Methods and compositions for treating liver disease

Abstract

The present disclosure relates to methods and compositions for treating hepatic encephalopathy (HE). In aspects and embodiments, there is provided a method of treating a human subject having, or at risk of progressing to, HE comprising, administering a pharmaceutical composition comprising an effective amount of an H1 -antihistamine and / or mast cell stabilizer.

Description

[0001] METHODS AND COMPOSITIONS FOR TREATING LIVER DISEASE

[0002] PRIORITY

[0003] This Application claims the benefit of, and claims priority to, US Provisional Application No. 63 / 609,187 filed December 12, 2023, which is hereby incorporated by reference in its entirety.

[0004] BACKGROUND

[0005] Hepatic encephalopathy (HE) is a reversible syndrome observed in some patients with advanced liver dysfunction. This syndrome is characterized by a wide spectrum of neuropsychiatric abnormalities resulting from the accumulation of neurotoxic substances in the brain. Management and treatment of HE is difficult as the pathological changes and mechanisms of the disease are not well understood.

[0006] There is a need for methods and pharmaceutical compositions for treating HE.

[0007] DETAILED DESCRIPTION

[0008] In aspects and embodiments, there is provided a method of treating a human subject having, or at risk of progressing to, hepatic encephalopathy (HE). In embodiments, the method comprises administering a pharmaceutical composition comprising an effective amount of an Hi -antihistamine and / or mast cell stabilizer.

[0009] Hepatic encephalopathy (HE) is the major neurological complication of severe liver disease. It presents in two forms, acute HE and chronic HE. Acute HE generally occurs following massive liver necrosis due to viral hepatitis (hepatitis B and C), hepatic neoplasms, vascular causes, or exposure to acetaminophen and other hepatotoxins. Acute HE can be associated with the abrupt onset of delirium, seizures, and coma. Chronic HE (portal- systemic encephalopathy) usually occurs in patients with alcoholic liver cirrhosis and is characterized by impaired neurological function, including changes in personality, altered mood, diminished intellectual capacity, and abnormal muscle tone and tremor. In both Chronic HE and Acute HE, the symptoms of neuropsychiatric abnormalities is the result of accumulation of neurotoxic substances in the bloodstream and brain. Some of the neurotoxic substances include ammonia, short-chain fatty acids, mercaptans, false neurotransmitters (e.g., tyramine, octopamine, beta-phenyl ethanolamines), manganese, and gamma- aminobutyric acid (GABA).

[0010] In embodiments, the subject has an acute or chronic liver dysfunction, and is optionally showing symptoms of HE. In embodiments, the liver dysfunction is selected from one or more of, cirrhosis, hepatitis B, hepatitis C, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), hepatocellular carcinoma, cholangiocarcinoma, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, Wilson disease, and Alpha- 1 antitrypsin deficiency. In embodiments, a subject having such ailments receives the therapy described herein to reduce the likelihood of developing HE or to reduce the severity of HE. In some embodiments, the subject is showing symptoms of HE, progression of which can be delayed or prevented according to the present disclosure or even reversed.

[0011] In embodiments, the subject has or is scheduled to have placement of a transjugular intrahepatic portosystemic shunt (TIPS). TIPS is a treatment tool in decompensated liver cirrhosis that may prolong transplant-free survival. HE can be induced or aggravated by TIPS, which presents a clinical challenge in these patients. Therefore, in some embodiments, the subject receives treatment as described herein in advance of TIPS placement and / or following TIPS placement to reduce the likelihood or severity of HE that may result from the procedure.

[0012] In some embodiments, the subject exhibits symptoms of HE. HE is classified according to the West Haven Criteria or the World Health Congress of Gastroenterology Criteria. Under the West Haven Criteria: Grade 1 HE includes symptoms of trivial lack of awareness, euphoria or anxiety shortened attention span, impaired performance of addition or subtraction; Grade 2 HE includes symptoms of lethargy or apathy, minimal disorientation for time or place, subtle personality change, and inappropriate behavior; Grade 3 HE includes symptoms of somnolence to semi-stupor, but responsive to verbal stimuli, confusion, gross disorientation; and Grade 4 HE symptoms include coma.

[0013] Under the World Health Congress of Gastroenterology Criteria, Type A (acute) HE is associated with acute liver failure, typically with cerebral edema; Type B (bypass) HE is caused by portal-systemic shunting (without associated intrinsic liver disease); and Type C HE (cirrhosis) is found in patients with cirrhosis subdivided into episodic, persistent, and minimal encephalopathy.

[0014] In embodiments, the subject has grade 1, grade 2, or grade 3 HE. In embodiments, the subject has Type A, Type B, or Type C HE. In embodiments, the subject has cirrhosis, and has episodic, persistent, or minimal HE.

[0015] In some embodiments, the subject has minimal HE. Minimal encephalopathy (MHE) is a form of HE that is not associated with any grossly evident signs of cognitive dysfunction but with cognitive deficits that can be demonstrated with neuropsychological testing. MHE has been shown to impair overall quality of life and ability to work and has been associated with a higher risk of motor vehicle accidents. Patients with MHE are also more prone to falls and have an increased risk of their condition progressing to overt HE.

[0016] It is believed that inflammation plays a big role in the mechanism of HE, in particular, the involvement of cytokines and lipopolysaccharide in the pathogenesis of acute and chronic HE (See Coltart I, Tranah TH, Shawcross DL. Inflammation and hepatic encephalopathy. Arch Biochem Biophys. 2013 Aug 15;536(2): 189-196.). For example, hepatic mast cells can increase and degranulate in the liver to release mediators including histamine, heparin, tryptase, interleukins, and transforming growth factor-beta 1, after injury. Further, resulting inflammation in the brain due to accumulation of toxic substances can induce further infiltration of immune cells, including but not limited to mast cells, into the brain.

[0017] Further, based on experience with mast cell stabilizers (such as ketotifen) and Hi- antihistamines (such as fexofenadine) in animal and cell models of inflammation and in human clinical trials, it is believed that these agents can be effective for reducing inflammation in the brain as well as the liver, and therefore can be effective agents for treating HE.

[0018] In aspects and embodiments, there is provided a method of treating a human subject having, or at risk of progressing to hepatic encephalopathy (HE) comprising, administering a pharmaceutical composition comprising an effective amount of an Hi -antihistamine and / or mast cell stabilizer. In embodiments, without wishing to be bound by theory, the active agent reduces inflammation in the liver as well as the brain, reducing the levels of toxic substances produced by the liver and reducing the neuroinflammatory impact of these substances. Hi antihistamines bind to H-l receptors and are generally used to treat allergies and allergic rhinitis. In embodiments, the Hi -antihistamine is selected from fexofenadine, loratadine, cetirizine and desloratadine. In embodiments, the Hi -antihistamine is fexofenadine.

[0019] Mast cell stabilizing drugs inhibit the release of allergic mediators from mast cells and are used most often clinically to prevent allergic reactions to common allergens. In embodiments, the mast cell stabilizer can reduce or inhibit degranulation by mast cells, as well as other cells such as basophils, eosinophils, and neutrophils. In embodiments, the mast cell stabilizer is selected from ketotifen, nor-ketotifen, cromoglicic acid, lodoxamide, nedocromil, olopatadine, bepotastine, alcaftadine, azelastine, and quercetin. In embodiments, the mast cell stabilizer is ketotifen or nor-ketotifen.

[0020] The Hi antihistamine or mast cell stabilizer can be in any pharmaceutically acceptable form, including, for example, all pharmaceutically acceptable salts thereof, stereoisomers and / or any mixtures thereof, all pharmaceutically acceptable zwitterions and / or any mixtures thereof, all pharmaceutically acceptable polymorphic forms and / or any mixtures thereof, and all pharmaceutically acceptable complexes (including solvates) and / or any mixtures thereof. Salts include their racemates, enantiomers, or any mixtures thereof. Particularly suitable salts comprise alkali-metal salts (e.g., sodium and / or potassium salts), alkaline earth metal salts (e.g., magnesium and / or calcium salts), aluminum salts, ammonium salts, salts of suitable organic bases (e.g., salts of alkylamines and / or-methyl-D-glutamine), salts of amino acids ( e.g., salts of arginine and / or lysine). Salts also include all enantiomeric salts formed with pharmaceutically acceptable chiral acids and / or bases and / or any mixtures of enantiomers of such salts (e.g., (+) tartrates, (-) tartrates and / or any mixtures thereof including racemic mixtures). In the case of ketotifen, a typical pharmaceutically acceptable salt is ketotifen fumarate. In the case of fexofenadine, a typical pharmaceutically acceptable salt is fexofenadine HC1. In embodiments, ketotifen and fexofenadine (including any pharmaceutically acceptable forms thereof) are provided as a co-therapy.

[0021] In embodiments, treating a subject with HE or a subject that may progress to HE results in reducing, eliminating, or preventing at least one symptom of the disease, the severity or duration of the disease, or reducing or eliminating inflammatory agents that result in HE. Treatment includes the prevention and / or attenuation of the symptoms and / or morbidity associated with the disease. A treatment is effective if it prevents or reduces a symptom associated with HE, especially reducing or preventing one or more of altered level of consciousness, lethargy, mood changes, personality changes, movement problems, slurred speech, sleep problems, anxiety, irritability, muscle twitches (myoclonus), difficulty concentrating, short attention span, flapping hand motion (asterixis), reduced alertness, and / or cognitive impairment. Further, a treatment is effective if it shortens the duration or severity of symptoms of the disease.

[0022] In embodiments, the composition is administered to provide systemic action, including in the liver and / or the central nervous system. In embodiments, the composition is administered enterally, parenterally, intranasally, rectally or buccally. In embodiments, the composition is administered orally, intravenously, intramuscularly, subcutaneously, intranasally, transdermally, or sublingually.

[0023] In embodiments, the composition comprising the mast cell stabilizer (e.g., ketotifen) and / or Hi antihistamine (e.g., fexofenadine) is administered by intravenous injection, and which can be a continuous infusion (e.g., in the case of hospitalized or immobile patients) or a bolus infusion. Such i.v. infusions can be provided daily (or more than once per day in a plurality of subdoses) or from one to five times per week, as needed to reverse or ameliorate the condition, or prevent progression to HE.

[0024] In embodiments, the composition comprising the mast cell stabilizer (e.g., ketotifen) and / or Hi antihistamine (e.g., fexofenadine) is administered rectally, and is in the form of a suppository.

[0025] In embodiments, for intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the pharmaceutically compositions can be employed, and the pH of the solutions can be suitably adjusted and buffered. In embodiments, for intravenous use, the total concentration of the solute(s) can be controlled in order to render the preparation isotonic.

[0026] In embodiments, the composition comprising the mast cell stabilizer (e.g., ketotifen) and / or an Hi antihistamine (e.g., fexofenadine) is in a form for oral delivery. In such embodiments, the therapy can be delivered for a long duration to control symptoms of HE (especially for mild cases), or prevent progression to HE in at-risk patient. In some embodiments, the composition is in the form of a tablet, a capsule, a lozenge or chewing gum. In embodiments, compositions according to the disclosure can be administered orally by any method known in the art. For example, the compositions can be administered in the form of tablets, including, e.g., orally-dissolvable tablets, chewable tablets; capsules; lozenges; pills (e.g., pastilles, dragees); troches; elixirs; suspensions; syrups; wafers; chewing gum; strips; films (e.g., orally-dissolving thin films); soluble powders; effervescent compositions; and the like. In embodiments, the composition is an orally-dissolving composition for sublingual or buccal delivery.

[0027] In the case of tablets for oral use, suitable carriers include lactose and corn starch, and lubricating agents such as magnesium stearate. For oral administration in capsule form, useful carriers can include lactose and com starch. Further examples of carriers and excipients include milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, calcium stearate, talc, vegetable fats or oils, gums and glycols. When aqueous suspensions are used for oral administration, emulsifying and / or suspending agents can be employed. In addition, sweetening and / or flavoring agents may be added to the oral compositions.

[0028] In embodiments, the composition consists essentially of the mast cell stabilizer (e.g., ketotifen) and / or the Hi antihistamine (e.g., fexofenadine) as active pharmaceutical ingredient. In this context, the term “consists essentially of’ means that additional active agents can be employed, where such active agents do not impact (e.g., reduce) the effect of the mast cell stabilizer and / or the Hi antihistamine for treating HE or preventing progression to HE. In embodiments, other active agents, including any other active agent intended to treat liver disease or HE, is not included in the composition. In embodiments, the composition consists of the mast cell stabilizer (e.g., ketotifen) and / or the Hi antihistamine (e.g., fexofenadine) as active pharmaceutical ingredients. In some embodiments, the composition consists of ketotifen or nor-ketotifen (in any pharmaceutically acceptable form) as the sole active agent.

[0029] In embodiments, the composition further comprises inactive agents, such as a pharmaceutical carrier, a pharmaceutical excipient, a sweetening agent, a flavoring agent, a taste masking ingredient, a diluent, alum, a stabilizer, a buffer, a coloring agent, a breath neutralizer, an emulsifying agent, a suspending agent, a nebulizing agent and combinations thereof. Other inactive agents useful for formulating the active agents are known in the art. In various embodiments, the pharmaceutical composition is a controlled release composition. Controlled release drug delivery achieves a certain level of the drug over a particular period time. The level typically is measured by plasma concentration. Methods for controlled release of drugs are well known in the art. An example of a controlled release formulation is a capsule containing beadlets, wherein one population of the beadlets dissolves at one time (e.g., in the stomach or duodenum) and a second population of the beadlets dissolve at delayed times dues to different types or amounts of beadlet coatings.

[0030] In embodiments, the composition comprises ketotifen (any pharmaceutically acceptable form thereof) at a dose of about 0.5 mg to about 5 mg. In embodiments, the daily dose of ketotifen is in the range of about 1 mg to about 10 mg, or about 1 mg to about 6 mg, or about 2 mg to about 5 mg, or about 3 mg to about 4 mg. In embodiments, the daily dose of ketotifen is in the range of about 2 mg to about 8 mg. In embodiments, the composition comprises ketotifen (any pharmaceutically acceptable form therefor) at a dose of about 4 mg. In embodiments, the composition comprises fexofenadine (any pharmaceutically acceptable form thereof) at a dose of about 25 mg to about 240 mg. In embodiments, the daily dose of ketotifen is in the range of about 50 mg to about 220 mg, or about 50 mg to about 200 mg, or about 50 mg to about 190 mg, or about 50 mg to about 180 mg.

[0031] In embodiments, oral dosage compositions or compositions delivered intranasally are administered once to five times daily, such as one to three times daily. In embodiments, the composition is administered parenterally (e.g., by i.v.) from once daily to once weekly.

[0032] In embodiments, non-limiting examples of daily amounts to be administered in the methods of the present invention follows. In embodiments, the daily amounts can be administered in one dose, or in multiple doses. In embodiments, quantities can be defined by ranges, and by lower and upper boundary ranges.

[0033] In embodiments, ketotifen is administered by oral dosage form from about 0.5 mg to about 10 mg daily: Examples of lower boundaries of this range include about 1 mg, about 3 mg, and about 4 mg. Examples of other upper boundaries of this range include about 5 mg, about 6 mg, about 4 mg, and about 2.8 mg. In embodiments, ketotifen is administered by oral dosage form from about 2 mg to about 8 mg daily, or from about 4 mg to about 8 mg daily. In embodiments, ketotifen is administered by intravenous injection form from about 1 mg to about 4 mg daily: Examples of lower boundaries of this range include about 1 mg, and about 2 mg. Examples of other upper boundaries of this range include about 3 mg and about 4 mg. An example of a typical dosage is about 1 mg - 4 mg / day, administered typically as 1 dose or 2 sub-doses.

[0034] In embodiments, ketotifen is administered (by any route) at least once daily. In embodiments, ketotifen is administered from about once daily to about three times daily. In embodiments, ketotifen is administered at least once per week. In embodiments, ketotifen is administered for at least two weeks. In embodiments, ketotifen is administered for at least about three weeks, or about one month.

[0035] In embodiments, fexofenadine is administered by oral dosage form from about 100 mg to about 240 mg daily: Examples of lower boundaries of this range include about 120 mg, about 140 mg, and about 160 mg. Examples of other upper boundaries of this range include about 200 mg, about 220 mg, and about 240 mg. An example of a typical dosage is about 150 mg - 200 mg / day, administered as one dose or two subdoses.

[0036] In embodiments, fexofenadine is administered by intravenous injection form from about 35 mg to about 80 mg daily: Examples of lower boundaries of this range include about 40 mg, about 45 mg, and about 50 mg. Examples of other upper boundaries of this range include about 70 mg, about 75 mg, and about 80 mg. An example of a typical dosage is about 40 mg - 80 mg / day, administered typically as one dose or two subdoses. In embodiments, fexofenadine is administered by intravenous injection form at a dosage of about 60 mg daily.

[0037] In embodiments, fexofenadine is administered (by any route) at least once daily. In embodiments, fexofenadine is administered from about once daily to about three times daily. In embodiments, fexofenadine is administered at least once per week. In embodiments, fexofenadine is administered for at least two weeks. In embodiments, fexofenadine is administered for at least about three weeks, or about one month.

[0038] In embodiments, additional treatments and medications for HE can be administered, and in some embodiments provide synergistic results. In embodiments, such treatments comprise one or more of antibiotics (e.g., rifaximin, neomycin / paromomycin / metronidazole, or vancomycin), lactulose / lactitol (a non-absorbable osmotic laxative that also helps convert ammonia to non-absorbable ammonium in the gastrointestinal tract), LOLA (L-omithine and L-aspartate preparation which increases the use of ammonia in the urea cycle to produce urea), and zinc (to correct underlying deficiency common in cirrhotic patients).

[0039] In embodiments, the subject is undergoing therapy with lactulose and / or lactitol. In embodiments, the subject is undergoing therapy with L-ornithine and L-aspartate. In embodiments, the subject is undergoing therapy with antibiotics. In embodiments, the antibiotics is selected from one or more of rifaximin, neomycin, paromomycin, metronidazole, minocycline, and vancomycin. In embodiments, the subject is undergoing therapy with zinc supplementation. In embodiments, any such agent can be co-formulated with the mast cell stabilizer (e.g., ketotifen) or Hi -antihistamine (e.g., fexofenadine).

[0040] In embodiments, the method prevents and / or reduces symptoms of HE. In embodiments, the symptoms are selected from one or more of altered level of consciousness, lethargy, mood changes, personality changes, movement problems, slurred speech, sleep problems, anxiety, irritability, muscle twitches (myoclonus), difficulty concentrating, short attention span, flapping hand motion (asterixis), reduced alertness, and / or cognitive impairment.

[0041] As used herein, the phrase “at least one of’ preceding a series of items, with the term “and” or “or” to separate any of the items, modifies the list as a whole, rather than each member of the list (i.e., each item). The phrase “at least one of’ does not require selection of at least one of each item listed; rather, the phrase allows a meaning that includes at least one of any one of the items, and / or at least one of any combination of the items, and / or at least one of each of the items. By way of example, the phrases “at least one of A, B, and C” or “at least one of A, B, or C” each refer to only A, only B, or only C; any combination of A, B, and C; and / or at least one of each of A, B, and C.

[0042] As used herein, the term “about”, unless the context requires otherwise, means ±10% of an associated numerical value.

[0043] As used herein, the term “comprising” indicates the presence of the specified feature, but allows for the possibility of other features, unspecified. This term does not imply any particular proportion of the specified features. Variations of the word “comprising,” such as “comprise” and “comprises,” have correspondingly similar meanings. The word “exemplary” is used herein to mean “serving as an example, instance, or illustration.” Any embodiment described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments.

[0044] A reference to an element in the singular is not intended to mean “one and only one” unless specifically stated, but rather “one or more.”

Claims

WHAT IS CLAIMED IS:

1. A method of treating a human subject having or at risk of progressing to hepatic encephalopathy (HE) comprising, administering a pharmaceutical composition comprising an effective amount of an Hi -antihistamine and / or mast cell stabilizer.

2. The method of claim 1, wherein the subject has an acute or chronic liver dysfunction.

3. The method of claim 2, wherein the liver dysfunction is selected from one or more of cirrhosis, hepatitis B, hepatitis C, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), hepatocellular carcinoma, cholangiocarcinoma, autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, Wilson disease, and Alpha- 1 antitrypsin deficiency.

4. The method of any one of claims 1-3, wherein the subject has a transjugular intrahepatic portosystemic shunt (TIPS).

5. The method of any one of claims 1-4, wherein the subject has grade 1, grade 2, or grade 3 HE.

6. The method of any one of claims 1-5, wherein the subject has Type A, Type B, or Type C HE.

7. The method of any one of claims 1-6, wherein the subject has cirrhosis, and has episodic, persistent, or minimal HE.

8. The method of any one of claims 1-7, wherein the Hi -antihistamine is selected from fexofenadine, loratadine, cetirizine and desloratadine.

9. The method of claim 8, wherein the Hi -antihistamine is fexofenadine.

10. The method of any one of claims 1-9, wherein the mast cell stabilizer is selected from ketotifen, nor-ketotifen, cromoglicic acid, lodoxamide, nedocromil, olopatadine, bepotastine, alcaftadine, azelastine, and quercetin.

11. The method of claim 10, wherein the mast cell stabilizer is ketotifen.

12. The method of any one of claims 1-11, wherein the composition is administered enterally, parenterally, intranasally, rectally or buccally.

13. The method of any one of claims 1-11, wherein the composition is administered orally, intravenously, intranasally, or sublingually.

14. The method of claim 13, wherein the composition is administered orally, is in the form of a tablet, a capsule, a lozenge or chewing gum.

15. The method of any one of claims 1-14, wherein the composition consists essentially of a mast cell stabilizer and / or an Hi antihistamine as active pharmaceutical ingredient.

16. The method of claim 15, wherein the composition consists of a mast cell stabilizer and / or Hi antihistamine as active pharmaceutical ingredient.

17. The method of any one of claims 1-16, wherein the composition further comprises a pharmaceutical carrier, a pharmaceutical excipient, a sweetening agent, a flavoring agent, a taste masking ingredient, a diluent, alum, a stabilizer, a buffer, a coloring agent, a breath neutralizer, an emulsifying agent, a suspending agent, a nebulizing agent and combinations thereof.

18. The method of any one of claims 10-17, wherein the composition is an oral dosage composition that comprises ketotifen at a dose of about 0.5 mg to about 3 mg.

19. The method of any one of claims 10-18, wherein the daily dose of ketotifen is in the range of about 1 mg to about 10 mg, or about 1 mg to about 6 mg, or about 2 mg to about 5 mg, or about 3 mg to about 4 mg.

20. The method of any one of claims 1-19, wherein the composition is administered once to five times daily.

21. The method of claim 20, wherein the composition is administered by intravenous injection, and which can be a continuous infusion or a bolus infusion.

22. The method of claim 21, wherein ketotifen is administered at a daily dose of about 1 mg to about 4 mg.

23. The method of any one of claims 1-9 or 12-17, wherein the composition is an oral dosage composition that comprises fexofenadine at a dose of about 150 mg to about 200 mg.

24. The method of any one of claims 1-9, 12-17, or 23, wherein the daily dose of fexofenadine is in the range of about 25 mg to about 240 mg, or about 50 mg to about 220 mg, or about 50 mg to about 200 mg, or about 50 mg to about 180 mg.

25. The method of any one of claims 1-24, wherein the composition is administered once to five times daily.

26. The method of claim 25, wherein the composition is administered by intravenous injection, and which can be a continuous infusion or a bolus infusion.

27. The method of claim 26, wherein fexofenadine is administered at a daily dose of about 40 mg to about 80 mg.

28. The method of any one of claims 1-27, wherein the composition is administered from once daily to once weekly.

29. The method of any one of claims 1-28, wherein the subject is undergoing therapy with lactulose and / or lactitol.

30. The method of any one of claims 1-28, wherein the subject is undergoing therapy with L-ornithine and L-aspartate.

31. The method of any one of claims 1-28, wherein the subject is undergoing therapy with antibiotics.

32. The method of any one of claims 1-28, wherein the subject is undergoing therapy with zinc supplementation.

33. The method of claim 32, wherein the antibiotics is selected from one or more of rifaximin, neomycin, paromomycin, metronidazole, minocycline, and vancomycin.

34. The method of any one of claims 1-33, wherein the method prevents and / or reduces symptoms of HE.

35. The method of claim 34, wherein the symptoms are selected from one or more of altered level of consciousness, lethargy, mood changes, personality changes, movement problems, slurred speech, sleep problems, anxiety, irritability, muscle twitches (myoclonus), difficulty concentrating, short attention span, flapping hand motion (asterixis), reduced alertness, and / or cognitive impairment.