Lipase inhibitor compositions and methods for treating diseases

Abstract

The present invention relates to methods and materials for treating diseases, disorders, and / or conditions associated with elevate lipase levels and / or activity. Diseases, disorders, and / or conditions can be selected from intestinal obstruction, spontaneous bacterial peritonitis, or cirrhosis, and / or one or more diseases, disorders, and / or conditions worsened by a pancreatic injury in a mammal (e.g., a human). For example, methods for using one or more lipase inhibitors to treat a mammal having or at risk of developing intestinal obstruction are provided.

Description

LIPASE INHIBITOR COMPOSITIONS AND METHODS FOR TREATING DISEASESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Serial No. 63 / 570,583, filed on March 27, 2024, the contents of which are incorporated by reference in their entirety.TECHNICAL FIELD

[0002] The present invention relates to lipase inhibitor compositions and methods for treating diseases, disorders, and conditions in a mammal (e.g., a human) and for treating a mammal having or at risk of developing one or more diseases, disorders, and / or conditions associated with elevated lipase level s / activity.BACKGROUND INFORMATION

[0003] The burden and cost of chronic illnesses, including gastrointestinal, liver, and pancreatic diseases places a heavy burden on the hospital system and are contributing causes of death. Post-operative adhesions occur with high frequency after digestive surgery, including 93-100% of upper abdominal laparotomies and 67-93% of lower abdominal laparotomies, and are responsible for significant morbidity. M. Ouaissi, J. of Visceral Surgery, 149:2 April 2012, el04-114. Additional treatments, including reduction in severity and morbidity of diseases are needed.SUMMARY

[0004] Provided herein are lipase inhibitor compositions and methods for using the same to treat one or more diseases, disorders, and / or conditions in a mammal (e.g., a human).

[0005] The methods provided herein are based, at least in part, on the discoveries that inhibition of lipase activity is able to reduce indices associated with diseases or disorders associated with elevated lipase level s / activity, including conditions worsened by pancreatic injury, as well as other conditions such as heart failure, cirrhosis, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcoholuse disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, cirrhosis, cirrhosis complications (e.g., hepatorenal syndrome,) abdominal adhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, obesity-related dyslipidemia, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), polycystic ovary syndrome (PCOS) with obesity and insulin resistance, neurodegenerative disease, and intestinal obstruction. In some embodiments, the conditions worsened by pancreatic injury may comprise bums, cardiac arrest, cardiovascular surgery, COVID-19, critical illness, neurosurgical critical illness, trauma, and / or traumatic brain injury. Accordingly, in some embodiments, provided herein are methods and compositions for limiting lipotoxicity and thereby reducing the likelihood of poor outcomes associated with pancreatic injury and other severe systemic conditions that are associated with elevated lipase levels and / or elevated lipase activity.

[0006] In some embodiments, the compound is:or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, methods and materials for treating diseases, disorders or conditions associated with elevated lipase levels and / or elevated lipase activity in a mammal (e.g., a human) are provided. In some embodiments, methods and materials for treating diseases, disorders or conditions associated with pancreatic injury in a mammal (e.g., a human) are provided. For example, methods and materials for administering one or more lipase inhibitors to a mammal (e.g., a human) having or at risk of developing pancreatic injury and having or at risk of having a condition, disease or disorder worsened by pancreatic injury, wherein the pancreatic injury may be, for example, from pancreatic diseases, disorders, and / or conditions in order to treat the mammal, are provided. As described herein, lipase inhibitors can be effective to reduce or slow the progression of diseases, disorders or conditions worsened by pancreatic injury, wherein the pancreatic injury may be, e.g., pancreatitis (e.g., chronic pancreatitis), pancreatic cancer, and / or post-operative pancreatic fistulas within a mammal (e.g., a human).

[0008] In some embodiments, lipase inhibitors can be effective to treat heart failure, cirrhosis, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, cirrhosis, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, obesity-related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or intestinal obstructions in a mammal (e.g., a human). In some embodiments, lipase inhibitors can be effective to reduce or slow the progression of developing heart failure, cirrhosis, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, cirrhosis, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, obesity-related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or intestinal obstructions in a mammal (e.g., a human). In some embodiments, one or more lipase inhibitors can be used to reduce the risk of developing heart failure, cirrhosis, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, cirrhosis, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or intestinal obstructions in a mammal (e.g., a human). The methods can comprise, consist essentially of, or consist of administering a lipase inhibitor to a mammal in need thereof.

[0009] In an aspect, methods for reducing intestinal obstruction, cirrhosis, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndromepericarditis, hepatic disease, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or heart failure in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a lipase inhibitor to a mammal in need thereof. The mammal can bea human. The inhibitor can be compound 767, also referred to as RABI-767, or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, methods for treating, reducing, or preventing progression of burns, cardiac arrest, cardiovascular surgery, COVID-19, critical illness, neurosurgical critical illness, trauma, and / or traumatic brain injury worsened by pancreatic injury in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0011] Unless otherwise defined, 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 pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0012] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.DESCRIPTION OF THE DRAWINGS

[0013] Fig. 1. Example evidence of pancreatic injury and mortality. Bar graph of illnesses and evidence of pancreatic injury (upper panel); chart of mortality % by illness with normal pancreatic enzymes and elevated pancreatic enzymes (lower panel).

[0014] Fig. 2. Cardiac dysfunction is worsened by pancreatic triglyceride lipase (PTL) in the presence of unsaturated triglyceride (GTL). Charts of stroke volume, End Diastolic Volume (EDV), and cardiac output over time; echocardiography at 24 h and 48 h.

[0015] Fig. 3. Cardiac induced pancreatic congestion and enzyme leak is not affected by PTL.

[0016] Fig. 4. Charts showing PTL leaks during heart failure, causes GTL lipolysis, and worsens shock, renal failure (Fig. 4, panel A); PTL leak in the presence of GTL causes inflammatory cell injury (Fig. 4, panel B); and PTL leak in the presence of GTL causes leukopenia, higher bacterial loads, mortality (Fig. 4, panel C).

[0017] Fig. 5. Representative images from mice treated with GTL and Interleukin (IL)- 12 / 18 including bowel adhesions (Fig. 5, panel A); images of normal fat, necrosed fat and adhesions in bowel (Fig. 5, panel B); and images of bowel adhesions (Fig. 5, panel C).DETAILED DESCRIPTION

[0018] The present invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. For example, features illustrated with respect to one embodiment can be incorporated into other embodiments, and features illustrated with respect to a particular embodiment can be deleted from that embodiment. In addition, numerous variations and additions to the embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention.

[0019] Unless otherwise defined, 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. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0020] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination.

[0021] Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted.

[0022] To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference herein in their entirety for all purposes.

[0023] As used herein, “a,” “an,” or “the” can mean one or more than one. For example, “a” cell can mean a single cell or a multiplicity of cells.

[0024] Also as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0025] Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ± 10%, ± 5%, ± 1%, ± 0.5%, or even ± 0.1% of the specified amount.

[0026] The term “consists essentially of’ (and grammatical variants), as applied to the compositions of this invention, means the composition can contain additional components as long as the additional components do not materially alter the composition. The term “materially altered,” as applied to a composition, refers to an increase or decrease in the therapeutic effectiveness of the composition of at least about 20% or more as compared to the effectiveness of a composition consisting of the recited components.

[0027] The term “therapeutically effective amount” or “effective amount,” as used herein, refers to that amount of a composition, compound, or agent of this invention that imparts a modulating effect, which, for example, can be a beneficial effect, to a subject afflicted with a disorder, disease or illness, including improvement in the condition of the subject (e.g., in one or more symptoms), delay or reduction in the progression of the condition, prevention or delay of the onset of the disorder, and / or change in clinical parameters, disease or illness, etc., as would be well known in the art. For example, a therapeutically effective amount or effective amount can refer to the amount of a composition, compound, or agent that improvesa condition in a subject by at least 5%, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0028] “Treat” or “treating” or “treatment” refers to any type of action that imparts a modulating effect, which, for example, can be a beneficial effect, to a subject afflicted with a disorder, disease or illness, including improvement in the condition of the subject (e.g., in one or more symptoms), delay or reduction in the progression of the condition, and / or change in clinical parameters, disease or illness, etc., as would be well known in the art.

[0029] “Pharmaceutically acceptable,” as used herein, means a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the compositions of this invention, without causing substantial deleterious biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The material would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art (see, e.g., Remington's Pharmaceutical Science,' 21sted. 2005).

[0030] “Concurrently” means sufficiently close in time to produce a combined effect (that is, concurrently can be simultaneously, or it can be two or more events occurring within a short time period before or after each other). In some embodiments, the administration of two or more compounds “concurrently” means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two compounds can be administered in the same or different formulations or sequentially. Concurrent administration can be carried out by mixing the compounds prior to administration, or by administering the compounds in two different formulations, for example, at the same point in time but at different anatomic sites or using different routes of administration.

[0031] The present disclosure provides methods for the treatment of diseases, disorders, or conditions associated with elevated lipase. Elevated lipase activity and / or elevated lipase levels can be defined relative to a reference level, for example, a serum lipase level of greater than 140 units per liter (U / L) of blood in a subject under 60 years old, or greater than 151 U / L in a subject over 60 years of age. In some embodiment, the serum lipase level is 1.5, 2,2.5, 3, 3.5, or 4 times greater than the normal range, i.e., reference lipase range for a subject. The present disclosure provides methods for the treatment of disorders or conditions worsened by pancreatic injury and / or elevated lipid concentrations (e.g., lipotoxicity), including nonesterified fatty acids (NEFAs).

[0032] In some embodiments, methods and materials for treating diseases, disorders or conditions worsened by pancreatic injury in a mammal (e.g., a human) are provided. For example, methods and materials for administering one or more lipase inhibitors to a mammal (e.g., a human) having or at risk of having a condition, disease or disorder worsened by pancreatic injury (e.g., burns, cardiac arrest, cardiovascular surgery, COVID-19, critical illness, neurosurgical critical illness, trauma, and / or traumatic brain injury). In some embodiments, the pancreatic injury may be, for example, from pancreatic diseases, disorders, and / or conditions. As described herein, lipase inhibitors can be effective to reduce or slow the progression of diseases, disorders or conditions worsened by pancreatic injury in a mammal (e.g., a human), e.g., wherein the pancreatic injury is pancreatitis (e.g., chronic pancreatitis), pancreatic cancer, and / or post-operative pancreatic fistulas.

[0033] In some embodiments, methods and materials for treating diseases, disorders or conditions including heart failure, cirrhosis, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, obesity- related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or intestinal obstructions within a mammal (e.g., a human) are provided. See, e.g., J. Visceral Surg. (2012) 149, e!04-el4; Peery et al., Gastroenterology 2022, 162:621-644, including Table 2 (Percentage of patients with 0 to 4 abdominal surgery (5) before a first episode of acute small bowel obstruction), Table 4 (Most Common GI, Liver and Pancreatic Principal Diagnoses from US Hospitals, 2018 showing acute pancreatitis, intestinal obstruction and inflammatory bowel disease), and Table 8 (Causes of Death from Nonmalignant GI, Pancreatic, and Liver Diseases in the United States, 2019 showing paralytic ileus and intestinal obstruction and acute pancreatitis, incorporated herein by reference in their entireties. In some embodiments, lipase inhibitors can be effective to reduce or slow the progression of developing heart failure, cirrhosis, spontaneous bacterialperitonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e g., hypertriglyceridemia), steatorrhea, obesity, obesity-related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or intestinal obstructions in a mammal (e.g., a human). In some embodiments, one or more lipase inhibitors can be used to reduce the risk of developing heart failure, cirrhosis, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e g., hypertriglyceridemia), steatorrhea, obesity, obesity-related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or intestinal obstructions in a mammal (e.g., a human).

[0034] In general, one aspect of this document features methods for reducing intestinal obstruction in a mammal. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof. Additional lipase inhibitors include, for example, orlistat, bis-sulfonate derivatives as described in Korkmaz et al., Journal of Molecular Structure, 1259, 2022, 132734, doi: 10.1016 / j.molstruc.2022.132734; chalcone- like inhibitors as described in Huo et al., Bioorganic & Medicinal Chemistry, Volume 29, 1 January 2021, 115853, monoacylglycerol lipase inhibitors (see, Deng, H. and Li, W., 2020. Acta Pharmaceutica Sinica B, 10(4), pp.582-602), including, for example, MJN110 (Selvaraj, et al., Cells 2021, 10(12), 3454) and JZL 184 (Priiser, et al., 2021. Molecular Cancer Therapeutics, 20(5), pp.787-802); benzodioxol derivatives as described in Hawash, et al,2021p.40; tetrahydrolipstatin, and other lipase inhibitors for obesity, (See, e.g., Liu, Tet al. 2020. Biomedicine & Pharmacotherapy, 128, p.110314), each of which is incorporated by reference in their entirety.

[0035] In an aspect, methods for treating, reducing, or preventing progression of a disease, disorder, or condition associated with elevated lipase levels or activity in a mammal (e.g., a human) are provided. In an aspect, methods for treating, reducing, or preventing progression of a disease, disorder, or condition worsened by pancreatic injury in a mammal (e.g., a human) are provided. In some embodiments, the conditions worsened by pancreatic injury comprise burns, cardiac arrest, cardiovascular surgery, COVID-19, critical illness, neurosurgical critical illness, trauma, and / or traumatic brain injury. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, methods for treating or reducing severity of cardiac arrest in a mammal are provided. See, Park et al., J Clin Med. 2022 Mar 4, 11 (5): 1426 doi .10.3390 / jcm 11051426; Degoricija, et al., Clin Chem Lab Med. 2019 Oct 25;57(11): 1799- 1804. doi: 10.1515 / cclm-2019~0037. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, methods for treating or reducing severity of cardiovascular surgery injury in a mammal are provided. See, Warshaw et al., Ann Surg. 1978Aug;188(2):197-201. doi: 10.1097 / 00000658-197808000-00012; Femandez-del Castillo, et al., N Engl J Med. 1991 Aug 8;325(6):382-7. doi: 10.1056 / NEJM199108083250602; Ding, et al., J Pers Med. 2022 Nov 3;12(11): 1838. doi: 10.3390 / jpml2111838. PMID: 36579569. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, methods for treating or reducing severity of critical illness in a mammal are provided. See, Manjuck, et al., Chest. 2005 Jan;127(l):246-50. doi:10.1378 / chest.127.1.246; Liu, et al., Pediatr Crit Care Med. 2021 Jan 1 ;22( l):el0-el 8. doi: 10.1097 / PCC.0000000000002525; Has et al., J Crit Care. 2014 Dec;29(6): 1130.e5-9. doi: 10.1016 / j.jcrc.2014.06.003; Branco, et al., Pediatr Crit Care Med. 2017 Jan;18(l):e35-e41. doi: 10.1097 / PCC.0000000000001 Oi l. Critical illness as used herein is defined as a patient in need of intensive care, with the defining attributes of a high risk of imminent death, vital organ dysfunction, requirement for care to avoid death, and potential reversibility. See, Kayambankadzanja, et al., BMJ Open. 2022 Sep 5;12(9):e060972. doi: 10.1136 / bmjopen- 2022-060972. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, methods for treating or reducing severity of neurosurgical critical illness in a mammal are provided. See, Lee, et al., J Chin Med Assoc. 2010 Jan;73(l):8-14. doi: 10.1016 / sl726-4901(10)70015-0. Neurosurgical critical illness as described herein include bleeding in or around the brain (subarachnoid hemorrhage, intracerebral hemorrhage, subdural hemorrhage, intraventricular hemorrhage), spinal cord disorders, nerve and muscle diseases, brain trauma, and brain tumors. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, methods for treating or reducing severity of trauma in a mammal are provided. See, Subramanian, et al., Trauma Mon. 2016 May 12;21(2):e20773. doi: 10.5812 / traumamon.20773. f. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, methods for treating or reducing severity of traumatic brain injury in a mammal are provided. See, De Toledo, et al., Neurocrit Care. 2009Dec;l l(3):322-9. doi: 10.1007 / sl2028-009-9265-l. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipaseinhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, methods for treating or reducing severity of COVID-19 in a mammal are provided. See, Hanley et al., Lancet Microbe. 2020 Oct;l(6):e245-e253. doi: 10.1016 / S2666-5247(20)30115-4; Lax et al., Ann Intern Med. 2020 Sep 1 ; 173(5):350-361. Doi: 10.7326 / M20-2566; Kiyak et al., Pancreatology. 2022 Jun;22(5):665-670; doi: 10.1016 / j.pan.2022.04.012; Benias et al., Pancreas. 2021 Oct 1 ;50(9): 1310-1313; doi: 10.1097 / MPA.0000000000001922; Yang et al., Pancreatology. 2022 May;22(4):539-546; doi: 10.1016 / j.pan.2022.03.014; Cartin-Ceba, et al., iScience. 2022 May 20;25(5): 104322.Doi: 10.1016 / j.isci.2022.104322; and Thomas, et al., JCI Insight. 2020 Jul 23;5(14):el40327: doi: 10.1172 / jci .insight 140327. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, methods for treating or reducing the severity of burns in a mammal are provided. See, Ryan et al., Postbum pancreatitis. Ann Surg. 1995Aug;222(2): 163-70. doi: 10.1097 / 00000658-199508000-00008; Wolfe, et al., N Engl J Med. 1987 Aug 13;317(7):403-8. doi: 10.1056 / NEJM198708133170702; Rieu, et al., Anesth Analg (Paris) 1977 Nov-Dec;34(6): 1323-9. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to amammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0044] In another aspect, methods for treating, reducing, or preventing progression of heart failure in a mammal are provided. In some embodiments, methods for treating or reducing severity of heart failure in a mammal are provided. See, Courelli, et al., Cell Mol Bioeng.2021 Aug 13;14(6):583-596. Doi: 10.1007 / sl2195-021-00693-w; Parissis, et al., J Interferon Cytokine Res. 2003 Jun;23(6):329-33. Doi: 10.1089 / 107999003766628179; Gupta, et al., Lancet. 1969 Dec 6;2(7632): 1209-13. Doi: 10.1016 / s0140-6736(69)90749-1. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human.The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0045] In another aspect, methods for treating, reducing, or preventing progression of cirrhosis in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0046] In another aspect, methods for treating, reducing, or preventing progression of spontaneous bacterial peritonitis in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0047] In another aspect, methods for treating, reducing, or preventing progression of intestinal obstruction in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0048] In another aspect, methods for treating, reducing, or preventing progression of cirrhosis complications (e.g., one or more of hepatorenal syndrome, portal hypertension, esophageal and gastric varices, ascites, splenomegaly, hepatic encephalopathy, spontaneous bacterial peritonitis, coagulopathy, variceal hemorrhage, gastric antral vascular ectasia (GAVE), hepatopulmonary syndrome, portopulmonary hypertension, cirrhotic cardiomyopathy, pleural effusion (hepatic hydrothorax), malnutrition and muscle wasting, hypoglycemia, gynecomastia, hypogonadism, or hepatocellular carcinoma (HCC)) in a mammal are provided. The methods can comprise, consist essentially of, or consist ofadministering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0049] In another aspect, methods for treating, reducing, or preventing progression of Crohn’s disease in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0050] In another aspect, methods for treating, reducing, or preventing progression of abdominal adhesion in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0051] In another aspect, methods for treating, reducing, or preventing progression of chronic kidney disease in a mammal are provided. The methods can comprise, consistessentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0052] In another aspect, methods for treating, reducing, or preventing progression of diabetes (e.g., type 1 or type 2 diabetes) in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0053] In another aspect, methods for treating, reducing, or preventing progression of alcohol use disorder in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0054] In another aspect, methods for treating, reducing, or preventing progression of inflammatory bowel disease in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0055] In another aspect, methods for treating, reducing, or preventing progression of severe acute respiratory distress syndrome in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0056] In another aspect, methods for treating, reducing, or preventing progression of pericarditis in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0057] In another aspect, methods for treating, reducing, or preventing progression of atherosclerosis in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0058] In another aspect, methods for treating, reducing, or preventing progression of hepatic disease in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0059] In another aspect, methods for treating, reducing, or preventing progression of hyperlipidemia (e.g., hypertriglyceridemia) in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0060] In another aspect, methods for treating, reducing, or preventing progression of steatorrhea in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0061] In another aspect, methods for treating, reducing, or preventing progression of obesity in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0062] In another aspect, methods for treating, reducing, or preventing progression of obesity-related dyslipidemia in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0063] In another aspect, methods for treating, reducing, or preventing progression of NAFLD in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0064] In another aspect, methods for treating, reducing, or preventing progression of NASH in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0065] In another aspect, methods for treating, reducing, or preventing progression of PCOS with obesity and insulin resistance in a mammal are provided. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0066] In another aspect, methods for treating, reducing, or preventing progression of a neurodegenerative disease in a mammal are provided. A neurodegenerative disease as described herein includes, without limitation, Alzheimer’s disease, Parkinson’s disease, Niemann-Pick disease, Gaucher’s disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s disease, Krabbe disease, Fabry disease, or metachromatic leukodystrophy. The methods can comprise, consist essentially of, or consist of administering a therapeutically effective amount of a lipase inhibitor to a mammal in need thereof. The mammal can be a human. The inhibitor can be compound 767 or a pharmaceutically acceptable salt thereof. The inhibitor can have the structure:or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to treat a disease, disorder, and / or condition associated with elevated lipase levels and / or activity. In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to treat diseases, disorders, and / or conditions worsened by a pancreatic injury in a mammal. In some embodiments, the conditions worsened by pancreatic injury comprise, bums, cardiac arrest, cardiovascular surgery, COVID-19, critical illness, neurosurgical critical illness, trauma, and / or traumatic brain injury. For example, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having one or more diseases, disorders, and / or conditions worsened by a pancreatic injury in a mammal) to treat, reduce, or prevent progression of a disease, disorder and / or condition of the mammal.

[0068] In some embodiments one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to treat a disease, disorder, and / or condition selected from intestinal obstruction, heart failure, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, cirrhosiscomplications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, obesity-related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or cirrhosis in a mammal. For example, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having one or more diseases, disorders, and / or conditions selected from intestinal obstruction, heart failure, spontaneous bacterial peritonitis, or cirrhosis in a mammal in need thereof.

[0069] In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to delay or prevent development of a disease, disorder, and / or condition associated with elevated lipase levels and / or activity. In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to delay or prevent development of a disease, disorder, and / or condition selected from heart failure, intestinal obstruction, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 daibetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, spontaneous bacterial peritonitis, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, obesity-related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or cirrhosis in a mammal. For example, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human at risk of developing one or more a disease, disorder, and / or condition selected from heart failure, intestinal obstruction, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, obesity-related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or cirrhosis in a mammal) of the mammal. In some cases, the methods and materials described herein can be effective to delay the development of a disease, disorder, and / or condition selected from heart failure, intestinal obstruction, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion,atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, obesity- related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or cirrhosis of a mammal at risk of developing one or more diseases, disorders, and / or conditions by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent relative to development of the disease in the mammal without treatment. In some cases, the methods and materials described herein can be effective to delay the development of one or more diseases, disorders, and / or conditions by, for example, at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more).

[0070] In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to delay or prevent development of diseases, disorders, and / or conditions worsened by a pancreatic injury in a mammal. For example, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having one or more diseases, disorders, and / or conditions worsened by a pancreatic injury in a mammal). For example, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human at risk of developing one or more diseases, disorders, and / or conditions worsened by a pancreatic injury in a mammal) to delay or prevent the development of diseases, disorders, and / or conditions worsened by a pancreatic injury of the mammal. In some cases, the methods and materials described herein can be effective to delay the development of one or more diseases, disorders, and / or conditions worsened by a pancreatic injury in a mammal at risk of developing the one or more diseases, disorders, and / or conditions by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some cases, the methods and materials described herein can be effective to delay the development of one or more diseases, disorders, and / or conditions worsened by a pancreatic injury in a mammal at risk of developing the one or more diseases, disorders, and / or conditions by, for example, at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more).

[0071] In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be used to improve survival of a mammal with a condition associated with elevated lipase. For example, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having one or more diseases, disorders, and / or conditionworsened by a pancreatic injury) to improve survival of the mammal. In some cases, the methods and materials described herein can be effective to improve survival of a mammal having one or more diseases, disorders, and / or conditions worsened by a pancreatic injury by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some cases, the methods and materials described herein can be effective to improve survival of a mammal having one or more one or more diseases, disorders, and / or conditions worsened by a pancreatic injury by, for example, at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more). In some embodiments, one or more lipase inhibitors can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having one or more diseases, disorders, and / or conditions selected from intestinal obstruction, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes, alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, heart failure, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, obesity-related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or cirrhosis in a mammal) to improve survival of the mammal. In some cases, the methods and materials described herein can be effective to improve survival of a mammal having one or more diseases, disorders, and / or conditions selected from heart failure, intestinal obstruction, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, obesity- related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or cirrhosis in a mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some cases, the methods and materials described herein can be effective to improve survival of a mammal having one or more diseases, disorders, and / or conditions selected from heart failure, intestinal obstruction, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, cirrhosis complications (e.g., hepatorenal syndrome), abdominaladhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, obesity-related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or cirrhosis by, for example, at least 6 months (e.g., about 6 months, about 8 months, about 10 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 4 years, about 5 years, or more).

[0072] Any type of mammal having or at risk for developing one or more diseases, disorders, and / or conditions can be treated as described herein. Examples of mammals that can have or be at risk for developing one or more diseases, disorders, and / or conditions and can be treated as described herein include, without limitation, humans, non-human primates such as monkeys, dogs, cats, horses, cows, pigs, sheep, rabbits, mice, and rats.

[0073] In some cases, methods described herein can include identifying a mammal (e.g., a human) as having or being at risk of developing one or more diseases, disorders, and / or conditions. Any appropriate method can be used to identify a mammal as having or as being at risk for developing one or more of the diseases, disorders, and / or conditions. For example, ultrasound, computerized tomography (CT) scan, and / or blood tests (e.g., for an increase in B-type natriuretic peptide, bilirubin such as a level greater than normal for age and sex) can be used to identify a human or other mammal as having or being at risk of developing a disease, disorder or condition as described herein. For example, imaging tests (e.g., CT) scans, magnetic resonance imaging (MRI), positron emission tomography (PET) scans, endoscopic ultrasound (EUS)), pancreatic tissue biopsy (for conditions worsened by pancreatic injury), and / or blood tests (e.g., for pancreatic tumor markers such as CAI 9-9) can be used to identify a human or other mammal as having pancreatic cancer that can worsen conditions described herein. For example, amylase levels (e.g., serum amylase levels) and / or imaging tests (e.g., contrast-enhanced CT and endoscopic retrograde cholangiopancreatography (ERCP)) can be used to identify a human or other mammal as having one or more pancreatic injuries that worsens conditions described herein.

[0074] A mammal (e.g., a human) having or at risk of developing one or more diseases, disorders, and / or conditions described herein can be administered or instructed to selfadminister any one or more (e.g., one, two, three, four, or more) lipase inhibitors. A lipase inhibitor can inhibit any appropriate lipase (e.g., a pancreatic lipase). For example, a lipase inhibitor can inhibit pancreatic lipase (PL) polypeptides and / or pancreatic lipase related protein 2 (PLRP2) polypeptides. In some cases, a lipase inhibitor can reduce or eliminate theability of the lipase to hydrolyze one or more lipids. A lipase inhibitor that can be used as described herein can inhibit a lipase that can hydrolyze any appropriate one or more lipids. In some cases, a lipase inhibitor that can be used to treat a mammal (e.g., a human) having or risk of developing one or more diseases, disorders, and / or conditions as described herein can inhibit a lipase that can hydrolyze a triglyceride (e.g., a neutral triglyceride). Examples of lipids that can be hydrolyzed by a lipase that can be inhibited by a lipase inhibitor that can be used to treat a mammal (e.g., a human) having or risk of developing one or more diseases, disorders, and / or conditions as described herein include, without limitation, linoleins (e.g., glyceryl trilinoleates). A lipase inhibitor can inhibit lipase polypeptide activity or lipase polypeptide expression. Examples of compounds that can reduce or eliminate polypeptide activity of a lipase include, without limitation, antibodies (e.g., neutralizing antibodies) and small molecules (e.g., 767) that target (e.g., target and bind to) a lipase. When a compound that can reduce or eliminate polypeptide activity of a lipase is a small molecule that targets (e.g., targets and binds) to a lipase, the small molecule can be in the form of a salt (e.g., a pharmaceutically acceptable salt). Examples of compounds that can reduce or eliminate polypeptide expression of a lipase include, without limitation, nucleic acid molecules designed to induce RNA interference of polypeptide expression of a lipase (e.g., a siRNA molecule or a shRNA molecule), antisense molecules, and miRNAs. In some cases, a lipase inhibitor that can be used to treat one or more pancreatic diseases, disorders, and / or conditions as described herein can be 767 or a pharmaceutically acceptable salt thereof and have the following structure:

[0075] In some cases, a lipase inhibitor that can be used to treat one or more pancreatic diseases, disorders, and / or conditions as described herein can be as described elsewhere (see, e.g., WO 2019 / 014434).

[0076] In some cases, one or more (e.g., one, two, three, four, or more) lipase inhibitors can be formulated into a composition (e.g., a pharmaceutically acceptable composition) for administration to a mammal (e.g., a human) having or at risk of developing one or morediseases, disorders, and / or conditions described herein (e.g., having or at risk of developing one or more diseases, disorders, and / or conditions associated with elevated lipase, e.g., a disorder or a condition selected from heart failure, intestinal obstruction, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, obesity-related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or cirrhosis, or, having or at risk of developing one or more diseases, disorders, and / or conditions worsened by a pancreatic injury). For example, one or more lipase inhibitors can be formulated together with one or more pharmaceutically acceptable carriers (additives), excipients, and / or diluents. Examples of pharmaceutically acceptable carriers, excipients, and diluents that can be used in a composition described herein include, without limitation, cyclodextrins (e.g., beta-cyclodextrins such as KLEPTOSE®), dimethyl sulfoxide (DMSO), sucrose, lactose, starch (e.g., starch glycolate), cellulose, cellulose derivatives (e.g., modified celluloses such as microcrystalline cellulose, and cellulose ethers like hydroxypropyl cellulose (HPC) and cellulose ether hydroxypropyl methylcellulose (HPMC)), xylitol, sorbitol, mannitol, gelatin, polymers (e.g., polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), crosslinked polyvinylpyrrolidone (crospovidone), carboxymethyl cellulose, polyethylene-polyoxypropylene-block polymers, and crosslinked sodium carboxymethyl cellulose (croscarmellose sodium)), titanium oxide, azo dyes, silica gel, fumed silica, talc, magnesium carbonate, vegetable stearin, magnesium stearate, aluminum stearate, stearic acid, antioxidants (e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium), citric acid, sodium citrate, parabens (e.g., methyl paraben and propyl paraben), petrolatum, dimethyl sulfoxide, mineral oil, serum proteins (e.g., human serum albumin), glycine, sorbic acid, potassium sorbate, water, alcohols (e.g., having an acyl chain of 2 or more carbons in length, including saturated (e.g., 16:0, 18:0, 20:0), monounsaturated (e.g., 16: 1, 18:1), and polyunsaturated chains (e.g., 18:2, 20:4, 22:6), e.g., ethanol, n-butanol, isopropyl alcohol, butanol, glycerol), salts or electrolytes (e.g., saline such as phosphate buffered saline, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyacrylates, waxes, wool fat, lecithin, and com oil.

[0077] In some embodiments, lipase inhibitors can be formulated into a composition comprising one or more phospholipids. In some embodiments, the phospholipid is formulated into a carrier for the lipase inhibitors, which may be in the form of emulsions, liposomes, or vesicles. In some embodiments, the phospholipid-containing carrier is capable of reducing degradation of a lipase inhibitor in vivo. In some embodiments, a phospholipidcontaining carrier can be degraded by phospholipases in vivo (e.g., pancreatic phospholipases), exposing the lipase inhibitor, thereby allowing the lipase inhibitor to inhibit lipase upon exposure to the in vivo environment. Liposomes and lipid nanoparticles (LNPs) are useful in embodiments of the invention and may comprise an ionizable lipid, a phospholipid, a cholesterol, a PEG lipid and optionally a polyphenol. Example LNPs include those disclosed in Schoenmaker et al., Int’l J. of Pharma, 601 : 120586 (2021), and Hou et al., Nature Review Materials, 6, 1078-1094 (2021), each of which is incorporated herein by reference. Vesicles comprised of phospholipids that self-assemble into spherical vesicles can also be used as a carrier for delivery of lipase inhibitors described herein. In some embodiments, an emulsion comprising phospholipids (e.g., water in oil or oil in water emulsions) can also be utilized in compositions described herein. Example phospholipids that can be included in compositions include, but are not limited to, unsaturated phosphatidylcholine, egg or soybean phosphatidylcholine, dipalmitoylphosphatidylcholine, lysophosphatidic acids, and phosphatidic acids, dioleoylphosphatidylethanolamine (DOPE), l,2-Dioleoyl-sn-glycero-3 -phosphocholine (DOPC), l-stearoyl-2-oleoyl-sn-glycero-3- phosphocholine (SOPC), and Distearoylphosphatidylcholine (DSPC).

[0078] In some cases, when a composition containing one or more (e.g., one, two, three, four, or more) lipase inhibitors is administered to a mammal (e.g., a human) having or at risk of developing one or more diseases, disorders, and / or conditions associated with elevated lipase, e.g., a disorder or a condition selected from intestinal obstruction, spontaneous bacterial peritonitis, Crohn’s disease, chronic kidney disease, diabetes, alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, heart failure, cirrhosis complications (e.g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e g., hypertriglyceridemia), steatorrhea, obesity, obesity-related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or cirrhosis, or, having or at risk of developing one or more diseases, disorders, and / or conditions worsened by a pancreatic injury, the composition canbe designed for oral or parenteral (including, without limitation, subcutaneous, intramuscular, intravenous, intradermal, intra-cerebral, intrathecal, intraabdominal, and intraperitoneal injections (e.g., peripan creatic)) administration to the mammal. Compositions suitable for oral administration include, without limitation, liquids, tablets, capsules, pills, powders, gels, and granules. Compositions suitable for parenteral administration include, without limitation, aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient.

[0079] In some cases, a composition containing one or more (e.g., one, two, three, four, or more) lipase inhibitors can be in the form of a sterile injectable suspension (e.g., a sterile injectable aqueous or oleaginous suspension). This suspension may be formulated using, for example, suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can 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. Examples of acceptable vehicles and solvents that can be used include, without limitation, saline, mannitol, water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils can be used as a solvent or suspending medium. In some cases, a bland fixed oil can be used such as synthetic mono- or diglycerides.

[0080] In some cases, a composition containing one or more (e.g., one, two, three, four, or more) lipase inhibitors can be presented in unit-dose or multi -dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.

[0081] A composition containing one or more (e.g., one, two, three, four, or more) lipase inhibitors can be administered to a mammal (e.g., a human) having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions in any therapeutically effective amount (e.g., any appropriate dose). A therapeutically effective amount of a composition containing one or more lipase inhibitors can be any amount that can treat a mammal having or at risk of developing one or more diseases, disorders, and / or conditions as described herein (e.g., having or at risk of developing one or more diseases, disorders, and / or conditions associated with elevated lipase, e.g., a disorder or a condition selected from Crohn’s disease,chronic kidney disease, diabetes (e.g., type 2 diabetes), alcohol use disorder, inflammatory bowel disease, severe acute respiratory distress syndrome, pericarditis, hepatic disease, intestinal obstruction, heart failure, spontaneous bacterial peritonitis, cirrhosis complications (e g., hepatorenal syndrome), abdominal adhesion, atherosclerosis, hyperlipidemia (e.g., hypertriglyceridemia), steatorrhea, obesity, obesity-related dyslipidemia, NAFLD, NASH, PCOS with obesity and insulin resistance, neurodegenerative disease, or cirrhosis, or, having or at risk of developing one or more diseases, disorders, and / or conditions worsened by a pancreatic injury) without producing significant toxicity to the mammal. The therapeutically effective amount can remain constant or can be adjusted as a sliding scale or variable dose depending on the mammal’s response to treatment. Various factors can influence the actual therapeutically effective amount used for a particular application. For example, the frequency of administration, duration of treatment, use of multiple treatment agents, route of administration, and / or severity of the one or more diseases, disorders, and / or conditions in the mammal being treated may require an increase or decrease in the actual therapeutically effective amount administered.

[0082] A composition containing one or more (e.g., one, two, three, four, or more) lipase inhibitors can be administered to a mammal (e.g., a human) having or at risk of developing one or more diseases, disorders, and / or conditions in any appropriate frequency. The frequency of administration can be any frequency that can treat a mammal having or at risk of developing one or more pancreatic diseases, disorders, and / or conditions without producing significant toxicity to the mammal. For example, the frequency of administration can be from about twice a day to about one every other day, once a day to about once a week, from about once a week to about once a month, or from about twice a month to about once a month. The frequency of administration can remain constant or can be variable during the duration of treatment. As with the therapeutically effective amount, various factors can influence the actual frequency of administration used for a particular application. For example, the therapeutically effective amount, duration of treatment, use of multiple treatment agents, and / or route of administration may require an increase or decrease in administration frequency.

[0083] A composition containing one or more (e.g., one, two, three, four, or more) lipase inhibitors can be administered to a mammal (e.g., a human) having or at risk of developing one or more diseases, disorders, and / or conditions for any appropriate duration. An effectiveduration for administering or using a composition containing one or more lipase inhibitors can be any duration that can treat a mammal having or at risk of developing one or more diseases, disorders, and / or conditions without producing significant toxicity to the mammal. For example, the effective duration can vary from several weeks to several months, from several months to several years, or from several years to a lifetime. Multiple factors can influence the actual effective duration used for a particular treatment. For example, an effective duration can vary with the frequency of administration, therapeutically effective amount, use of multiple treatment agents, and / or route of administration.

[0084] In some cases, methods for treating a mammal (e.g., a human) having or at risk of developing one or more diseases, disorders, and / or conditions as described herein (e.g., by administering one or more lipase inhibitors) can include administering to the mammal one or more (e.g., one, two, three, four, or more) lipase inhibitors as the sole active ingredient to treat the mammal. For example, a composition containing one or more lipase inhibitors can include the one or more lipase inhibitors as the sole active ingredient in the composition that is effective to treat a mammal having or at risk of developing one or more diseases, disorders, and / or conditions.

[0085] In some cases, methods for treating a mammal (e.g., a human) having or at risk of developing one or more diseases, disorders, and / or conditions as described herein (e.g., by administering one or more lipase inhibitors) also can include administering to the mammal one or more (e.g., one, two, three, four, five or more) additional agents used to treat one or more pancreatic diseases, disorders, and / or conditions to the mammal and / or performing therapies used to treat one or more pancreatic diseases, disorders, and / or conditions on the mammal. For example, a combination therapy used to treat one or more diseases, disorders, and / or conditions can include administering to the mammal (e.g., a human) one or more lipase inhibitors described herein and one or more (e.g., one, two, three, four, five or more) agents used to treat one or more diseases, disorders, and / or conditions. Examples of agents that can be administered to a mammal to treat pancreatitis (e.g., chronic pancreatitis) include, without limitation, acetaminophen, ibuprofen, opioids (e.g., codeine and morphine), pancreatic enzymes, anti-inflammatories, and any combinations thereof. Examples of agents that can be administered to a mammal to treat pancreatic cancer include, without limitation, gemcitabine, 5 -fluorouracil (5-FU), oxaliplatin, albumin-bound paclitaxel, capecitabine, cisplatin, irinotecan, and any combinations thereof. Examples of agents that can beadministered to a mammal to treat pancreatic fistulas include, without limitation, somatostatins, somatostatin analogues, and any combinations thereof. In cases where one or more lipase inhibitors are used in combination with additional agents used to treat one or more pancreatic diseases, disorders, and / or conditions, the one or more additional agents can be administered at the same time (e.g., in a single composition containing both one or more lipase inhibitors and the one or more additional agents) or independently. For example, one or more lipase inhibitors described herein can be administered first, and the one or more additional agents administered second, or vice versa.

[0086] In some cases, a combination therapy used to treat one or more diseases, disorders, and / or conditions can include administering to the mammal (e.g., a human) one or more (e.g., one, two, three, four, or more) lipase inhibitors described herein and performing one or more (e.g., one, two, three, four, five or more) additional therapies used to treat one or more pancreatic diseases, disorders, and / or conditions on the mammal. Examples of therapies used to treat pancreatitis (e.g., chronic pancreatitis) include, without limitation, endoscopic retrograde cholangiopancreatography, surgical removal of the gallbladder, and / or surgical removal of pancreatic fluid. Examples of therapies used to treat pancreatic cancer include, without limitation, surgery, radiation therapy, surgery to remove one or more tumors within the pancreas, and / or surgical removal of all or part of the pancreas. Examples of therapies used to treat pancreatic fistulas include, without limitation, total parenteral nutrition and / or fistulectomy. In cases where one or more lipase inhibitors described herein are used in combination with one or more additional therapies used to treat one or more pancreatic diseases, disorders, and / or conditions, the one or more additional therapies can be performed at the same time or independently of the administration of one or more lipase inhibitors described herein. For example, one or more lipase inhibitors described herein can be administered before, during, or after the one or more additional therapies are performed.

[0087] In some cases, a combination therapy used to treat one or more diseases, disorders, and / or conditions can include administering to the mammal (e.g., a human) one or more (e.g., one, two, three, four, or more) lipase inhibitors described herein and performing one or more (e.g., one, two, three, four, five or more) additional therapies, including surgical and medicinal therapies. In some embodiments, the additional therapy can be used to treat one or more of burns (ultrasound mist therapy, IV fluids, bum creams and ointments including bacitracin and silver sulfadiazine, and IV antibiotics), critical illness (e.g., neurosurgicalcritical illness), cardiac arrest (e.g., oxygen therapy, extracorporeal membrane oxygenation, cardioverter device), surgery, trauma, traumatic brain injury (e.g., diuretics, anticonvulsants and / or analgesics), cardiovascular events, and COVID-19 (e.g., antivirals such as remdesivir, nirmatrelvir and ritonavir, and immune modulators such as baricitinib, tocilizumab). In some embodiments, the additional therapy can be used to treat one or more of cirrhosis (e.g., antivirals such as adefovir, etecavir, lamivudine, antibiotics such as erythromycin, azithromycin, rifampin, isoniazid, and chelating agents such as D-penicillamine, trientine), heart failure (e.g., angiotensin-converting enzyme (ACE) inhibitors such as Captopril, Enalapril, Fosinopril, Lisinopril, Perindopril, Quinapril, Ramipril, Trandolapril, Benazepril, and Moexipril; angiotensin receptor blockers (ARBs) such as Candesartan, Losartan, and Valsartan; Angiotensin-receptor neprilysin inhibitors such as Sucubitril; If channel blocker such as ivabradine; beta blockers such as betaxolol, carvedilol, labetalol, propranolol; SGLT- 2 inhibitors such as empagliflozin and dapagliflozin; Hydralazine and isosorbide dinitrate; and aldosterone antagonists such as spironolactone and eplerenone), spontaneous bacterial peritonitis (e.g., antibiotics such as cefotaxime, ceftriaxone, ofloxacin, and adjunctive intravenous albumin), Crohn’s disease (e.g., aminosalicylates, corticosteroids, immunomodulators, and biologic therapies), chronic kidney disease, diabetes (e.g., insulin, metformin, GLP-1 receptor agonist, and SGLT-2 inhibitor), alcohol use disorder (e.g., disulfiram, naltrexone, and acamprosate), inflammatory bowel disease (e.g., 5- aminosalicyclic acids, immunomodulators, corticosteroids, and biologies), severe acute respiratory distress syndrome (e.g., supplemental oxygen therapy, sedation and fluid management), pericarditis(antibiotics for bacterial infection, antifungals for fungal pericarditis, corticosteroids, and water pills), hepatic disease (e.g., dandelion, milk thistle, dietary modifications), bowel obstruction (e.g., IV fluids, surgery, antibiotics such as cefazolin and cefotoxin, analgesics, and antiemetic such as promethazine or ondansetron), hepatorenal syndrome (e.g., terlipressin, midodrine, octreotide, or albumin infusion), atherosclerosis (e.g., atorvastatin, rosuvastatin, aspirin, antihypertensives, angioplasty, or stenting), hyperlipidemia (e.g., atorvastatin, simvastatin, ezetimibe, PCSK9 inhibitors, or fibrates), steatorrhea (e.g., pancrelipase or pancreatic enzyme replacement therapy), obesity (e.g., semaglutide, liraglutide, or orlistat), obesity-related dyslipidemia (e.g., statins, fibrates, omega-3 fatty acids), NAFLD (e.g., semaglutide, liraglutide, orlistat, or pioglitazone), NASH (e.g., semaglutide, liraglutide, orlistat, pioglitazone, FXR agonists, or vitamin E), PCOS withobesity and insulin resistance (e.g., metformin, oral contraceptives, semaglutide, liraglutide, or orlistat), or neurodegenerative disease (e.g., cholinesterase inhibitors, NMDA receptor antagonists, anti-amyloid therapies, dopamine replacement, dopamine agonists, riluzole, edaravone, antidepressants, ocrelizumab, fingolimod, or corticosteroids).

[0088] In certain instances, a course of treatment and the severity of one or more symptoms related to the condition being treated (e.g., one or more diseases, disorders, and / or conditions) can be monitored. Any appropriate method can be used to determine whether or not the severity of a symptom is reduced. For example, the severity of a symptom of one or more diseases, disorders, and / or conditions can be assessed using ultrasound, CT scan, and / or blood tests (e.g., for an increase in amylase and / or lipase such as a level greater than about threefold the upper limit of normal) at different time points.

[0089] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.ExamplesExample 1: Pancreatic Injury in Acute Illnesses is Assessed with Worse Clinical Outcomes

[0090] Previous studies suggest acute illnesses associated with pancreatic enzyme elevation may have worse outcomes. The acute illnesses include burns, critical illness, surgery, trauma, traumatic brain injury, cardiovascular events and COVID- 19. A comprehensive literature search was therefore conducted for acute illnesses to look for objective evidence of pancreatic injury and the associated outcomes.

[0091] Results: 13 studies ranging from 89-3244 patients associated elevated serum lipase (n-13) or amylase (n=6) with worse outcomes. These included one study each for burns (3.5x increased mortality), cardiac arrest (3.7x increased mortality), neurosurgery (39.5% vs 17.4% mortality), critical illness (2.3-fold increased mortality), heart failure (higher inflammatory markers). COVID-19 with lipase elevation (n=3 included a metanalysis with 21 studies) showed significantly increased (24.6% vs 6.4%; p<0.05) mortality. The proportion of patients with hyperlipasemia ranged from 20-50%. Similar patterns were noted in trauma, traumatic brain injury, and cardiovascular surgery (2 studies). Abdominal imaging showed pancreatitis in 11 / 25 (44%) critically ill neurosurgery patients, 4 / 13 (31%) bums, 11 / 50(22%) critically ill patients, with frank pancreatitis diagnosed in 58 / 986 (6%) of cardiac valvesurgery cases. Additionally, 5 / 11 (45%) patients dying with COVID-19, 41 / 179 (52%) children dying of critical illnesses and 22 / 95 (23%) patients dying after 24 hours of undergoing emergent surgery had pancreatic injury on autopsy. As provided in Table 1, a literature search for the acute illness mentioned in the first column was done for parameters of pancreatic injury, i.e., pancreatic enzyme (lipase or amylase) elevation, and direct (autopsy) or imaging evidence (e.g., CT scan or ultrasound) of injury. The associated outcomes mentioned in the study are detailed in the column on the far right.

[0092] The literature search revealed presence of pancreatic injury, as evidenced by elevated pancreatic enzymes (46 +7-22%), imaging (26.5 + / -17%) and autopsy (37 + / -11%), in 2.3-57% of cases of common acute illnesses such as burns, critical illness, surgery, trauma, traumatic brain injury, cardiovascular events, and COVID-19. There is association between pancreatic injury in acute illnesses with poor clinical outcomes such as increased mortality.Table 1. Clinical studies on outcomes of patients with pancreatic injury (white background) and elevated NEFA (gray background) in acute illnesses.Example 2: Pancreatic Triglyceride Lipase (PNLIP) Mediated Unsaturated Visceral Fat Lipolysis Worsens Sepsis During Heart Failure

[0093] This Example describes evaluation of whether a pancreatic lipase leak during heart failure could result in sepsis via the hydrolysis of visceral triglyceride.

[0094] Elevated serum pancreatic enzymes have been associated with worse outcomes in burn, hemorrhage, critical illness and post cardiac surgery. The pancreas is sensitive to ischemia (Krejci, et al., Br J Anaesth. 2000 Apr;84(4):468-75. doi: 10.1093 / oxfordjournals.bja.a013472) and heart failure has an increased risk of sepsis (Abu Dagher, et al., BMJ Open. 2018 Aug l;8(7):e022185. doi: 10.1136 / bmjopen-2018-022185). Additionally, unsaturated fatty acids impair macrophage function and phagocytosis via immune cell injury. Therefore, pancreatic lipase leak during heart failure was evaluated to determine whether it could result in sepsis via the hydrolysis of visceral triglyceride.Methods

[0095] Heart failure was induced with doxorubicin (15 mg / kg) in C57bl / 6 or pancreatic triglyceride lipase knock out (PTL - / -) mice. The triglyceride of linoleic acid (glyceryl trilinoleate, GTL) was administered (100 pL / 30 gm mouse) 6 hours later in some mice. GFP E coli were administered (1 million / mouse, IP) after 24 hours. Echocardiography was done at baseline, day 1 and 2. Blood was analyzed for inflammatory cell viability, lipase activity, unbound fatty acids (uFA). Mice were followed for 7 days.Results

[0096] In C57bl / 6 mice, consistent with heart failure, doxorubicin caused hypotension (reduced carotid pulse distension to 279 + / -66pm from 480 + / -72pm), BUN elevation (3 U7- 13 vs 15 + / -5 mg / dl), and pancreatic congestion (increased water content 83 2% vs. 68 5%), a higher serum lipase than controls (496 + / -344 vs. 119 + / -12 U / L, p<0.001) with no pancreatic histological damage. The stroke volume (SV) decreased from 39 + / -2.5 to 25 + / -1.6 pl at 24 hours, but then normalized with no significant increase in uFA, annexin V positive WBCs, severe leucopenia, bacterial loads or increase in mortality. GTL increased serum uFA (46 + / - 22nM vs. 4.0 + / -1.4nM), worsened carotid pulse distension (110+ / - 23 pm), SV (13 + / -2.7 1 at 48 hours) increased BUN (72 + / -11 mg / dl), and circulating annexin V positive WBCs (19 + / - 15% vs. 1 + / -0% in controls, p<0.001), worsened leucopenia (2800 + / -70 / mm3), impaired clearance of E. coli (to 12 + / -6 billion / mouse) and caused 100% mortality by day 3. PTL - / - mice given doxorubicin +GTL had a lower serum lipase (46 + / -13U / L), lower uFA (13 + / - 1.5nM), improved pulse distention (260 + / -76pM), SV (30 + / -2.8pL), BUN (37 + / -19 mg / dl), and improved survival at 7 days (4 / 7, p<0.03), with a normalization of WBC counts and annexin V positive circulating WBCs to control levels This was associated with complete prevention of an increase in peritoneal bacterial loads.

[0097] Conclusion: Pancreatic injury during heart failure can be mild and self-limited, in the presence of hydrolysable triglyceride / fat. However, the leakage of pancreatic lipases like PTL can result in unregulated lipolysis of this fat resulting in worsening of shock, renal failure, inflammatory cell injury and impaired bacterial clearance. This combination of events can result in the development of sepsis during sterile diseases like heart failure.

[0098] Heart failure can result in pancreatic congestion and a pancreatic enzyme leak. PTL leaked during heart failure can cause lipolysis of visceral unsaturated triglyceride. PTL mediated lipotoxicity can impair cardiac function by reducing the stroke volume and end- diastolic volume. The worsening of heart failure by PTL can be associated with shock, renalfailure. PTL mediated lipotoxicity can result in inflammatory cell injury, leucopenia and increase loads of bacteria which are normally cleared. Thus, PTL mediated lipotoxicity can result in sepsis and worsen heart failure and higher mortality.

[0099] These results demonstrate that one or more lipase inhibitors can be used to treat heart failure and reduce mortality associated therewith.Example 3: Bowel Adhesions

[0100] One dose IL12 / 18 + GTL was injected into a mouse with necropsy at 5-days. At necropsy, bowel adhesions and necrosed fat was found. FIG. 5, panels A-C.Other Embodiments

[0101] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for treating a disease, disorder, or condition associated with an elevated lipase level and / or an elevated lipase activity in a mammal, the method comprising administering a therapeutically effective amount of a lipase inhibitor to the mammal, thereby treating the disease, disorder, or condition.

2. The method of claim 1, wherein the disease, disorder or condition is a disease or disorder worsened by a pancreatic injury in a mammal.

3. The method of claim 1 or 2, wherein the disease or disorder comprises burns.

4. The method of claim 1 or 2, wherein the disease or disorder comprises cardiac arrest, cardiovascular surgery, or heart failure.

5. The method of claim 1 or 2, wherein the disease or disorder is critical illness.

6. The method of claim 5, wherein the critical illness is a neurosurgical critical illness.

7. The method of claim 1 or 2, wherein the disease or disorder comprises trauma.

8. The method of claim 7, wherein the disease or disorder comprises traumatic brain injury.

9. The method of claim 1 or 2, wherein the disease or disorder comprises COVID-19.

10. The method of any one of claims 2-9, wherein the pancreatic injury is chronic pancreatitis or acute pancreatitis, pancreatic cancer, or a post-operative pancreatic fistula.

11. The method of claim 1, wherein the disease or disorder is Crohn’s disease.

12. The method of claim 1, wherein the disease or disorder is Chronic Kidney disease.

13. The method of claim 1, wherein the disease or disorder is diabetes (e.g., type 2 diabetes).

14. The method of claim 1, wherein the disease or disorder is alcohol use disorder.

15. The method of claim 1, wherein the disease or disorder is inflammatory bowel disease.

16. The method of claim 1, wherein the disease or disorder is severe acute respiratory distress syndrome.

17. The method of claim 1, wherein the disease or disorder is pericarditis.

18. The method of claim 1, wherein the disease or disorder is a gastrointestinal tract ulcer.

19. The method of claim 1, wherein the disease or disorder is hepatic disease.

20. The method of claim 1, wherein the disease or disorder is an intestinal obstruction.

21. The method of claim 1, wherein the disease or disorder is spontaneous bacterial peritonitis.

22. The method of claim 1, wherein the disease or disorder is cirrhosis.

23. The method of claim 1, wherein the disease or disorder is cirrhosis complications(e.g., hepatorenal syndrome).

24. The method of claim 1, wherein the disease or disorder is abdominal adhesion.

25. The method of claim 1, wherein the disease or disorder is atherosclerosis.

26. The method of claim 1, wherein the disease or disorder is hyperlipidemia (e.g., hypertriglyceridemia).

27. The method of claim 1, wherein the disease or disorder is steatorrhea.

28. The method of claim 1, wherein the disease or disorder is obesity.

29. The method of claim 1, wherein the disease or disorder is obesity-related dyslipidemia.

30. The method of claim 1, wherein the disease or disorder is non-alcoholic fatty liver disease (NAFLD).

31. The method of claim 1, wherein the disease or disorder is non-alcoholic steatohepatitis (NASH).

32. The method of claim 1, wherein the disease or disorder is polycystic ovary syndrome (PCOS) with obesity and insulin resistance.

33. The method of claim 1, wherein the disease or disorder is a neurodegenerative disease.

34. The method of any one of claims 1-33, wherein said mammal is a human.

35. The method of any one of claims 1-34, wherein said inhibitor comprises the structure:or a pharmaceutically acceptable salt thereof.

36. The method of anyone of claims 1-35, wherein the said inhibitor is administered through oral administration or parenteral administration.

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