WO2022115481A1

WO2022115481A1 - Methods and compositions for treating post-acute infection gastrointestinal disorders

Info

Publication number: WO2022115481A1
Application number: PCT/US2021/060624
Authority: WO
Inventors: Pravin Chaturvedi
Original assignee: Napo Pharmaceuticals, Inc.
Priority date: 2020-11-24
Filing date: 2021-11-23
Publication date: 2022-06-02

Abstract

Presented herein are methods for treating diarrhea associated with Post Acute Infection Syndrome (PAIS) by administering to a patient in need thereof, a proanthocyanidin polymer composition from C. lechleri, preferably crofelemer. The PAIS may be associated with SARS- CoV2 infection.

Description

METHODS AND COMPOSITIONS FOR TREATING POST-ACUTE INFECTION

GASTROINTESTINAL DISORDERS

FIELD OF THE INVENTION

[0001] The present invention is directed to methods of preventing, ameliorating and/or treating gastrointestinal disorders, particularly, diarrhea. More specifically, the methods presented herein prevent, ameliorate or treat diarrhea associated with post-acute infectious syndrome (PAIS), particularly associated with coronavirus infection, such as such as SARS- CoV2, using a proanthocyanidin polymer composition from C. lechleri, preferably crofelemer.

BACKGROUND

[0002] Coronavirus is a family of viruses that causes several human diseases, including the common cold, Middle East respiratory syndrome (MERS), and severe acute respiratory syndrome (SARS), such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV2).

[0003] Some people with SARS-CoV2 infection develop gastrointestinal symptoms either alone or with respiratory symptoms. Recently, researchers found that a third of patients with a mild case of SARS-CoV2 had symptoms affecting the digestive system (Cholankeril el al, Gastroenterology, 159(2), P775-777, 2020). Another study found that anywhere from 3 to 79 percent of people with SARS-CoV2 develop gastrointestinal symptoms (Tian el al, Aliment Pharmacol Ther. 2020 May; 51(9): 843-851).

[0004] Diarrhea commonly occurs in people with SARS-CoV2 and may persist even after acute infection has resolved. A recent study examined 206 patients with a mild case of SARS- CoV2 and found that 48 people had only digestive symptoms and another 69 had both digestive and respiratory symptoms. Of the combined total of 117 people with gastric distress, 19.4 percent experienced diarrhea as their first symptom (Han et al. Am J Gastroenterol. 2020 Apr 15). Another case paper reported three SARS-CoV2 confirmed patients with persistence of gastrointestinal symptoms and SARS-CoV-2 RNA in stool samples on re-admission after SARS-CoV2 pneumonia had resolved. In fact, the authors speculated that persistence of intestinal infection caused by SARS-CoV2 led to the re-admission at the first discharge or time of waiting for discharge (Wang etal, International Journal of Infectious Diseases, Volume 95, 2020, Pages 433-435). Moreover, the fact that fecal nucleic acid was readily detected in stool and rectal swabs of patients with SARS-CoV2 suggests environmental contamination by feces and induced aerosolization transmission of patients with SARS-CoV2. This highlights the need to properly manage the digestive symptoms of patients with SARS-CoV2 infection.

[0005] Some patients suffering from SARS-CoV2 experience recurrent fevers, persistent constipation or diarrhea, intense bouts of fatigue, debilitating brain fog and vivid hallucinations for months after recovering from their initial illness (“long haulers” or “post-acute COVID-19 syndrome”). The syndrome appears to affect those with mild as well as moderate-to-severe disease. The incidence, natural history and etiology of these symptoms is currently unknown. However, sequelae can include dehydration, malnutrition, cardiovascular issues, and even death.

[0006] Therefore, diarrhea associated post-acute infectious syndrome, including diarrhea associated with post-acute and long-term phases of SARS-CoV2 infections, represents an important and unmet clinical need requiring more effective management. Currently prescribed therapies are only partially effective or are plagued by unacceptable side effects such as constipation and the potential for addiction. The development of a drug for the prophylaxis, treatment and/or symptomatic relief of PAIS-associated diarrhea with a low potential for drug- drug interactions, effects on drug metabolism, or abuse potential, together with a physiological correction of improving stool consistency from watery to formed stools, would provide an important benefit for subjects suffering from post-acute or long phases of SARS-CoV2 infections.

SUMMARY

[0007] Disclosed herein are methods of preventing, ameliorating and/or treating diarrhea in human subjects diagnosed with or suspect of having a viral infection, and, in particular, PAIS. The methods presented herein prevent, ameliorate, manage or treat viral infection associated and PAIS-associated diarrhea.

[0008] In one aspect, provided herein are methods of treating PAIS-associated diarrhea in a human subject, comprising administering to a subject in need thereof a composition comprising an effective amount of a proanthocyanidin polymer composition from C. lechleri, in embodiments SB300 or crofelemer, to treat, ameliorate or prevent PAIS-associated diarrhea. In certain embodiments, the crofelemer is an enterically protected formulation. [0009] In one aspect, provided herein are methods of treating PAIS-associated diarrhea in a human subject, wherein said subject has been diagnosed with, has serum reactivity against, or is suspected of having been infected with SARS-CoV, SARS-CoV2, or other corona viruses or other viral infections associated with PAIS-associated diarrhea by administration of an effective amount of a proanthocyanidin polymer composition from C. lechleri, in embodiments SB300 or crofelemer. In particular embodiments, the subject may have recovered from the acute phase of the infection, for example, recovered breathing function, but continues to suffer from PAIS associated with the viral infection. In embodiments, the subject had been diagnosed with or suspected to have had the viral infection at least or about 4 weeks, 6 weeks, 8 weeks, 3 months or 4 months or longer before beginning treatment with the proanthocyanidin polymer composition. In embodiments, provided are methods of reducing the risk of developing PAIS- associated diarrhea in a human subject who has been diagnosed with SARS-CoV, SARS- CoV2, or other corona viruses or other viral infections associated with PAIS-associated diarrhea by administration of a proanthocyanidin polymer composition from C. lechleri, in embodiments SB300 or crofelemer.

[0010] According to certain embodiments, the proanthocyanidin polymer composition, which may be, in embodiments, SB-300 or crofelemer, may be administered in combination with other therapeutics for the treatment and management of the viral infection and PAIS. In particular embodiments, other therapeutics for the treatment and management of the viral infection and PAIS include but are not limited to interferon alpha 2b, interferon beta la, corticosteroids, including dexamethasone, immunomodulators (e.g, azathioprine, 6- mercaptopurine, and/or methotrexate), mitoxantrone, tyrosine kinase inhibitors (e.g. ruxolitinib, imatinib), anti-viral medications (e.g. monupiravir, lopinavir, PF-07321332, ritonavir, remdesivir, favipiravir, oseltamivir, sofosbuvir, and combinations thereof, including the combination of ritonavir and PF-07321332), and anti-inflammatory monoclonal antibodies.

[0011] In certain embodiments, the subject exhibits Grade 1, Grade 2, Grade 3 or Grade 4 diarrhea in accordance with the Common Toxicity Criteria from the National Cancer Institute. [0012] In various embodiments, the proanthocyanidin polymer composition, which may be in embodiments, SB-300 or crofelemer, is administered after a subject begins to exhibit symptoms of PAIS-associated diarrhea.

[0013] In certain embodiments, the proanthocyanidin polymer composition, in particular, SB-300 or crofelemer, is administered until symptoms of PAIS-associated diarrhea are ameliorated and then the administration of the proanthocyanidin polymer composition is discontinued.

[0014] In various embodiments, provided are methods of treatment, management, amelioration or prevention of diarrhea associated with PAIS in a subject where the administration comprises: administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering about 500 mg per day; administering about 1000 mg per day; administering about 125 mg two times per day; administering about 250 mg two times per day; or administering about 500 mg two times per day of crofelemer, particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof. In other embodiments, the crofelemer is formulated for oral administration but is not enterically protected, e.g., does not have an enteric coating. In other embodiments, the dosage of the proanthocyanidin polymer composition, including in embodiments, SB-300y, is bioequivalent to about 250 mg to about 1000 mg per day; about 250 mg per day; about 500 mg per day; about 1000 mg per day; about 125 mg two times per day; about 250 mg two times per day; or about 500 mg two times per day of an oral dosage form of crofelemer that is enterically protected.

[0015] In one aspect, presented herein are methods of treating (that is, improving) stool consistency in a subject diagnosed with PAIS-associated diarrhea, comprising: administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering about 500 mg per day; administering about 1000 mg per day; administering about 125 mg two times per day; administering about 250 mg two times per day; or administering about 500 mg two times per day of crofelemer, particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof (or is a dosage of a proanthocyanidin polymer composition, including SB-300, that is bioequivalent to the dosage of an enteric protected formulation of crofelemer). [0016] In one aspect, presented herein are methods of improving stool consistency in a subject diagnosed with PAIS-associated diarrhea, comprising: administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering about 500 mg per day; administering about 1000 mg per day; administering about 125 mg two times per day; administering about 250 mg two times per day; or administering about 500 mg two times per day of crofelemer, particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof (or is a dosage of a proanthocyanidin polymer composition, including S-300, that is bioequivalent to the dosage of an enteric protected formulation of crofelemer).

[0017] In one aspect, presented herein are methods of alleviating watery diarrhea in a subject diagnosed with PAIS-associated diarrhea, comprising: administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering about 500 mg per day; administering about 1000 mg per day; administering about 125 mg two times per day; administering about 250 mg two times per day; or administering about 500 mg two times per day of crofelemer, particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof (or is a dosage of a proanthocyanidin polymer composition, including SB-300, that is bioequivalent to the dosage of an enteric protected formulation of crofelemer).

[0018] In one aspect, presented herein are methods of decreasing the number of bowel movements per day, by 1, 2 or 3 bowel movements per day, in a subject diagnosed with PAIS- associated diarrhea, comprising: administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering about 500 mg per day; administering about 1000 mg per day; administering about 125 mg two times per day; administering about 250 mg two times per day; or administering about 500 mg two times per day of crofelemer, particularly, enterically protected crofelemer formulated as a tablet for oral administration, to a subject in need thereof (or is a dosage of a proanthocyanidin polymer composition, including SB-300, that is bioequivalent to the dosage of an enteric protected formulation of crofelemer).

[0019] The dosages may be the amount of a composition containing a proanthocyanidin polymer composition from C. lechleri, including, for example, SB-300, that is bioequivalent to the dose of an enteric protected formulation of crofelemer. [0020] In one embodiment, a human subject is considered treated if the subject demonstrates one or more of a decrease in the number of bowel movements per day, a decrease in the number of watery bowel movements per day, an improvement in the daily or weekly abdominal score for pain or discomfort, an improvement in the score for daily stool consistency, a decrease in stool consistency score (from watery to formed), a decrease in the number of days per week that subjects experienced urgency, a decrease in the number of days per week that the subject experienced fecal incontinence.

[0021] In one embodiment, a human subject is considered treated if the subject demonstrates an improvement in the score for daily stool consistency.

[0022] In one embodiment, a human subject is considered treated if the subject demonstrates a decrease in stool consistency.

[0023] In one embodiment, a human subject is considered treated if the subject demonstrates a decrease in the number of watery bowel movements per day.

[0024] In one embodiment, a human subject is considered treated if the subject demonstrates a decrease in the number of bowel movements per day.

[0025] In one embodiment, symptoms increased or decreased are measured from a baseline.

[0026] In one embodiment, the administering occurs for about 3 to 12 weeks or about 12 to 24 weeks or until the human subject has not longer post-acute infectious syndrome.

Other embodiments are disclosed below.

DETAILED DESCRIPTION

[0027] Proanthocyanidin polymer compositions of C. lechleri, particularly, crofelemer, and more particularly, enteric coated crofelemer formulated for oral administration, but also SB300 and various formulations of SB300, reduce, ameliorate, prevent or eliminate the gastrointestinal symptoms in a subject diagnosed with PAIS-associated diarrhea. Thus, administration of crofelemer, or other proanthocyanidin polymer composition of C. lechleri may reduce dehydration, malnutrition, and cardiovascular issues. [0028] The methods disclosed herein involved the administration of effective amounts of a proanthocyanidin polymer, e.g., crofelemer, to subjects diagnosed with PAIS-associated diarrhea or at risk of developing PAIS-associated diarrhea.

I. Definitions

[0029] Where a term is provided in the singular, the inventors also contemplate aspects of the invention described by the plural of that term. As used in this specification and in the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise, e.g., "a compound" includes a plurality of compounds. Thus, for example, a reference to "a method" includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure.

[0030] “Ameliorate,” “amelioration,” “improvement” or the like refers to, for example, a detectable improvement or a detectable change consistent with improvement that occurs in a subject or in at least a minority of subjects, e.g., in at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100% or in a range between about any two of these values. Such improvement or change may be observed in treated subjects as compared to subjects not treated with crofelemer, where the untreated subjects have, or are subject to developing, the same or similar disease, condition, symptom or the like. Amelioration of a disease, condition, symptom or assay parameter may be determined subjectively or objectively, e.g., self-assessment by a subject(s), by a clinician's assessment or by conducting an appropriate assay or measurement. Amelioration may be transient, prolonged or permanent or it may be variable at relevant times during or after crofelemer is administered to a subject or is used in an assay or other method described herein or a cited reference, e.g., within timeframes described infra, or about 1 hour after the administration or use of crofelemer to about 7 days, 2 weeks, 28 days, or 1, 3, 6, 9 months or more after a subject(s) has received such treatment.

[0031] The “modulation” of, e.g., a symptom, level or biological activity of a molecule, or the like, refers, for example, that the symptom or activity, or the like is detectably increased or decreased. Such increase or decrease may be observed in treated subjects as compared to subjects not treated with crofelemer, where the untreated subjects have, or are subject to developing, the same or similar disease, condition, symptom or the like. Such increases or decreases may be at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 1000% or more or within any range between any two of these values. Modulation may be determined subjectively or objectively. Modulation may be transient, prolonged or permanent or it may be variable at relevant times during or after crofelemer is administered to a subject or is used in an assay or other method described herein or a cited reference, e.g., within times descried infra, or about 1 hour of the administration or use of crofelemer to about 2 weeks, 28 days, 3, 6, 9 months or more after a subject(s) has received crofelemer.

[0032] As used herein, “subject” includes an animal, particularly a mammal, including a human, diagnosed with or suspected of having or having had a viral infection associated with PAIS- diarrhea, and having or being at risk for PAIS-associated diarrhea or who could otherwise benefit from the administration of the proanthocyanidin polymer composition as described herein, such as a human subject.

[0033] The language “a therapeutically effective amount” of a compound refers to an amount of the proanthocyanidin polymer composition, including, in embodiments, SB-300 or crofelemer which is effective, upon single or multiple dose administration to the subject, in treating, managing, or ameliorating the symptoms of the PAIS-associated diarrhea.

[0034] The term “administration” or “administering” includes routes of introducing crofelemer to a subject to perform its intended function. Examples of routes of administration that may be used include injection, oral, inhalation, vaginal, rectal and transdermal. The pharmaceutical preparations may be given by forms suitable for each administration route. For example, these preparations are administered in tablet or capsule form, by injection, inhalation, ointment, or suppository. Administration may also be by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred. Depending on the route of administration, crofelemer can be coated with or disposed in a selected material to protect it from natural conditions that may detrimentally affect its ability to perform its intended function. Crofelemer can be administered alone, or in conjunction with either another agent or agents as described above or with a pharmaceutically-acceptable carrier, or both. Exemplary enteric coated forms of crofelemer are described in, for example, US Patent 7,556,831. [0035] Administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.

[0036] The phrase “pharmaceutically acceptable” refers to proanthocyanidin polymer compositions, including crofelemer, as described herein, compositions containing proanthocyanidin polymer compositions, including crofelemer, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0037] The phrase “pharmaceutically-acceptable carrier” includes pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.

[0038] The term “treat” or “treatment” as used herein is intended to include the reduction or amelioration of the progression, severity, and/or duration of a condition or one or more symptoms caused by PAIS-associated diarrhea or resulting from the administration of one or more therapies.

[0039] For example, treating PAIS-associated diarrhea may include an improvement of the following symptoms of PAIS-associated diarrhea, including, for example, a decrease in the number of bowel movements per day (frequency), a decrease in the number of watery bowel movements per day, a decrease in symptom frequency (urgency, fecal incontinence), a decrease in symptom severity (abdominal pain or discomfort), a decrease in daily stool consistency score (watery to formed), or a decrease in stool consistency leading to formed stools from watery stools. The severity of PAIS-associated diarrhea may be characterized according to Common Toxicity Criteria for diarrhea, adapted from the National Cancer Institute (see, e.g., Stein et al., Ther. Adv. Med. Oncol. 2:51-43 (2010). In this criteria, Grade 1 is an increase of greater than 4 stools per day over baseline (or mild increase in ostomy output compared to baseline); Grade 2 is an increase of 4 to 6 stools per day over baseline (moderate increase in ostomy output compared to baseline); Grade 3 is an increase in greater than 7 stools per day over baseline, with incidences of incontinence and hospitalization indicated (severe increase in ostomy output compared to baseline); and Grade 4 is life-threatening consequences with urgent intervention indicated. Thus, treatment may include reduction in one, two or three grades of the criteria. Alternatively, PAIS-associated diarrhea may be characterized by stool frequency and consistency, as measured by the Bristol Stool scale.

[0040] The term “obtaining” as in “obtaining crofelemer” or other proanthocyanidin polymer composition, including SB-300, is intended to include purchasing, synthesizing, isolating, extracting or otherwise acquiring crofelemer or SB-300.

II. Active Compounds

A. Proanthocyanidins

[0041] Proanthocyanidins are a group of condensed tannins. Crude extracts from medicinal plants, for example, Pycanthus angolenis and Baphia nitida, have been shown to have anti diarrheal qualities in animal tests (Onwukaeme and Anuforo, 1993, Discovery and Innovation, 5:317; Onwukaeme and Lot, 1991, Phytotherapy Res., 5:254). Crude extracts which contain tannins, in particular extracts from carob pods and sweet chestnut wood, have been proposed as treatments or prophylactics (U.S. Pat. No. 5,043,160; European Patent No. 481,396).

[0042] Proanthocyanidins are comprised of at least two or more monomer units that may be of the same or different monomeric structure. The monomer units (generally termed "leucoanthocyanidin") are generally monomeric flavonoids which include catechins, epicatechins, gallocatechins, epigallocatechins, flavanols, flavonols, and flavan-3,4-diols, leucocyanidins and anthocyanidins. Therefore, the polymer chains are based on different structural units, which create a wide variation of polymeric proanthocyanidins and a large number of possible isomers (Hemingway et al., 1982, J. C. S. Perkin, 1: 1217). Larger polymers of the flavonoid 3-ol units are predominant in most plants, and are found with average molecular weights above 2,000 daltons, containing 6 or more units (Newman et al., 1987, Mag. Res. Chem., 25:118).

[0043] Proanthocyanidin polymers are found in a wide variety of plants, particularly those with a woody habit of growth (e.g., Croton spp. and Calophyllum spp.). A number of different Croton tree species, including Croton sakutaris, Croton gossypifolius, Croton palanostima, Croton lechleri, Croton erythrochilus and Croton draconoides, found in South America, produce a red viscous latex sap called Sangre de Drago or "Dragon's Blood". U.S. Pat. No. 5,211,944 first described the isolation of an aqueous soluble proanthocyanidin polymer composition from Croton spp. and the use of the composition as an antiviral agent (See also Ubillas et al., 1994, Phytomedicine, 1:77). The proanthocyanidin polymer composition was shown to have antiviral activity against a variety of viruses including, respiratory syncytial, influenza, parainfluenza and herpes viruses. U. S. Pat. No. 5,211,944 also discloses the isolation of an aqueous soluble proanthocyanidin polymer composition from Calophyllum inophylum and the use of this composition as an antiviral agent.

[0044] Exemplary proanthocyanidin polymer compositions useful in the methods presented herein are preferably isolated from a Croton spp. or Calophyllum spp. by any method known in the art. For example, the proanthocyanidin polymer composition may be isolated from a Croton spp. or Calophyllum spp. by the method disclosed in U.S. Pat. No. 5,211,944 or in Ubillas et al., 1994, Phytomedicine 1: 77-106.

[0045] In one specific embodiment, a proanthocyanidin polymer composition useful in the methods presented herein is crofelemer.

[0046] Crofelemer is an oligomeric proanthocyanidin extracted and purified from the red, viscous latex of the plant Croton lechleri of the family Euphorbiace. The plant is widely distributed throughout tropical Central America and South America and is widely recognized by ethnobotanists and local healers for its medicinal properties (McRae 1988), including for the treatment of diarrhea. Crofelemer is believed to exert its anti-diarrhea effect through luminal/apical blockade and/or negative modulation of CFTR (cystic fibrosis transmembrane conductance regulator) chloride (C1-) channel and calcium activated chloride channel (CaCC) (Tradtrandip et al., 2010). Crofelemer has demonstrated in vitro activity against cholera toxin, forskolin, E coli LT and STa toxin-mediated Cl- secretion, and to normalize electrolyte and fluid accumulation in CT-treated mice (Gabriel 1999, Fischer 2004, Adam 2005) via its effects on the CFTR channel. Crofelemer also significantly improved the symptom of secretory diarrhea in humans due to enterotoxigenic E. coli (DiCesare 2002), which is also thought to evoke secretory diarrhea through activation of CFTR (Kunzelmann 2002). Blockade of the CFTR channel could be anticipated to have negative consequences in humans, even mimicking cystic fibrosis. However, crofelemer negatively modulates the CFTR chloride channel in the gastrointestinal mucosa and restores the normal gating function of the channel, thus restoring the physiologic function of this important chloride ion channel in the gut. Crofelemer also has virtually no systemic oral bioavailability in humans. When studied, the results indicated that there was little or no absorption of crofelemer from the GI tract, and that crofelemer was well tolerated by healthy male or female subjects as well as HIV/AIDS patients (MacArthur et al., 2013) and patients with other acute infections from bacteria such as Vibrio cholera and Escherichia coli. Crofelemer also demonstrated improvement in abdominal pain and discomfort in male and female patients with diarrhea-predominant irritable bowel syndrome (d-IBS) (Nee et al, 2019). Thus, the site of action of crofelemer is topical (on the luminal side) in the gastrointestinal tract.

[0047] Crofelemer (CAS 148465-45-6) is an oligomeric proanthocyanidin of varying chain lengths derived from the Dragon's Blood Croton lecheri of the family Euphorbiaceae. Crofelemer has an average molecular weight of between approximately 2100 daltons (ranging between 1500 daltons and 2900 daltons). The monomers comprising crofelemer comprise catechin, epicatechin, gallocatechin, and epigallocatechin. The chain length of crofelemer ranges from about 3 to about 30 units with an average chain length of about 7 units. The structure of crofelemer is shown below.

Wherein the average n=6.

[0048] Another method for isolating crofelemer can be found in U.S. Patent Publication No. 2005/0019389, the contents of which are expressly incorporated herein. [0049] In addition, the proanthocyanidin polymer composition may be SB 300, as described, for example, by Fischer, H. et al., (2004, J. Ethnopharmacol. , 93(2-3):351-357). SB300 is a natural product extract that is particularly amenable for use in a non-enterically coated or protected formulations and compositions. In an embodiment, a pharmaceutically acceptable composition comprising a proanthocyanidin polymer from Croton lechleri and employed in the treatment methods of the invention can be obtained from C. lechleri, e.g., as described in WO 00/47062 to Shaman Pharmaceuticals, Inc., the contents of which are incorporated herein, and formulated as a food or dietary supplement or nutraceutical formulation, especially in a non-enterically coated formulation.

[0050] In other embodiments, a raw latex obtained from a Croton species or a Calophyllum species or an extract obtained from a Croton species or a Calophyllum species are useful in the methods presented herein. Exemplary extracts are described in Persinos et al., 1979, J. Pharma. Sci. 68:124 and Sethi, 1977, Canadian J. Pharm. Sci. 12:7.

III. Methods of Treatment

[0051] Provided herein are methods of treating, preventing, or alleviating or ameliorating diarrhea and/or other gastrointestinal symptoms associated with viral infection, particularly, PAIS comprising administering to a subject in need thereof an effective amount of a proanthocyanidin composition from C. lechleri, in embodiments, SB-300 or crofelemer, alone or in combination with other anti-viral agents or other therapeutics useful for the treatment or management of diarrhea associated with the viral infection, including the PAIS associated with the viral infection. Exemplary diarrhea that can be treated or prevented using the methods presented herein include PAIS-associated diarrhea. In some embodiments, said diarrhea or gastrointestinal symptoms are associated with PAIS of coronavirus, particularly PAIS of SARS-CoV2. The subject is preferably a human. The subject may be a mammal that suffers from PAIS-associated diarrhea, including primates, equines, bovines, ovines, rodents, felines, or canines.

[0052] In one embodiment, treating PAIS-associated diarrhea includes an improvement of the following symptoms of PAIS-associated diarrhea, including, for example, a decrease in the number of bowel movements per day (frequency), a decrease in the number of watery bowel movements per day, a decrease in symptom frequency (loose/watery stools, urgency, fecal incontinence), a decrease in symptom severity (abdominal pain or discomfort), a decrease in daily stool consistency score (watery to formed), or a decrease in stool consistency leading to formed stools from watery stools. In certain embodiments, the treatment results in a reduction in the Grade of the Common Toxicity Criteria for diarrhea, for example, from Grade 4, to Grade 3, Grade 2 or Grade 1; or from Grade 3, to Grade 2 or Grade 1; or from Grade 2 to Grade 1. In certain embodiments, the treatment results in an improvement such that the subject does not meet any of the Common Toxicity Criteria Grades, i.e., is no longer suffering from diarrhea.

[0053] In other specific embodiments, treatment can also include, for example, one or more of a decrease in the number of bowel movements per day, a decrease in the number of watery bowel movements per day, an improvement in the daily abdominal score for pain or discomfort, an improvement in the score for daily stool consistency, a decrease in the number of days per week or per month that subjects experienced urgency, or a decrease in the number of days per week or per month that subjects experienced fecal incontinence.

[0054] In one aspect, provided herein are methods of treating diarrhea in a subject diagnosed with PAIS comprising administering to a subject in need thereof a composition comprising an effective amount of a proanthocyanidin polymer composition of C. lechleri, in embodiments, SB-300 or crofelemer, to treat PAIS-associated diarrhea. In specific embodiments, the crofelemer is an enterically coated oral dosage form. In other embodiments, the crofelemer is an oral dosage form that is not enterically protected. In other embodiments, SB-300 is administered.

[0055] In certain embodiments, the proanthocyanidin polymer composition, in embodiments, SB-300 or crofelemer, is administered until symptoms of PAIS-associated diarrhea are ameliorated and then administration of the proanthocyanidin polymer composition is discontinued.

[0056] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration may vary depending upon the age, weight and mammalian species treated, the particular compounds employed, and/or the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine pharmacological methods. [0057] In one aspect, provided herein are methods of treating stool consistency in a subject diagnosed with PAIS-associated diarrhea, wherein a subject is considered treated if there is an improvement in the score for daily stool consistency and/or a decrease in stool consistency score a measured throughout the day or days or weeks comprising administering to a subject in need thereof a composition comprising an effective amount of proanthocyanidin polymer composition, in embodiments SB-300 or crofelemer, to treat stool consistency. This decrease may be measured from a baseline. The baseline may be determined in the days to week prior to treatment with the proanthocyanidin polymer composition. Treatment comprises administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering 1000 mg per day; administering about 125 mg two times per day; or administering about 500 mg two times per day of crofelemer, preferably an enteric coated oral dosage form, to a subject in need thereof or a dosage of a proanthocyanidin polymer composition (including a non-enteric protected oral dosage form of crofelemer or SB-300) that is bioequivalent to 250 mg to about 1000 mg per day; about 250 mg per day; 1000 mg per day; about 125 mg two times per day; or about 500 mg two times per day of enteric protected oral dosage form of crofelemer.

[0058] In one aspect, provided herein are methods of alleviating watery diarrhea in a subject diagnosed with PAIS-associated diarrhea, wherein a subject is considered treated if the subject experiences a decrease in the number of watery bowel movements per day (by 1, 2 or 3 or more) and/or over days, a week or weeks of administration of the proanthocyanidin polymer composition, in embodiments, SB-300 or crofelemer, comprising administering to a subject in need thereof a composition comprising an effective amount of the proanthocyanidin polymer composition (e.g., SB-300 or crofelemer) to alleviate watery diarrhea.

[0059] This decrease may be measured from a baseline. The baseline may be determined in the days to one or more weeks prior to treatment with the proanthocyanidin polymer composition. Treatment comprises administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering 1000 mg per day; administering about 125 mg two times per day; or administering about 500 mg two times per day of crofelemer, preferably an enteric coated oral dosage form of crofelemer, to a subject in need thereof, or, alternatively, a dosage of a proanthocyanidin polymer composition (including a non-enteric protected oral dosage form of crofelemer or SB-300) that is bioequivalent to 250 mg to about 1000 mg per day; about 250 mg per day; 1000 mg per day; about 125 mg two times per day; or about 500 mg two times per day of enterically protected oral dosage form of crofelemer.

[0060] In one aspect, presented herein are methods for decreasing the number of bowel movements per day, wherein a subject is considered treated if there is a decrease in the number of bowel movements per day as measured from a baseline comprising administering to a subject in need thereof a composition comprising an effective amount of proanthocyanidin polymer composition (e.g., crofelemer or SB-300) to decrease the number of bowel movements per day (by 1, 2 or 3 from baseline) or to 1 or 2 bowel movements per day (including on average over a course of 2, 3, or 4 days).

[0061] The baseline may be determined in the days to week prior to treatment with the proanthocyanidin polymer composition. Treatment comprises administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering 1000 mg per day; administering about 125 mg two times per day; or administering about 500 mg two times per day of crofelemer, preferably an enteric coated oral dosage form of crofelemer, to a subject in need thereof, or, alternatively, a dosage of a proanthocyanidin polymer composition (including a non-enteric protected oral dosage form of crofelemer or SB-300) that is bioequivalent to 250 mg to about 1000 mg per day; about 250 mg per day; 1000 mg per day; about 125 mg two times per day; or about 500 mg two times per day of enterically protected oral dosage form of crofelemer.

[0062] The proanthocyanidin polymer composition, in embodiments, crofelemer (including, in embodiments, enteric coated crofelemer) or SB-300, may be administered, for example, once a day, twice a day, three times a day, or four times or more often as necessary per day. Crofelemer, in embodiments, enteric coated crofelemer, may be administered in doses, for example of from about between 25 mg BID to about 3000 mg TID, preferably crofelemer is administered from between about 125 mg to about 1000 mg per day. In another embodiment, crofelemer is administered between 125 mg BID to about 500 mg BID depending of symptoms (or a bioequivalent amount of a proanthocyanidin polymer composition, including crofelemer that is not enteric coated or SB-300). In another embodiment, crofelemer is administered as 125 mg BID. In another embodiment, crofelemer is administered as 500 mg BID. Crofelemer may be administered orally, for example, in tablet form, powder form, liquid form or in capsules. In preferred embodiments, the crofelemer is formulated as an enteric coated oral dosage form. In other embodiments, the crofelemer is an oral dosage form that is not enteric coated. In other embodiments, SB-300 is administered.

[0063] In exemplary embodiments, the subject is orally administered 250, 500, or 1000 mg/ day of enteric protected crofelemer or is administered a dose of a proanthocyanidin polymer composition, including crofelemer or SB-300, that is bioequivalent to an oral dosage form of enteric coated crofelemer administered at 250, 500, or 1000 mg/day.

[0064] In specific embodiments, the subject is administered 125, 250 or 500 mg p.o. b.i.d (orally twice per day) enteric coated crofelemer or a dosage of a proanthocyanidin polymer composition bioequivalent to 125, 250 or 500 mg p.o. b.i.d enteric coated crofelemer. Other appropriate dosages for methods may be determined by health care professionals or by the subject. The amount of crofelemer administered daily may be increased or decreased based on the weight, age, health, sex or medical condition of the subject. One of skill in the art would be able to determine the proper dose for a subject based on this disclosure and the data presented in the Examples, which follow.

[0065] In other embodiments, the subject is treated with the proanthocyanidin polymer composition, in embodiments, crofelemer or SB-300, for 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 or more weeks or 26 or more weeks or until the PAIS or the diarrhea associated with the PAIS has resolved. Length of treatment may vary depending on the type and length of disease and the proper length of treatment may be easily determined by one of skill in the art having the benefit of this disclosure.

[0066] Subjects in need thereof include subjects having or that are susceptible to or who have PAIS-associated diarrhea.

[0067] In certain embodiments, the subject is administered proanthocyanidin polymer composition, in embodiments crofelemer or SB-300, for treatment of PAIS-associated diarrhea in combination with one or more anti-diarrheals, such as, but not limited to, loperamide, octreotide, probiotics and any other agent useful for the treatment of PAIS-associated diarrhea. [0068] According to certain embodiments, the proanthocyanidin polymer composition, which may be, in embodiments, SB-300 or crofelemer, may be administered in combination with other therapeutics for the treatment and management of the viral infection and PAIS- associated diarrhea. In particular embodiments, other therapeutics for the treatment and management of the viral infection and PAIS include but are not limited to interferon alpha 2b, interferon beta la, corticosteroids, including dexamethasone, immunomodulators (e.g, azathioprine, 6-mercaptopurine, and/or methotrexate), mitoxantrone, tyrosine kinase inhibitors (e.g. ruxolitinib, imatinib), anti-viral medications (e.g. monupiravir, lopinavir, PF-07321332, ritonavir, remdesivir, favipiravir, oseltamivir, sofosbuvir, and combinations thereof, including the combination of ritonavir and PF-07321332), and anti-inflammatory monoclonal antibodies.

IV. Pharmaceutical Preparations

[0069] Also provided herein are pharmaceutical compositions, comprising an effective amount of a crofelemer or a proanthocyanidin polymer composition described herein, including, in embodiments, SB-300, and a pharmaceutically acceptable carrier. In a further embodiment, the effective amount is effective to treat PAIS-associated diarrhea.

[0070] Examples of the preparation and use of crofelemer have been described in US Patent 7,556,831, US Patent Publication 20070254050 and US Patent Publication 20080031984, all of which are incorporated herein by reference in their entirety.

[0071] One embodiment includes pharmaceutical compositions comprising crofelemer and a pharmaceutically acceptable carrier. In preferred embodiments, the pharmaceutical composition is an enterically protected oral dosage form, such as a tablet or capsule. Alternatively, the pharmaceutical composition is an oral dosage form that is not enterically protected.

[0072] In addition, the proanthocyanidin polymer composition may be SB 300, as described, for example, by Fischer, H. et al., (2004, J. Ethnopharmacol. , 93(2-3):351-357). SB300 is a natural product extract that is particularly amenable for use in a non-enterically coated or protected formulations and compositions.

[0073] The pharmaceutical compositions described herein may further comprise excipients, for example, one or more of a diluting agent, binding agent, lubricating agent, disintegrating agent, coloring agent, flavoring agent or sweetening agent. Compositions may be formulated for selected coated and uncoated tablets, hard and soft gelatin capsules, sugar- coated pills, lozenges, wafer sheets, pellets and powders in sealed packet. For example, compositions may be formulated for topical use, for example, ointments, pomades, creams, gels and lotions.

[0074] In certain embodiments, these pharmaceutical compositions are suitable for topical or oral administration to a subject. In other embodiments, as described in detail below, the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.

[0075] A pharmaceutical carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0076] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0077] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0078] Compositions containing crofelemer or a proanthocyanidin polymer composition, including, SB-300, include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.01% to about 99% of active ingredient, for example, from about 5% to about 70%, or from about 10% to about 30%.

[0079] Liquid dosage forms for oral or rectal administration of proanthocyanidin polymer composition, including, in embodiments, crofelemer or SB-300, may include, for example, pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0080] Suspensions, in addition to crofelemer may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Dosage forms for the topical or transdermal administration of crofelemer can include, for example, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The ointments, pastes, creams and gels may contain, in addition to crofelemer, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to a crofelemer, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0081] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions can include, for example, water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0082] In one embodiment, crofelemer is enteric coated so as to protect it from degradation by the acidic conditions of the stomach and/or from interactions with proteins, such as pepsin, present in the stomach, e.g., an enteric protected formulation. In a specific embodiment, crofelemer is in tablet form. In yet another embodiment, the tablet is enteric coated, e.g., Eudragit®. In one embodiment, crofelemer is formulated as an enteric coated bead or granule in an enteric coated capsule shell. In another embodiment, crofelemer is formulated in a delayed release composition.

[0083] In certain embodiments, the composition is formulated with a compound or compounds which neutralize stomach acid. Alternatively, the pharmaceutical composition containing the composition is administered either concurrent with or subsequent to or after administration of a pharmaceutical composition which neutralize stomach acid. Compounds, such as antacids, which are useful for neutralizing stomach acid include, but are not limited to, aluminum carbonate, aluminum hydroxide, bismuth subnitrate, bismuth subsalicylate, calcium carbonate, dihydroxyaluminum sodium carbonate, magaldrate, magnesium carbonate, magnesium hydroxide, magnesium oxide, and mixtures thereof. Compounds that are able to reduce the secretion of stomach acid and/or are able to reduce the acidity of stomach fluid are well known in the art and include, but are not limited to, antacids (aluminum hydroxide, aluminum carbonate, aluminum glycinate, magnesium oxide, magnesium hydroxide, magnesium carbonate, calcium carbonate, sodium bicarbonate), stomach acid blockers and a combination of any of the foregoing. In general, any drug that has been approved for sale by the relevant government agency and is able to reduce the production of stomach acid and/or reduce the acidity of stomach fluid can be administered in combination with an inhibitor molecule, such as crofelemer, in accordance with the methods presented herein.

[0084] In a particular embodiment where crofelemer is not enteric coated, crofelemer is formulated with one or more compounds that are able to reduce the secretion of stomach acid and/or able to reduce the acidity of stomach fluid. In an exemplary embodiment, crofelemer is formulated in a controlled release (delayed release) composition, such as Merck GEM, Alza OROS, wax matrix (release is primarily delayed until after the formulation passes out of the stomach and into the intestine).

[0085] Also provided herein are pharmaceutical formulations of crofelemer comprising the composition along with a pharmaceutically acceptable carrier, at a dose which is therapeutically effective at treating PAIS-associated diarrhea. In one embodiment, a directly compressible crofelemer (e.g., that can be directly compressed, without excipients, into a tablet of pharmaceutically acceptable hardness and friability) compressed into a tablet, optionally with a lubricant, such as but not limited to magnesium stearate, is enteric coated. These formulations can be prepared by methods known in the art, see, e.g. methods described in Remington's Pharmaceutical Sciences, 18th Ed., ed. Alfonso R. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0086] In a specific embodiment, the proanthocyanidin polymer composition comprises crofelemer (CAS 148465-45-6).

[0087] In a more another embodiment, a composition is enteric coated. Enteric coatings are those coatings that remain intact in the stomach, but will dissolve and release the contents of the dosage form once it reaches the small intestine. A large number of enteric coatings are prepared with ingredients that have acidic groups such that, at the very low pH present in the stomach, i.e. pH 1.5 to 2.5, the acidic groups are not ionized and the coating remains in an undissociated, insoluble form. At higher pH levels, such as in the environment of the intestine, the enteric coating is converted to an ionized form, which can be dissolved to release the inhibitor molecule. Other enteric coatings remain intact until they are degraded by enzymes in the small intestine, and others break apart after a defined exposure to moisture, such that the coatings remain intact until after passage into the small intestines.

[0088] Polymers which are useful for the preparation of enteric coatings include, but are not limited to, shellac, starch and amylose acetate phthalates, styrene-maleic acid copolymers, cellulose acetate succinate, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate (grades HP-50 and HP-55), ethylcellulose, fats, butyl stearate, and methacrylic acid-methacrylic acid ester copolymers with acid ionizable groups. In one embodiment, the pharmaceutical composition contains a polymeric proanthocyanidin composition and the enteric coating polymer Eudragit^® L 30D, an anionic copolymer of methacrylic acid and methyl acrylate with a mean molecular weight of 250,000 Daltons. In another embodiment, the enteric coating polymer is Eudragit^® L 30D-55. Application of the enteric coating to the crofelemer composition can be accomplished by any method known in the art for applying enteric coatings. For example, but not by way of limitation, the enteric polymers can be applied using organic solvent based solutions containing from 5 to 10% w/w polymer for spray applications and up to 30% w/w polymer for pan coatings. Solvents that are commonly in use include, but are not limited to, acetone, acetone/ethyl acetate mixtures, methylene chloride/methanol mixtures, and tertiary mixtures containing these solvents. Some enteric polymers, such as methacrylic acid-methacrylic acid ester copolymers can be applied using water as a dispersant. The volatility of the solvent system must be tailored to prevent sticking due to tackiness and to prevent high porosity of the coating due to premature spray drying or precipitation of the polymer as the solvent evaporates.

[0089] In another embodiment, the pharmaceutical composition comprising crofelemer is formulated as enteric coated granules or powder (microspheres with a diameter of 300-5001) provided in either hard shell gelatin capsules or suspended in an oral solution for pediatric administration. The enteric coated powder or granules may also be mixed with food, particularly for pediatric administration.

[0090] The granules and powder can be prepared using any method known in the art, such as but not limited to, crystallization, spray-drying or any method of comminution, for example, using a high speed mixer/granulator. Exemplary formulations may be found, for example, in the following US patents and applications US Patent No. 7,341,744; USSN 11/510,152; and USSN 12/175,131.

[0091] Regardless of the route of administration selected, crofelemer is formulated into pharmaceutically-acceptable dosage forms by methods known to those of skill in the art.

V. Kits

[0092] Kits are also provided herein, for example, kits for treating a diarrhea, e.g., PAIS- associated diarrhea in a subject suffering therefrom. The kits may contain, for example, crofelemer or a pharmaceutical composition comprising crofelemer and instructions for use. The instructions for use may contain prescribing information, dosage information, storage information, and the like.

[0093] Label instructions include, for example, instructions to take the crofelemer for at least 3 days for the treatment of PAIS-associated diarrhea. The instructions could also read, for example, take from between 125mg BID to 500mg BID of crofelemer until resolution of symptoms. The instructions could also read, for example, take 125mg BID of crofelemer until resolution of symptoms. The instructions could also read, for example, take 500mg BID of crofelemer until resolution of symptoms of CID.

EXAMPLE

[0094] It should be appreciated that the invention should not be construed to be limited to the example, which is now described; rather, the invention should be construed to include any and all applications provided herein and all equivalent variations within the skill of the ordinary artisan. Example 1: A Study of Crofelemer treatment in SARS-CoV2 patients with persistent diarrhea

[0095] Study Design: This study will look at the efficacy of the drug crofelemer in treating diarrhea in post-acute SARS-CoV2 syndrome patients.

[0096] Protocol:

[0097] Approximately 50 patients will be randomly assigned to the treatment arm or the control. Patients on the treatment arm will take one tablet of crofelemer twice a day (each tablet is 125 mg), to be swallowed whole without chewing or crushing. Patients on the control arm will not receive crofelemer at any time on this study.

[0098] Eligibility Criteria:

[0099] Patients eligible for the study much be as follows: Willing and able to provide written informed consent; man or woman >18 years of age; confirmed diagnosis of SARS- CoV2 infection and persistent symptoms after recovering from their initial illness; have a negative pregnancy test at time of informed consent for women of childbearing potential; and be able to read, understand, follow the study procedure and complete crofelemer, rescue medication, and bowel movement diaries. Patients not eligible for the study include women who are breastfeeding; those with ongoing irritable bowel syndrome (IBS) or colitis (including but not limited to ulcerative colitis, Crohn's disease, microscopic colitis, etc.); those using investigational drugs within 3 weeks of signing consent or foreseen use during the study, laxatives within the past 7 days, chronic laxatives (> 30 consecutive days), or anti-diarrheal agents (including but not limited to loperamide, octreotide, bismuth, tincture of opium, atropine, probiotics in any form other than food) within the past 7 days,. Patients are also excluded if they have any of the following: any type of ostomy; total colectomy; fecal incontinence; ongoing radiation induced diarrhea or constipation or planned radiotherapy to the abdomen or pelvis while on study.

[0100] Effectiveness Variables:

[0101] Stool frequency and consistency, as measured by the Bristol Stool scale, will be the primary outcome measure. Patients will keep daily bowel movement diaries monitoring stool frequency and consistency. [0102] The pharmacological effects of crofelemer on reducing diarrhea severity will be assessed by: a) Determining the proportion of “responders” defined as human subjects with <7 watery stool for at least 2 weeks of the 4-week treatment period; b) Evaluating the average number of watery stools per week in the treatment group compared to placebo; c) Comparing the stool consistency determined by the average fecal scores per week in the treatment group versus placebo; and d) Evaluating the changes in body weight, clinical chemistry, and hematologic parameters across the treatment group and placebo.

[0103] Use of anti -diarrheal medications (other than study drug) will be assessed as secondary outcome measure.

[0104] Summary statistics will be computed at each week and pair-wise p-values will be computed via t-test to determine differences for the crofelemer-treated groups from the control group. Analysis of covariance (ANCOVA) will be conducted using baseline fecal scores as a covariate. Least Squares Mean (LSM) results will be adjusted for baseline scores.

[0105] All publications, patents, and patent applications cited herein are hereby incorporated herein by reference in their entirety.

Claims

What is claimed is:

1. A method of treating diarrhea in a human subj ect diagnosed with post-acute infectious syndrome (PAIS) and having diarrhea comprising administering to a subject in need thereof a composition comprising an effective amount of a proanthocyanidin polymer composition from C. lechleri, to treat PAIS-associated diarrhea.

2. The method of claim 1 wherein the proanthocyanidin polymer composition is crofelemer or SB300.

3. The method of claim 1 or 2, wherein post-acute infectious syndrome is post-acute SARS-CoV2 syndrome.

4. The method of any of claims 1 to 3, wherein the proanthocyanidin polymer composition is administered after a subject exhibits symptoms of PAIS-associated diarrhea.

5. The method of any of claims 1 to 4, wherein the proanthocyanidin polymer composition is administered until symptoms of PAIS-associated diarrhea are ameliorated and then the administration is discontinued.

6. The method of any of claims 2 to 5, wherein the administering comprises administering about 250 mg to about 1000 mg per day; administering about 250 mg per day; administering about 500 mg per day; administering about 1000 mg per day; administering about 125 mg two times per day; administering about 250 mg two times per day; or administering about 500 mg two times per day of crofelemer, or an amount of a proanthocyanidin polymer composition bioequivalent thereto, to a subject in need thereof.

7. The method of any of claims 1 to 6, wherein the crofelemer is administered as an enteric coated oral dosage form.

8. The method of any of claims 1 to 6, wherein the proanthocyanidin polymer composition is administered as an oral dosage form that is not enteric coated.

9. The method of any of claims 1 to 8, wherein a subject is considered treated if the subject demonstrates one or more of a decrease in the number of bowel movements per day, a decrease in the number of watery bowel movements per day, an improvement in the daily abdominal score for pain or discomfort, an improvement in the score for daily stool consistency, a decrease in stool consistency, a decrease in the number of days per week that subjects experienced urgency, a decrease in the number of days per week that subjects experienced fecal incontinence, or a decrease in the unscheduled visit for a significant worsening of diarrhea.

10. The method of any of claims 1 to 9, wherein the administration results in a decrease in 1, 2 or 3 Grades of the Grade of diarrhea according to the Common Toxicity Criteria.

11. A method of treating diarrhea in a human subj ect diagnosed with post-acute infectious syndrome (PAIS), said method comprising administering to said human subject a composition comprising crofelemer at a dose of 125 mg twice per day or an amount of a proanthocyanidin polymer composition bioequivalent thereto.

12. A method of slowing the progression of or reducing the risk of developing diarrhea associated with PAIS in a subject in need thereof, said method comprising administering to said human subject a composition comprising crofelemer at a dose of 125 mg twice per day or an amount of a proanthocyanidin polymer composition bioequivalent thereto.