlorobelizypsulfonyl]amino] ethyl)-1-(diplienyhnethyl)-111-indol- 3-yl]propyllbelizoic acid (WAY-196025), efipladib, 4-.sup.1,215-chloro-2-(2-{[(3,4dichlorobenzypsulfonyl]aminomethyl)-1-(diphenylmethyl)-1H-indol-3-yllethoxy}benzoic acid, Ecopladib. (E)-N-[(2S,4R)-4-[N-(biphenyl-2-ylmethyl)-N-2-methylpropylamino]-1-[2-(2,-4difluorobenzoybbenzoyl]pyrrolidin-2-yl]methyl-3-[4-(2,4-dioxothiazolidi n-5-ylidenemethyl) plienyl]acrylamide (RSC-3388), berberine, glutamine, darapladib or a pharmaceutically acceptable salt thereof.
[0144] “Metalloprotease inhibitors” include, but are not limited to, prinomastat. BB-94 (marimastat), BB-2516 (batimastat), vorinostat, cefixime and doxycycline. Other metalloprotease inhbitors that may be used in the invention include but are not limited to, TAPI-2, TAPI-1, EGTA, EDTA, phosphoramadon, TSPI-0, Luteolin, alendronate, tanomastat, ilomastat, prinomastat, nafamostat, collagenase inhibitor 1, Ro-32-3555, lactobionic acid, o-phenantroline, ecotin, 4-epi-chlortetracycline, teracyclMe, doxycycline or related antibiotic with additional, salutary antimicrobial effect, n-dansyl-d-phenylalanine, 20[R]ginsenosideRh2, pro-leu-gly-hydmxymate, gm6001, actinonin, arp-100, MMP9 inhibitor I, MMP2 inhibitor I, SB-3CT, Thiorphan (DL), 4-epi-demeclocycline, zinc methacrylate, funalenone, and their analogs, derivatives, pharmaceutically acceptable salts, enantiomers, diastereomers solvates and polymorphs and mixtures thereof.
[0145] Unexpectedly, use of at least one PLA2 inhibitor and/or a metalloprotease inhibitor as described herein in combination with one or more antibiotics as described herein has been found to be particularly effective to ameliorate, inhibit and/or reduce the likelihood of an injured patient or subject at risk of becoming infected or who has become infected such that the infection will produce one or more of sepsis, septic shock, an acute inflammatory syndrome such as systemic inflammatory response syndrome (SIRS) and/or acute respiratory distress syndrome (ARDS).
[0146] The term ”neo-natal ARDS” is used to describe a common clinical critical disease and is one of the main causes of death and disability in neonates. The etiology and pathogenesis of neonatal ARDS are complicated. It is an acute pulmonary inflammatory disease caused by the lack of pulmonary surfactant (PS) related to various pathological factors. It is often difficult to distinguish neonatal ARDS from other diseases. Prior to the present invention, there was no specific treatment method for this disease, although respiratory support, PS replacement, extracorporeal membrane oxygenation, nutrition support and liquid management are main treatment strategies. The term “meconium aspiration syndrome” or MAS is a life-threatening type of neonatal ARDS with high rates of mortality and no approved treatments, meconium aspiration syndrome (MAS) is known to damage surfactant. It is known that surfactant function is damaged and correlates with lung aeration and as consequence of these changes, surfactant nanostructure is also damaged. Meconium is the first feces, or stool, of the newborn. meconium aspiration syndrome occurs when a newborn breathes a mixture of meconium and amniotic fluid into the lungs around the time of delivery. meconium aspiration syndrome, a leading cause of severe illness and death in the newborn, occurs in about 5 percent to 10 percent of births. It typically occurs when the fetus is stressed during labor, especially when the infant is past its due date. Until the present invention, there was no known effective therapeutic method for meconium aspiration syndrome or MAS.
[0147] Pharmaceutical compositions comprising combinations of an effective amount of an antibiotic as disclosed herein, often according to the present invention including one or additional PLA2 inhibitor anclior metalloprotease inhibitor as otherwise described herein, all in effective amounts, in combination with a pharmaceutically effective amount of a carrier, additive or excipient, represent a. further aspect of the present invention. These may be used in combination with at least one additional, optional bioactive agent, especially agents which can be used to address additional symptoms of the patient or subject to be treated.
[0148] The compositions of the present invention may be formulated in a conventional marnrner using one or more pharmaceutically acceptable carriers and may also be administered in controlled-release formulations. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts of electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilica.te, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[0149] The compositions of the present invention may be administered orally, intratracheally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, among others. The temi “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally (including via intubation through the mouth or nose into the stomach), intraperitoneally or intravenously.
[0150] Sterile injectable forms of the compositions of this invention may be aqueous, a stabilized liquid or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol.
[0151] The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating, agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
[0152] Alternatively, the phamiaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient Which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
[0153] The pharmaceutical compositions of this invention may also be administered topically,. especially to treat skin bacterial infections or other diseases which occur in or on the skin. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a. suitable enema formulation. Topically-acceptable transdermal patches may also be used.
[0154] For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers or administered by microneedle patch. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, wliite petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
[0155] Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol. 2-octyldodecanol, benzyl alcohol and water.
[0156] For ophthalmic use, the pharmaceutical compositions may be fornmlated a.s micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
[0157] The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, .absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional soluhilizing or dispersing agents.
[0158] The amount of compound in a pharmaceutical composition of the instant invention that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host and disease treated, the particular mode of administration. Preferably, the compositions should be formulated to contain between about 0.05 milligram to about 750 milligrams or more, more preferably about 1 milligram to about 600 milligrams, and even more preferably about 10 milligrams to about 500 milligrams of active ingredient, alone or in combination with at least one additional compound which may be used to treat a pathogen, especially a bacterial (often a gram-negative bacterial) infection or a. secondary effect or condition thereof.
[0159] Methods of treating patients or subjects in need for a particular disease state or condition as otherwise described herein, especially a pathogen, especially a bacterial infection, ire particular, a gram-negative bacterial infection, comprise administration of an effective amount of a pharmaceutical composition comprising therapeutic amounts of one or more of the novel. compounds described herein and optionally at least one additional bioactive (e.g. additional antibiotic) agent according to the present invention. The amount of active ingredient(s) used in the methods of treatment of the instant invention that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. For example, the compositions could be formulated so that a therapeutically effective dose of between about 0.01. 0.1. 1, 5, 10, 15, 20, 25, 30 , 35.40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 100 mg/kg of patient/day or in some embodiments, greater than 100, 110, 120, 130. 140, 150. 160, 170, 180, 190 or 200 250 mg/kg of the novel compounds can be administered to a patient receiving these compositions.
[0160] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a. variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or condition being treated.
[0161] A patient or subject (e.g. a human) suftering from a bacterial infection can be treated by administering to the patient (subject) an effective amount of a compound according to the present invention including pharmaceutically acceptable salts, solvates or polymorphs, thereof optionally in a pharmaceutically acceptable carrier or diluent, either alone, or in combination with other known antibiotic or pharmaceutical agents, preferably agents which can assist in treating the bacterial infection or ameliorate the secondary effects and conditions associated with the infection. This treatment can also be administered in conjunction with other conventional therapies known in the art.
[0162] The present compounds, alone or in combination with other agents as described herein, can be administered by any appropriate route, for example, orally, parenterally, intravenously, intra.derinally, subcutaneously, or topically, in liquid, cream, gel, or solid form, or by aerosol form.
[0163] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication, without causing serious toxic effects in the patient treated. A preferred dose of the active compound for all of the herein-mentioned conditions is in the range from about 10 ng/'kg to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipientlpatient per day. A typical topical dosage will range from about 0.01-3% wt/wt in a suitable carrier.
[0164] The compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing less than ling, 1 in to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form. An oral dosage of about 25-250 mg is often convenient.
[0165] The active ingredient is preferably administered to achieve peak plasma concentrations of the active compound of about 0.00001-30 mM, preferably about 0.1-30 μM. This may be achieved, for example, by the intravenous injection of a solution or formulation of the active ingredient, optionally in saline, or an aqueous medium or administered as a bolus of the active ingredient. Oral administration is also appropriate to generate effective plasma concentrations of active agent.
[0166] The concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering of supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
[0167] Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
[0168] The tablets, pills, capsules, troches, sachets and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a dispersing agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit fora is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents.
[0169] The active compound or pharmaceutically acceptable salt thereof can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
[0170] The active compound or pharmaceutically acceptable salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as other anticancer agents, antibiotics, antifimgals, anti-inflammatories, or antiviral compounds. In certain preferred aspects of the invention, one or more chimeric antibody-recruiting compound according to the present invention is co-administered with another anticancer agent andlor another bioactive agent, as otherwise described herein.
[0171] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution,. fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens: antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
[0172] If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).
[0173] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled and/or sustained release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
[0174] Liposomal suspensions or cholestosonies may also he pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound are then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
EXAMPLES
[0175] Unbekalownst to the investigators, juvenile pigs in a herd shipped for research were not prophylaxed for Streptococcus suis (S. suis) a bacterium that is lethal to pigs and can also cause lethality in humans when exposed to sick of colonized animals. One juvenile pig (Sus domesticus) became weak after becoming febrile 12 hours after major resuscitation and was euthanized. The pathologist noted an unusually high bacterial load immediately, which was visibly apparent on microscopy. Tissues and catheter tip were cultured, confirming S. suis infection. The medication itself was cultured and no bacterial contamination was detected. A second juvenile pig which was being treated with LY315920 alone and a single antibiotic dose given to the surviving members of the heard for experimental envenoming survived for >100 hours until euthanized as scheduled at the end of the study period with an non-curative dose of antibiotics. On autopsy it was noted that the pig had significant evidence of S. suis infection, but the animal had only received antibiotics following realization that a first animal had died of septicemia rather than as a result of experimental envenoming, by taipan venom.
Further Examples: Viruses and Bacteria Including COVID-19 and Anthrax
[0176] In severe cases of infection such as those caused by coronaviruses (e.g. SARS, MERS, COVID-19. bacteria such as anthrax, fungi, or co- and secondary infections), the immune system may overreact and start attacking lung cells, neural tissues with accompanying or preceding endothelial damage all resulting in maladaptive elevations of MP and sPLA2 activity as well as other inflammatory species of phospholipase and cytokines. The lungs become obstructed with fluid and dying cells, making it difficult to breathe, neurological complications occur and a substantial percentage of infections can lead to ARDS and death (such as seen with severe coronavirus syndromes such as SARS, MERS and COVID-19 or influenza with or without secondary bacterial pneumonias).
[0177] Coronaviruses SARS-CoV and MERS-CoV have, for example, age dependent mortality that has been linked to sPLA2 that was as high as 6% in the 25-44 age group and 15% in the 45-64 year-old age and up to more than 50% case fatality rates in older age groups..sup.1 The inventors have unexpectedly realized that early administration of these drugs alone or in combination would abort and/or substantially inhibit the sPLA2 and metalloprotease elevations that heralding severe outcomes resulting from acute pulmonary inflammation and cellular injury that can result in long-term pulmonary compromise in survivors. When possible, sPLA2 and MP inhibitors should be administered orally before infection or resulting inflaimnatoiy, pulmonary, vascular, neurological and renal sequelae become severe. The following examples are relevant to this analysis.
Example 1
[0178] A healthcare worker or field workers encounter a patients with an undefined respiratory illness or newly identified outbreak of a high fatality rate coronavirus or anthrax bacterium in the out of hospital or in hospital setting and suspect an infectious agent. Because of the high-risk occupational environment and risk of transmission from patient to health care worker, an orally bioavailable MP and/or PLA2 inhibitor is administered with or without an antiviral with or without a metalloprotease-suppressing antibiotic medication such as azithromycin (antibiotic) for prophylaxis or to abrogate early symptoms or signs of infection heralding more life-threatening consequences of virally-induced inflammatory responses. Therapy could be instituted prior to onset of severe signs or symptoms or prophylactically resulting in less severe consequences of infection, avoiding intensive care and ventilatory support. This patient or healthcare can be maintained on entirely oral medications for the duration of disease or high risk occupationalibigh risk contact exposure.
Example 2
[0179] A patient has a virally- or bacterially-mediated inflammatory response requiring intravenous medications and intensive care. The patient might or might not have ARDS, neurological sequelae but is sufficiently ill that intravenous infusion of medications are required. Intravenous infusions of an MP andior PLA2 inhibitor decrease the acuity and dependence on intensive resources because of the suppression of maladaptive MP and/or PLA2-related inflammatory and cytotoxic responses. Once stabilized, this patient can be transitioned to an oral formulation of a MP andlor PLA2 inhibitor, reducing risk of relapse and long-ter i pulmonary, vascular or neurological damage.
[0180] Example 3 Systematic study of forty-one cases of documented inhalational anthrax from the Sverdlovsk epidemic of 1979 traced to release of aerosols of Bacillus anthracis were carried out. Respiratory function was compromised by mediastinal expansion, large pleural effusions, and hematogenous and retrograde lymphatic vessel spread of B. anthracis to the lung with consequent pneumonia. These pathologic findings are consistent with previous experimental studies showing transport of inhaled spores to mediastinal lymph nodes, where germination and growth lead to local lesions and systemic spread, with resulting edema and cell death, owing to the effects of edema toxin and lethal toxin. An inhaled, intratracheally applied, IV or oral combination or single agent approach using MP or sPLA2 inhibitors is both prophylactic and therapeutic in human and non-human species. Vero (African green monkey) cell culture exposed to toxic metalloproteases “zincins” and related toxin metalloproteases and phospholipases demonstrates the efficacy of sPLA2 and metalloprotease inhibition to protect cell junction. integrity.
Further Examples
Methods
[0181] Mouse Studies: C57BL/6 mice weighing approximately 20 grams were anesthetized using propylene glycol/isoflurane with standard nose-cone procedure. Protection study: Controls (
[0182] Histology and Interpretation: After 24 or 48 hours, mice were euthanized under deep anesthesia using propylene glycol/isoflurane followed by cervical dislocation and rapid dissection of hmgs and kidneys. The lungs inflated with 10% neutral buffered formalin and the kidney placed directly into 10% neutral buffered fonnalin after nicking the capsule. Tissues were sent to IDEXX Laboratories for mounting and staining with hematoxylin and eosin. Microscopic examination of stained lung sections was conducted and scores were assigned to each section of lung based upon ATS criteria as described by Aeffher et al. Tox Path, 43:1074-1092, 2015. A minimum of 25 high power fields were examined by orienting the slide ID tag to the left of the left lung and alternating fields using the fine control outside the atelectatic tissues. Statistics: Scores were averaged and Students t-test applied (two tails, type 2, p<0.05 considered significant).
[0183] Enzymatic Assays: Viper, elapid and colubrid venom MP enzymatic activities were optimized Experiments to determine MP activity used validated substrate for MP (DQ Gelatin) and assay run per EnzCliek gelatinase assay manufacturer's instructions. These kits were stored as specified if stored at −20°C. PBS is the buffer in the case of MP assays, and absorbance is measured at 495 nm. Substrate for MP is DQ Gelatin and the assay is run per EnzChek gelatinase assay manufacturer's instructions. Dose response curves were constructed by comparing Asorbance with different doses of serially diluted inhibitors and compared to controls to determine the IC.sub.50 for each venom-drug pair and for direct comparison of drugs for their effect on MP activity for each venom (
Cell Culture and Electric Cell-Substrate Impedance Sensing (ECIS) Studies
[0184]
[0185] The ECIS-Zθ is an in vitro system that monitors real-time cellular behaviors and movements via gold film electrodes. cell membranes essentially act as insulators. Consequently current flows unrestrained in the absence of cells and constrained once a cell monolayer is established. Changes in the current flow are measured as impedance (Z), which gives insight into two aspects of cellular behaviors and movements at different frequencies. At low frequencies (<10,000 Hz), the cell bodies force the current to flow ba.solaterally or through the intercellular space between the cell borders. Therefore, resistance (R) is measured at low frequencies and provides information on the barrier integrity. Conversely, the opposition created by the cell membrane is relatively small at high frequencies (>10,000 Hz), so current flows capacitively through the cell bodies. Capacitance (C) is a measure of the electrode coverage by the cells and is indicative of cell migration, as well as cell monolayer disruption following injuries. ECIS can also produce reproducible wounding, models by mechanically disrupting a cell monolayer. The ECIS set up can be used to wound a cell monolayer using high current pulse produced via the electrodes. The severity of injury is dependent on the level of current and the duration of the application. The injured or dead cells then detach from the electrode surfice whiCh is measured as a rapid increase in the electrode capacitance and a reduction in the resistance. The system then returns to its normal operation and monitors the subsequent recovery as neighboring cells migrate to fill the exposed electrode and re-establish a cell monolayer, see Gu, et al., Biosensors, (Basel), 2018, Oct. 11, 8(4). 90.
[0186] Methods and compositions for achieving accelerated treatment of wounds and burns, anthrax metalloprotease toxin (lethal factor) driven complications, ARDS, neo-natal and pediatric acute respiratory distress syndrome (neo-natal/pediatric ARDS), including meconium aspiration syndrome are described based on the experimentals described herein above. Thus, the experimentals described above evidence the following observations,. among others: [0187] 1. Oral prinomastat alone unexpectedly outperformed all inhibitors to treat LPS-Oleic Acid induced ARDS but there were additional benefits from combinations of sPLA2 and metalloprotease inhibition; [0188] 2. Locally (respiratory tract) applied of AZD2716 alone prevented and rescued young (˜19-20 g) mice from LPS-Oleic Acid induced ARDS, most notably from pulmonary edema. This has significant implications for treatment of neonatal and pediatric ARDS. [0189] 3. Low dose Prinomastat+varespladib potentiated both rescue of cultured tissue and accelerated wound healing of experimentally injured tissues in cell culture.
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