Control of cellular redox levels

Abstract

Disclosed herein are compositions and methods for regulating redox status and / or reducing oxidative stress in a subject, the methods and compositions comprising TLR agonists comprising bacterial lysates and / or lysate fractions. Also disclosed are compositions and methods comprising bacterial lysates and / or lysate fractions formulated or administered in combination with one or more other therapeutic or pharmaceutical agents. Oct 2023 2023251534 20

Description

[0001] This application is a divisional application of Australian Patent Application No. 2016352986, which is the national phase of International Application No. PCT / US2016 / 061247, which in turn claims the benefit of U.S. Provisional Application No. 62 / 253,542, filed November 10, 2015. U.S. Provisional Application No. 62 / 253,542 is also a continuation-in-part of U.S. Application No. 14 / 640,075, filed March 6, 2015, which is a continuation of U.S. Application No. 14 / 034,044, filed September 23, 2013, which claims the benefit of U.S. Provisional Application No. 61 / 704,090, filed September 21, 2012. U.S. Provisional Application No. 62 / 253,542 is also a continuation-in-part of U.S. Application No. 13 / 743,194, filed January 16, 2013, which claims the benefit of U.S. Provisional Application No. 61 / 586,975, filed January 16, 2012. All of the above-identified applications are hereby incorporated by reference in their entireties. BACKGROUND

[0002] The innate immune response is one of the pathways that regulates inflammation. Inflammation is stimulated by chemical factors released by injured cells and serves to establish a physical barrier against the spread of infection, and to promote healing of any damaged tissue following the clearance of pathogens. The process of acute inflammation is initiated by cells already present in all tissues, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells, and mastocytes. These cells present receptors, contained on the surface or within the cell, named pattern recognition receptors (PRRs), which recognize molecular patterns that are broadly shared by pathogens but are distinguishable from those of the host. These molecular patterns are collectively referred to as pathogen-associated molecular patterns (PAMPs). Immune cells undergo activation when one of their PRRs recognizes a PAMP and in response release inflammatory mediators.

[0003] PAMPs are thus structures associated with groups of pathogens that are recognized by cells of the innate immune system. A vast array of different chemical types can serve as PAMPs, including glycans and glycoconjugates. These structures can also be referred to as small molecular motifs which are conserved within a class of microbes. They are recognized by Tolllike receptors (TLRs) and other PRRs in both plants and animals. 2023251534 20 Oct 2023

[0004] TLRs are conserved receptors that recognize structures from bacteria, fungi, protozoa, and viruses. Although the TLR receptor is located on the surface of the plasma membrane, binding to the receptor is transmitted transmembrane and results in an intercellular signaling response. TLR signaling ultimately leads to the induction or 2023251534 20 Oct 2023 sappression of genes that orchestrate the inflammatory response. Activation of a particular TLR, for example. Initiates a series of intracellular events resulting in an immune response characterized by the production of pro-inflammatory cytokines, TLR signaling originates from die cytoplasmic Toll-interleukin 1 (TIR) domain, conserved among alt TLRs. The adapter molecule MyD88, containing both a TIR. domain and a death domain, associates with the TIR domain of TLRs and IRAK proteins. Phosphorylation of IRAK leads to association with TRAF6 and subsequent activation of NF-kB and secretion of pro-inflammatory cytokines. A52R, an immunoregulatory protein from the vaccinia virus, has previously been Shown to be an intracellular inhibitor of TIR-dependent signaling. When expressed in HEK291 cells, Ao^R was shown to inhibit XI-kB activation in response to stimulation by a variety of TLRs, including TLR4, TLR5, and the combination of TLR2 and 6, and TLR2 and L In addition, A52R inhibited NF-kB activation in response to Poly (1 :0 k a synthetic ligand for TLR3, TLRS has been implicated in an anti-viral innate immune response (QOOSJ    One of the primary responses of activation is to shift the redox status of a cell Reactive Oxygen species (ROS) can be produced for defensive purposes. The very presence of ROS consumes antioxidants ('reductants) and results in a more oxidative redox statox. Not only can ROS and oxidative conditions result in cellular damage with concomitant activation of genes, redox status itself controls gene expression. For example, when conditions become more oxidative, easily oxidized chemical groups such as sulfhydryl groups on certain proteins become oxidized. The oxidized state of these proteins is then recognized, leading to arm nflon of specific genes, such ns genes controlling redos status and promoting or controlling inflammation, or genes producing aberrant or disease-promoting proteins. (00061    Inflamma tion is part of the complex biological response of body tissues io harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation can also result from autoimmune disorders (where body tissues are incorrectly recognized as being, foreign). Inflammation Initially serves as a protective response that involves immune cells, blood \ csscls, and molecular mediators-. One purpose of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatoty process, and to initiate tissue repair. It is useful to differentiate inflammation from infection conceptually, as there are many pathological situations where inflammation is not driven by microbial invasion or infection, for example, atherosclerosis, type Ilf hipcrsensim ity. naiima, and ischemia. There are also pathofovieal mtuauonx where microbial invasion does net result in classic inflammatory response, for example, as in eosinophilia. Whereas too little inflammation could lead to progressive tissue destruction by - 2 - o ri S. «« , to rs ft S production and release of free radicals and other ROS fem damaged and / or inflamed tissues and as a result contributes to or causes oxidative stress. At the same, time, mOarnnistipn can result from oxidative stress when ROS damage tissues. As such, indammatton and the various conditions associated with it can also be regarded as an “oxidative stress-related when bacteria and their products activate an uncontrolled network of host-derived mediators, such as pro-inflammatory cytokines which can lead to multi-organ failure, cardiovascular collapse and death An abnormal TLR signaling response could lead to exaggerated cell* activation responses contributing to sepsis. j0008| Inflammation (whether chronic or acute) results from and leads to the increased & 2023251534   28 Aug 2026 certain number of ROS including free radicals are naturally produced by the body due to cell metabolism. For instance, the synthesis of some hormones involves the generation of free radicals while polymorphonuclear leukocytes use the production of free radicals as a form of “chemical warfare” to kill bacteria, thereby guarding the body against infections. Other free radicals, such as Nitric Oxide (NO) are fundamental for the homeostasis of the body, because they act as chemical messengers to modulate important functions, including vascular tone, platelet aggregation, cell adhesion, and so on.

[0010] Free radicals are potentially dangerous because they spontaneously tend to fill their unfilled external orbital with a second electron. The presence of two electrons in the same orbital is the condition of maximal stability—minimum energy. Therefore, when a free radical collides with a “target molecule”, having one or more “available” electrons, such as the molecule of an unsaturated fatty acid (e.g., arachidonic acid), it immediately “extracts” an electron from the target molecule. Due to this effect—“oxidation”—the original free radical loses its potential dangerousness whilst the newly generated molecule is “oxidized” and, in turn, may become a new free radical, thus perpetuating the reaction, if no antioxidants are available to damp it. The reaction can continue to other molecules, including carbohydrates, lipids, amino acids, peptides, proteins, nucleotides, nucleic acids and so on (“chain reaction effect”). Such action by free radicals can result in varying degrees of tissue damage and can cause (or conversely result from) inflammatory responses. An initial or primary site of ROS release may be an appropriate response to an invading microorganism, but the invader is not destroyed or if redox homeostasis is not restored following destruction of the invader, the redox state may spread and the continuing secondary oxidative redox state may result in a chronic, damaging pathology with collateral tissue damage. An example would be traumatic brain injury (TBI) which leads to localized inflammation and oxidative redox status in the brain. If homeostasis is not reestablished, chronic oxidative redox status may result leading to long term tissue damage and chronic traumatic encephalopathy (CTE).

[0011] There thus exists a need in the art for compositions and methods for controlling cellular redox levels. SUMMARY

[0012] The methods and compositions disclosed herein are not limited to specific advantages or functionality. [0012a] In a first aspect, the present invention provides a method of regulating redox status in a subject, the method comprising administering to the subject a composition comprising: 2023251534   28 Aug 2026 a Toll-like receptor (TLR) agonist comprising at least one lysate and / or lysate fraction of an inactivated bacterium comprising the entire cellular contents of the bacterium cell, wherein: the TLR agonist activates TLR 2 and TLR 4 in the subject; and the bacterium is inactivated by a heat treatment of the bacterium followed by a lysozyme treatment of the bacterium; wherein administration of an effective amount of the composition to the subject measurably reduces oxidative stress levels in the subject and decreases the amount of isoprostane in the urine or blood of the subject. [0012b] In a second aspect, the present invention provides use of a composition comprising a Toll-like receptor (TLR) agonist comprising at least one lysate and / or lysate fraction of an inactivated bacterium comprising the entire cellular contents of the bacterium cell in the manufacture of a medicament for regulating redox status in a subject, the bacterium is inactivated by a heat treatment of the bacterium followed by a lysozyme treatment of the bacterium; wherein administration of an effective amount of the composition to the subject measurably reduces oxidative stress levels in the subject and decreases the amount of isoprostane in the urine or blood of the subject. [0012c] In a third aspect, the present invention provides a pharmaceutical formulation comprising the composition as recited in the first aspect and one or more pharmaceutical agents.

[0013] In one aspect, the disclosure provides toll-like receptor (TLR) agonist compositions for regulating redox status in a subject, the composition comprising: (a) a TLR 2023251534 20 Oct 2023 agonist comprising at least one lysate and / or lysate fraction of a bacterium, wherein, the TLR agonist activates at least one or more TLRs or NLRs, tbT an optional promoter for enhancing absorption of the composition; and (c) an optional carnet for increasing a volume of the composition, wherein administration of an effective amount of the composition to the subject measurably reduces oxidative stress levels in the subject. |W4| In another aspect, the disclosure provides methods of regulat ing redox status in a subject, the method comprising administering s therapeutically effective amount of a lysate composition, according to the disclosure to a subject in need thereof In some embodiments, redox status regulation is assessed by measuring changes in isoprostane concentration in the subject. |0015| In another aspect, the disclosure provides methods of regulating redox status in a subject, the method comprising the steps of: (a) repeatedly administering to a subject in need thereof doses spaced apart tn time and consisting of a composition comprising 01 a toll-like receptor (TLR) agonist comprising at least one lysate and / or lysate fraction of a bacterium, wherein the agonist activates at least one or more different TLRs or NLRs; (ii) an. optional promoter for enhancing absorption of the composi tion; and (iii) an optional carrier for increasing a volume of the composition; and (b) making measurements of a bodily fluid of the subject to detect changes in oxidative stress levels. In another aspect, the disclosure provides methods of decreasing the amount of isoprostane in the urine or blood of a subject, the method comprising the steps of: (a) determining the level of isoprostane in the urine or blood of the subject; (b) administering to the subject an effect n e amount of a composition comprising: (i) a toh-hke receptor (Tl.R.i agonist comprising at least one bacterial lysate and / or lysate fraction horn a bacterium, wherein the TLR agonist activates at least one or more different TLRs or NLRs; and (ii) an optional promoter for enhancing .absorption of the composition; and (c) continuing administration of the composition until the level of isoprostane in the urine or blood of the subject is decreased. |0dl7| In another aspect, the disclosure provides compositions comprising: (a) a bacterial lysate and / or lysate fraction, capable of activating at least one or more toll-like receptors (TLRs) or Nod-like receptors (NLRs); (b) an optional promoter for enhancing absorption of the composition; and (c) an optional carrier for increasing a volume of die composition. |0018|    In another aspect, the disclosure provides pharmaceutical formulations comprising lysate compositions according to the disclosure, wherein the pharmaceutical formulation is 2023251534 20 Oct 2023 fofmulated for buccal or sublingual administration. In some embodiments, the pharmaccu&al formulations are formulated to dissolve in not less than 1 mimue after administration. 100191    In another aspect, the disclosure provides methods of producing a bacterial lysate comprising the steps of: (a) fermenting a bacterium in a growth medium to the stationary growth phase to produce a fermentation broth; (b) harvesting bacteria from the fermentation broth; (c) pasteurizing the harvested bacteria; and (d) lysing the pasteurized bacteria with a lysozyme to produce a bacterial lysate. In some embodiments, the bacteria are harvested in the mid-logarithmic phase, the late-logarithmic phase, the early stationary' phase, the mid-stationary phase, or the late stationary phase. [0020| In another aspect, the disclosure provides bacterial lysates produced according to methods comprising the steps of: (a) fermenting a bacterium in a growth .medium to the stationary growth phase to produce a fermentation broth: (b) harvesting bacteria from the fermentation broth, to pasteurizing the harvested bacteria; and td> lysing the pasteurized bacteria with a lysozyme to produce a bacterial lysate. In some embodiments, the bacteria are harvested in the mid-logarithmic phase, the Ute-logarithmic phase, the early stationary phase, the mid-stationary phase, or the late stationary phase.

[0021] In another aspect, the disclosure provides methods for alleviating one or more oxidative stress-related side effects assoc iated with administration of a pharmaceutical agent, the method comprising administering in combination with the pharmaceutical agent a therapeutically effective amount of a lysate composition comprising: (a) a lysate and / or lysate fraction of a bacterium: (b) an optional promoter for enhancing absorption of the composition: and (cl an optional carrier for increasing a volume of rhe composition; wherein the pharmaceutical agent and lysate composition are administered simultaneously or in any order, and through the same or different routes of administration. [0$22| In another aspect, the disclosure provides methods for treating oxidative stress-related diseases or conditions in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising: (al a bacterial lysate and or lysate fraction capable of activating at least one or more tbil-like receptors (TLRs) or Nod-hke receptors (Ns Rs) - (bi an optional promoter for cnhanvmg absorption of the composition; and (c) an optional carrier for increasing a volume of the composition. [O(123| hi another aspect, the disclosure provides methods for reducing oxidative stress in a subject, the method comprising: (a) determining the level of oxidative stress in the subject by measuring the ampupt of isoprostane in the urine.or blood of the subject; (b) administering to the subject an effective amount of a composition comprising: (i) a toll-hke tcceptor (TLR) *6- 2023251534 20 Oct 2023 agonist comprising at least one lysate and / or lysate fraction from a bacterium, wherein the TLR agonist activates at least one or mare TLRs or NLRs; and (ii) an optional promoter for enhancing absorption of the composition; and (c) continuing administration of the composition until the level of oxidative stress is reduced, as determined by a decreased amount of isoprostane in the mine of the subject. (0024( In another aspect, the disclosure provides therapeutic combinations comprising: fa) a lysate composition comprising (i) a bacterial lysate and / or lysate fraction capable of activating at least one or more toll-like receptors (TLRs) or Nod-like receptors (NLRs); (ii) an optional promoter for enhancing absorption of the composition; and (iii) an optional carrier for increasing a volume of the composi tion: and (b) one or more pharmaceutical agents; wherein the lysate composition and the one or more pharmaceutical agents are administered simultaneously or in any order, and wherein the lysate composition and the one or more pharmaceutical agents are administered via the same or different routes of administration, (0025( In another aspect, the disclosure provides pharmaceutical formulations comprising the combination of ta) a lysate cotnp>'»Uk>a compusmg (i) a bacterial Ksatc and oi lysate fraction capable of activating at least one or more toll-like receptors (TLRs) or Nod-like receptors ■ NLRs): (ii) an optional promoter for enhancing absorption of the composition; and (iii) an optional carrier Cor increasing a volume of the composition; and (b) one or more pharmaceutical agents. In some embodiments, the one or more pharmaceutical agents are selected from the group consisting of: an antispasmodic, a motility stimulant, an H2-Receptor antagonist antimuscarinic; a chelate, a prostaglandin analog, an aminosalicylate, a corticosteroid, an drug affecting immune response, a stimulant laxative, a drug affecting bi! tary composition and flow, a bite acids sequestrant, a dopamine antagonist, a proton pump inhibitor, an opioid, an opioid receptor antagonist, an analgesic, a sleep drug, a cardiac glycoside, a phosphodiesterase inhibitor, a thiazide, a diuretic, a potassium sparing diuretic, an aldosterone antagonist, an osmotic diuretic, a drug lot arrhythmia, a beta adrenoreceptor blocking -drug, a hypertension drug, a drug affecting the reuin-angioteusm system, a nitrate, a calcium blacker, an amiaugrnal drag, a peripheral vasodilator, a sympathomimetic, an anticoagulant; a protamine, an antiplatelet drug, a fibrinolytic drug, an antifibrinolytic drug, a lipid regulating drug, an omega force fatty acid compound, a. CNS drug, an anti-infective, or another drug selected from the group consisting of Benztropine, procyclidine, biperiden. Amantadine. Bromocriptine, Rergahde, Entacapone, Tolcapoue, Selegeline, Pramipexole. budesonide. formoterol, quetiapine fumarate, olanzapine, pioglitazone, munielukast, 2023251534 20 Oct 2023 Zoledromic Acid, valsartati, latanoprost Iibcsaitan, Clopidogrd, Atomoxctine, Dexamfetamine, Methylphenidate, Modafinil, Bleomycim Dactinomycin, Daunorubicin, Idarubic sn. Mitomycin, Mitoxantrohe, Azacitidine, Capedtabine, Cladribine, Clofarabine, Cytarabine, Fludarabine, Fiourouraeil, Gemcitabine, mercaptopurine, methotrexate, Nelarabine, Pemeteexed, Raltitrexed, Thioguanine, Apomorphine, Betamethasone, Cortisone, peflazacort, Dexamethosonc, Hydrocortisone, Methylprednisolone, Prednisolone, Triamcinolone, Cidosporine, Sirolimus, 'Tacrolimus, Interferon Alpha, and Interferon Beta. [0026j In another aspect, the disclosure prov ides formulations comprising (a) a lysate composition comprising (i) a bacterial lysate and / or Is sate fraction capable of activating at feast one or more tolMike receptors (TLRs) or Nod-1 tkc receptors (NDRs); (ii) an optional promoter for enhancing absorption of the composition; and ( hi) an optional carrier for increasing a volume of the composition; and (b) an isolated human anti-TNFalpha antibody or amigen-hindmg fragment thereof or TNF inhibitor. In some embodiments the imman anri-TNFalpha antibody or antigen-binding fragment thereof is adalimumab. In another aspect, the disclosure prox ides uses of such formulations in the manufacture of a medicament for the treatment of ihcumatoid arthritis (RA), late-onset RA, or psoriatic arthritis in a subject. In ■another aspect, the disclosure provides methods for the treatment of rheumatoid arthritis (RA), late-onset RA, or psoriatic arthritis in a subject, the method comprising administering to foe subject a tiierapeuticully effective amount of such formulations:. [00271 In some embodiments of any of the methods or composi tions disclosed herein, the bacterium is a Gram-positive or Gram-negative bacterium.. In some embodiments of any of the methods m con^ositions disclosed heiem tin Gram-povjx e bu terium is selected from the group consisting of a bactenum of /               fanuh, a bacterium of bkrepffK^’ec'iK'eiu family, a bacterium of                   family, and a bacterium of <d«'Ci '< > tamih In some embodiments, the Gram-positive bacterium is selected from the group consisting of Bacidus coagukms, .Litctobacitius sportgenes, Streptococcus itser / unpkdi^,                          Hijidobaetcrtw.7 anhi!dli\ subspecies mmnufo. B^dctbaci^um infanib^ Sifk / obacferiutii Bift^obaetenunt brevb, iMCta'bdci'ihis aci^ofihilm, iMcfvbtK^ pfan'tmim, faaobactf / us' cw'ei, Laeioba^^ Mbruec^’i, Lac / dbiK^^ delbrueckii subspecies bidgaricMS’, Lac / xoceus kiclis, ImcIgcoccus kictis subspecies An' / M', ,Sh'cp^><<« cisv / <.{<. XirefH<>n«.i vs tlKTmophidi>, hitidohdi. umun r\ Bijidubaftcrtum breve, Pediococcus eiekhkiedci, and              heh’efk-ux. [0028| In some embodiments of any of the methods or compos itions disclosed herein, the Gram-negative bacterium is selected from the group consisting of a bacterium of -8- 2023251534 20 Oct 2023 genus. K / efemZ / u genus, Xnnf / i<jffidrias genus, genus, and In some embodiments, the Gram-negative bacterium is selected from the group consisting of ^ / e&weZZa        ShigeUa.Tnnriwamm           and [00291 In some embodiments of any of the methods or compositions disclosed herein, the TLR agonist, lysate, lysate fraction, or ceil wall fraction activates at least one or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NODI, and NOD2. In some embodiments, the TLR agonist, lysate, lysate fraction, or cell wall fraction activates two or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NODI, andNOD2. In some embodiments, the TLR. agonist, lysate, lysate fraction, or cell wall fraction activates TLR. 2 and TLR 4. In some embodiments, the TLR agonist, lysate, lysate fraction, or cell wall fraction activates Uirce or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NODI, andNODZ,

[0030] In some embodiments of any of the methods or compositions disclosed, herein, the promoter is selected from the group consisting of amino acids, amino sugars, and sugars. In some embodiments, the carrier is selected from the group consisting of a binder, a gum base, and combinations thereof. In some embodiments, the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer. in some embodiments, the binder is selected from the group consisting of a sugar, a sugar alcohol, and combinations thereof. In some embodiments, the sugar alcohol is selected from the group consisting, of mannitol, sorbitol, xylitol, and combinations thereof.

[0031] In some embodiments., the compositions are manufactured as a dosage form selected from the group consisting of a lozenge, a chewing gum, a chewable tablet, a candy , and a dissolving tablet. In some embodiments, the dosage form delivers the TLR agonist to an prat mucosa. In some embodiments, the oral mucosa is selected from the group consisting of the sublingual mucosa buccal mucosa, and a combination thereof.

[0032] In some embodiments of any of the methods and compositions disclosed herein, the compositions are formulated for oral mucosal delivery';, in. some embodiments, the compositions are formulated for sublingual or buccal delivery. In some embodiments, the compositions are formulated to dissolve in. not less than I minute after administration.

[0033] These as wellas other aspects, advantages, and-akernatives. will become apparent to those of ordinary skill in the art by reading the following detailed description, with reference where appropriate io the accompanying drawings, and taken together with the accompanying claims. 2023251534 20 Oct 2023 BRIEF DESCRIPTION OF THE DRAWINGS (0034) Figure 1 shows a diagrammatic representation of a toll-like receptor (TLR) showing various response pathways. |003S| Figure 2 shows the exemplary srimulatory elteets of a composition of the present invention on select TLR / NLR cell lines; the values in the graph correspond to an average of three screening experiments. )0036( Figiire 3 shows results of TER. stimulation for a / Wfococcur acidilactici lysate as compared to a Lactobadilus bidgancns lysate. [0037) Figure 4 shows results of TLR stimulation for bacillus coagulanx lysates with di tiering times ofharxcM. (0038) Figure 5 shows results of TLR stimulation for Gram-positive bacterial lysates from Lactobacillus ackiopkihis, Lactobacillus helvificus, Lactobacillus planianan, and Streptococci® Ihertnophilus. (003.9( Figure 6 shows results of TLR stimulation for Grain-negative bacterial lysates from Escherichia coll, Klebsiella oxy facta, Magcl / aflexnerL Xanthomotws catnpestris. and .PsetjAwumas^^ [0040) Figure 7 shows the results of TLR stimulation for aJfanlkomoftas Mimpexfrts lysate as compared to xanthan gum. Figure 8 shows a decrease in the levels of urinary isoprostane in the urine of PTSD-diagnosed combat veterans following administration of a composition of the disclosure. {0O42'| Figure 9 shows a decrease in sleep deficits of PTSD-diagnosed combat veterans followingadministration of a composition of the disclosure. [0043) Figure 10 shows a decrease in neuropathy symptoms in PTSD-diagnosed combat veterans following administration of a composition oi the disclosure, [0044)    Figure 11 shows an improvement in the overall mood of PTSD-diagnosed combat veterans folio wing administration of a composition of the disclosure. [0045) Figure 12 shows an increase in overall energy levels in PTSD-diagnosed combat veterans following administration of a composition of the disclosure. [0046) Figure 13 shows an increase in overall satisfaction with the health of the joints of PTSD-diagnosed combat veterans following administration of a composi tion of the disclosure. 2023251534 20 Oct 2023 [0047| Figure 14 stows ah increase in levels of satisfaction of the digestive health of PTSD-diagnosed combat veterans following administration of a composition of the disclosure. [0M8| Figure 1.5 shows a decrease in levels of irritability of PTSD-diagnosed combat veterans following administration of a composition of the disclosure. |(W49| Figure 16 shows an increase in overall levels of self-reported satisfaction with sexual function of PTSD-diagnosed combat veterans following administration of a composition of the disclosure. [0050$    Figure 17 shows a decrease in daytime sleepiness of PTSD-diagnosed combat veterans following administration of a composition of the disclosure. [0051| Figure 18 shows an increase in overall levels of self-reported satisfaction with the lives PTSD-diagnosed combat veterans following administration of a composition of the disclosure. jQ()52] Figure 19 shows a decrease in levels of depression in PTSD-diagnosed combat veterans following administration of a composition of the disclosure. (00531 Figure 20 shows a decrease in isoprostane levels in an individual with a history of concussion following administration of a lysate of the disclosure. DETAILED DESCRIPTION |O054| All publications, patents and patent applications cited herein are hereby expressly incorporated by reference for all purposes. (0055) Cellular redox (oxidation-reduction) state varies widely. Oxidation and reduction reactions are key to cellular bioenergetics. Normally whim oxidation of food molecules results in electron transport and -ultimate capture of energy as energy rich molecul es such as NADP (nicotinamide adenine dinueleotide phosphate) and ATP (adenosine triphosphate), TLRs are activated in such a manner such that downstream oxidation, reduction reactions arc balanced. As used herein, foe term “balance” refers to a homeostatic balance; that is, not necessarily a situation in. which the amount of oxidation equals the amount of reduction in a given system, but rather where oxidation and reduction are in immunologic and thus metabolic homeostasis for tire host However, there are a number of cellular sitaatio.es where the redox state changes. Usually, the cell is -armed with antioxidant molecules, but where such molecules become depleted, the redox status of the cell changes. Oue likely cause for this is the purposeful production of reactive oxygen species (ROS) such as 02 ' (superoxide radical), OH (hydroxyl radical) and foydrogen peroxide) for defense c or similar purposes. 2023251534 20 Oct 2023 When the redox balance is shifted, oxidative stress may ensue. Oxidative stress is a pathological condition triggered by the damaging action.....on the cells and tissues of the body—of abnormally increased levels of ROS. Oxidative stress is the direct consequence of an increased, immunologically uncontrolled generation of ROS and / or a reduced physiological activity of antioxidant defenses against excess ROS. Inflammation (whether chronic or acute) as well as other stresses and infection can lead to the increased production and release of ROS from damaged and / or inflamed tissues thereby shifting the redox balance of the cell and as a result contribute to oxidative stress. At the same time, inflammation can resul t from oxidative stress as ROS damage tissues; A wide range of diseases and disease states are associated with changes in redox, state and oxidative stress brought on by chronic or acute inflammation or vice versa. Current therapies for treating chronic or acute inflammation do not come without harmful side effects. Described herein are compositions and methods for altering redox levels in the treatment of oxidative stress and related conditions. jOOSSJ Before describing the disclosed methods and compositions in detail, a number of terms will be defined. As used herein., the singular forms “a”, “an” and “the”' include plural referents unless the context clearly dictates otherwise. For example, reference to “nuclctc acid” means one or more nucleic acids. J0057] For the purposes of describing and defining this invention it is noted that the term “substantially” is utilized herein to represent the inherent degree of uncertainty that can be attributed to any quantitative comparison, value, measurement, or other representation. The term “substantially” is also utilized herein to represent the degree by which a qu anti rati ve representation can vary from a stated reference without resulting in a change in the basic function of the subject matter at issue. (00581 As described above, pathogen-associated molecular patterns (RAMPs) can activate innate immune responses by stimulating TLRs. which generally are activated, by conserved non-sclf biochemical structures, thus protecting a host from infection. Bacterial lipopolysaccharide (LPS) is found on the bacterial cell membrane of some bacteria, and is considered to be the prototypical PAMP 1 PS is specifically recognized by TLR4, a recognition receptor of the innate immune system. Other PAMPs Include bacterial flagellin (recognized by TLR5), lipoteichoic acid, peptidoglycan, and nucleic acid variants normally associated with viruses, such as doable-stranded RNA (dsRNA), recognized by TLR3 or umnethyiated CpG motifs, recognized by TLR9, In some vases however, PAMPs reduce mfi.immauon i PS t exo-polysaccharide). a material that typically stimulates an immune response, has been shown to stimulate ■■ 12 - 2023251534 20 Oct 2023 negative regulators of TLRs, thus leading to a reduced inflammatory response. More specifically, EPS has been shown to stimulate expression of immunoglobin IL-4 related receptor, toll interacting protein, 8-cell lymphoma 3-encoded protein, A20, mitogen-activated protein kinase phosphate-"!, and interleukin associate kinase M, and has been shown to lead to the negative regulation of TLRs and inflammation . These .seemingly contradictory effects of PAMPs are at least partly explained, by the innate immune system’s interaction with the microbiome. The immune system does not exist in a vacuum. Even when an organism has no active inflammatory responses taking place, immune cells are responding to an onslaught of PAMPs from, the environment— -particularly from the microbiome. Given the various TLR receptors that are activated are producing a downstream redox state that is in immunologic and metabolic homeostasis, the system issues an44 All Clear”'signal to avoid inadvertent responses which might damage the essential microbi-ome constilnen's Hence, presenting the right combination of PA MPs to the cells of the innate immune system can. control the entire redox system, down-regulating or up-regulating it to achieve, or in some cases restore, immunologic and metabolic homeostasis. (0061] Figure 1 shows a diagrammatic representation of a transmembrane a TLR. Although the ligand accepting (stimuli) portion of the molecule is located on the surface of the plasma membrane, the transmembrane domain of die protein is able to conduc t signal to the cytoplasmic surface of the membrane through conformational changes that occur when a ligand is bound. A t the cytoplasmic surface this signal (arrows) is coupled to a number of different signaling pathways Proliferation.diffcrentiauon and stress-response pathways are shown. Note that one TLR type does not simultaneously control both pathways as in this generalized diagram. Rather some TLRs eonuol one pathway or set or pathways and other TLRs control a different pathway or set of pathways. In addition, it is likely that one type of TLR controls different padmay s depending on which cell type it is located in; thus, delivering the correct balance of TLR agonists is important for maintaining homeostasis. The downstream signaling mechanisms may be shared to a greater or loser extent. In Figure 1, the proliferation response largely uses the ERK pathway whereas the stress response uses the MEKKand TAK pathways. In each pathway. signal molecules are phosphorylated and there can be a phosphorylation cascade to amplify the signal. Ultimately-the .phosphorylated, .protein enters the nucleus (through the nuclear pores) where the phosphorylate intermediates alter both transcription and translation. In this way, TLRs are able to control entire suites of genes. In all, thousands of genes are activated by TLR - 13 - 2023251534 20 Oct 2023 signaling, and collectively, the TL-Rs constitute one of the most plciottopic yet tightly regulated gateways for-gene modulation. One of the'primary responses of TLR activation is to shift the downstream redox ■status of the cell when warranted. The initiation of a redox change and the resulting inflammatory response to pathogens is a critical component of the innate immune response designed to control infection. Inflammation (whether chronic or acute) results from and leads to the increased production and release of free radicals and other ROS from damaged and / or inflamed tissues and as a result contributes to or causes oxidathe stress At the same time, inflammation can resultymw oxidative stress when ROS damage tissues. As such, inflammation and the various conditions associated with it can also be regarded as an “oxidative stress-related disease or condition.” (00641 Oxidative stress, being a biochemical condition, generally does not exhibit any specific clinical symptoms or clinical signs apart from rhe specific pathological conditions it induces. It may generally remain undiscovered, with concomitant damage to the patient, until a clinician suspects its existence and decides to assay for oxidative stress. (00651 Various common diseases and / or conditions are frequently associated with oxidative stress. One example is Alzheimer’s disease. Studies have shown that chronic oxidative stress increases the levels of tan phosphorylation, a known biomarker of Alzheimer’s disease. Studies have also shown that oxidative stress -results in tau4nduced nemodegeneration in models of Alzheimer’s disease. |'O066j    Other known “oxidative stress-related diseases or conditions” include, but are not limited to- aawloplasmincmia, acute and chronic alcoholic liver diseases, acute autoimmune myocarditis, acute chest syndrome of sickle cell disease, acute pancreatitis, acute respiratory distress syndrome, alcoholic liver disease, Amyotrophic Lateral Sclerosis, arterial / systemic hypertension, asbestosis, asthma, ataxia telangiectasia, atherosclerosis, atopic dermatitis, brain ischemia, bronchopulmonary dysplasia, burns, some cancers, cardiopulmonary bypass, cardiovascular diseases, cataract, cellulitis, chanotherapeutic side-effect, chronic fatigue syndrome, chronic Hepatitis C, chronic kidney disease, chronic obstructive pulmonary disease, chrome renal failure, colitis, coronary: artery disease, Creutzfeldt-Jakob disease, Crohn’s disease, cutaneous leishmaniasis, cystic fibrosis, diabetes mellitus type 1, diabetes mellites type 2,, dyslipidemia, Down’s syndrome, eclampsia, end-stage renal disease, erectile dysfunction, Friedreich ataxia, headache, heart failure, / fe / feotimver pyM infection / inflammation, hemodialysis side effects, hepatic cirrhosis. Human Immuntrdetlciency Virus infection, Huntington disease, hyperbaric diseases, tn sleep apnea, spherocytosis, spinal cord injury, stroke, synuclemopadiies, systemic amyloidosis, systemic, lupus erythematosus, systemic sclerosis (scleroderma), thrombophily tauopathics, traumatic stress tubercolosis, unstable angina, uremia, venous insufficiency, Werner syndrome, and Zellweger syndrome. }0067j Oudatne stress ntedtatvs the patho'ogwal symptoms of a great mam disorders 9* S' 2 rs JZ5 2 e o ***** feedback loop that can maintain damaging oxidative redox status. |0070J koprosianes, such as FS’isoprostanes, arc finis accurate markets of oxidative redox status in both animal and human models of oxidative stress, and measurement of isoprostaues has emerged as one of the most reliable approaches to assess oxidative stress in viva due to their inherit stability and their ease of measurement in bodily fluids such as urine £ O' O o cz* 2023251534 20 Oct 2023 biomarkers, such as but not limited.to C-reactive protein, serum amyloid A, arid cytokines, are limited in their ability to pick up low grade changes in Inflammation and consequently limited in their ability to pick up low grade redox changes. An alternative is to focus on biomarkers, such as isoprosianes, to measure redox status, and mechanisms to alter redox states [0(173}    Redox can be changed either by increasing reducing species i antioxidants) or by decreasing oxidants, There has been little success in ecocnUmg hartnM redox levels through added antioxidants or antioxidant therapy (we Ho et al. Biological markers of oxidative stress: Applications to cardiovascular research and practice. 2013 Redox Biology). There is evidence for the long tern use ofdietwy anuox’dants perhaps as pje^emame agent'-. Howvu vhen the immune system is not. able to achieve or maintain .homeostatic redox levels, added antioxidants: are generally ineffective at correcting the balance, [00741 An alternative route to affecting redox status is to aim at downstream targets; such strategies include the use of aspirin and glucocorticoids to block NF-kB activation and the targeting ofspecific -inflammatory mediators such as TNF-a- Given their role in mediating the innate immune response and inflammation. TLRs present another target for controlling the innate and inflammatory responses. [0075| As discussed above, TLRs help mediate tlte innate immune response by inducing or suppressing genes that orchestrate the Inflammatory reaction, TLRs recognize and respond to a variety of signals. These signals bind to specific TLRs to promote or block signal. pathv, av s that can induce or suppress genes mediating inflammation. By targeting specific TLRs with specific agents immune responses and inflammatory possesses can be mediated [0076) Inhibition of multiple TLR-depended responses or activation of specific ones by targeting a common signaling component, may prove to be an effective approach to controlling an inflammatory response. Accordingly, compositions: disclosed hereto may be used to treat an oxidative stress disorder associated with a TLR-signalmg pathway (s.g., TLR-induced inflammation), the method comprising the administration of a therapeutically dtectoe amount of a composition as described herein, wherem the TLR affected is one oi more Of TLR2, TLR4, TLR5, TLR7 and T.LR9. [00'77] As used herein, the term “therapeutically effective amount” refers to an amount administered to a subject that is sufficient to cause a desired effect in the subject. [0078| As used herein, the terms “pharmaceutical formulation” and “pharmaceutical composition” refer to a preparation which is in such, form as to permit, a biological, activity of an active ingredient to be effective, and which, contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. The terms -17- § K' £* S' £ § § g. S 8 8 n S a. tn ■© 8 a 96 W downregutate the activity ofTLRs thus leading to reduced or regulated levels of inflammation \\ hen die proper balance of Tl.R activation is achieved, cellular redox siams is optimized and oxidative stress is reduced. This can be achieved by providing compositions containing PAMPs that simultaneously bind to two or more different types of TLRs. j0081|    In some cases a lysate of a single type of mictoorganism can act as an agonist to 2 fj. ST o o' o O" 3 o ex £2 g Ox JZL A 2023251534 20 Oct 2023 applying or augmenting the normal microbiome signal, which reasserts homeostasis and “resets” the overall system by interrupting the positive feedback loop that powers abnormal redox status and oxidative stress. PM84| The therapeutically active compositions of the present disclosure' include a nonsynthetic biologically active agent, preferably one or more cell wall fractious of one or more microorganisms including Gram-positive bacteria, Gram-negative bacteria, or combinations thereof, such as in the form of a lysate, along with a promoter, and. optionally, one or more other additives, including control-release ingredients, so as to allow the composition to be absorbed into, or interact with, a mucosal wall of a subject in need of therapy. 10085| As used herein, the terms “dose” and “dosage” shall encompass bolus or loading dose, and also encompass chronic or maintenance dosing. According to the present invention, the active therapeutic agent is alysate, lysate fraction, or cell wall fraction of a bacterium, such as a Gram-positive bacterium or a Gram-negative bacterium in an amount ranging from about 0,01 mg therapeutic agent per kilogram of body weight to about 100 mg per kilogram body weight, as required to act as agonists for two of more TLRs depending upon the specific therapeutic application. In some embodiments, tile active therapeutic, agents of the disclosure are administered in a dosage of from about 0.01 mg therapeutic agent per kg body weight to about 10 gm therapeutic agent per kg body weight. In some embodiments, the active therapeutic agents of the disclosure are administered in a dosage of from about 0,01 mg therapeutic agent per kg body weight tv about I gm therapeutic agent pct kg body weight. In some embodiments. the active rherapcutic agents of rhe disclosure are administered in a dosage of from about 0.01 mg therapeutic agent per kg body weight to about 50 mg therapeutic agent per kg body weight. In some embodiments, the active therapeutic agents of the disclosure are administered in a dosage of from about 9.05 mg therapeutic agent per kg body weight to about 30 mg therapeutic agent per kg body weight. In some embodiments, die active therapeutic agents of the disclosure are administered in a dosage of from .about 0 of mg therapeutic agen t per kg body weight to about 5 mg therapeutic agent per kg body weight. In some embodiments, the active therapeutic agents disclosed herein are administered in a dosage of about 0.1 mg therapeutic agent per kg body weight, or of about 0.2 mg therapeutic agent per kg body weight, or of about 0.3 mg therapeutic agent per kg body weight, or of about 0.4 mg therapeutic agent per kg body v c< girt, or of about 0,5 mg therapeutic agent per kg body weight, or of about 0 »> ng therapeutic agent per kg body weight, or ofabout 0.7 mg therapeu tic agent per kg body weight, or of about 0.8 mg therapentL agent per kg body weight ot of about 0.9 mg therapeutic agent per kg body weight, or of about 1 mg therapeutic -19 - 2023251534 20 Oct 2023 agent per kg body weight, or of about 2 mg therapeutic agent per kg body weight, or of about 3 mg therapeutic agent per kg body weight, or of about 4 mg therapeutic agent per kg body weight, or ofabout 5 mg therapeutic agent per kg body weight, or ofabout 6 mg therapeutic agent per kg body wei ght , or of about 7 mg therapeutic agent per kg body weight, or of about 8 mg therapeutic agent per kg body weight, or of about 9 mg therapeutic agent per kg body weight, or of about 10 mg therapeutic agent per kg body weight. In some embodiments, the above dosages describe the total amount of active ingredient administered per day to a subject, wherein the total amount may be divided among two or more administrations per day, or may be the amount administered in a single daily dosage. |&086| As used herein, the terms “therapeutic agent” and “active ingredient1 refer to a lysate, lysate fraction, and / or cell wall fraction of the disclosure, or a combination thereof, as apposed to the non-aetive ingredients in in a composition or formulation. 10087)    In some embodiments, foe pharmaceutical compositions disclosed hemin am administered in formulations, such as in oral formulations, including tablet formulations, comprising from about 0.01 mg to about 10 gm active ingredient par dose, or of from about 0.5 mg to about 50 mg active ingredientper dose, or of from about 3 mg to about 30 mg active ingredient per dose, or of from about 10 to about30 mg active ingredient per dose. In some embodiments, the pharmaceutical formulations are for mulated and / or administered with about 0.5 mg, or about I mg, or about 5 mg, or about 10 mg, or about 15 mg, or about 20 mg, or about 25 mg, or about 30 mg active ingredient per dose, hi some embodiments, the pharmaceutical compositions of foe disclosure are formulated as tablets, with each tablet comprising atom 0 nw to about 30 mg active ingredient per tablet In some embodlmcnrs. the tablets each comprise aboutt» 5 mg active ingredient. In some emtodiments. the tablets each comprise about 1 mg active ingredient In some ernbodirnents, the tablets each compose about 5 mg active ingredient In some embodiments, foe tablets each comprise about 10 mg active ingredient la some embodiments, the tablets each, comprise about 15 mg active ingredient In some embodiments, the tablets each comprise about 25 mg aetise ingredient In some embodiments, the tablets each comprise about 40 mg active ingredient. In some embodiments, foe tablets each comprise about 50 mg actnc ingredient. In some embodiments, the tablets each comprise about 1 gm active ingredient. In some embodiments the -tablets each comprise about 10 gm active ingredient |0088| In some embodiments the pharmaceutical formulations of the disclosure are administered from one time per day to three times per day. la some embodiments, the pharmaceutical formulations of the disclosure are administered once per day. In some embodiments, foe pharmaceutical fbanulattom of the disclosure arc administered two times per -20- 2023251534 20 Oct 2023 day. In some embodiments, the pharmaceutical formulations of the disclosure are administered three times per day. f 00891    In some embodiments, the pharmaceutical formulations are administered at a dosage level and frequency such that the subject receives a total of from about 0.01 mg io about 10 gm of active therapeutic agent per day, or a total of horn about 1 mg to about 1 gm of active therapeutic agent per day, ora total of from about 5 mg to about 1 gm of active therapeutic agent per day, or a total of from about 5 mg to about 500 mg active therapeutic par day, or a total of from about 12 to about 375 mg per day In some embodiments, the pharmaceutical formulations of the disclosure are administered at a dosage level and 'fluency such Unit the subject receives a total of about I mg, or about 2 mg, or about. 3 nag. or about. 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, orabout 8 mg, or about 9 mg, or about 10 mg, or about 1.1 mg, or about 12 mg, or about 13 mg, or about 14 mg, or about 15 nig active ingredient (re., lvsate, lysate fraction, and'br cell wall fraction, or combination thereof) per day, or more t<- needed, In some embodiments, the pharmaceutical formulations of the disclosure are administered at a dosage level and frequency such that the subject receives a total of about 12 mg, or about 24 mg, or about 36 mg, or about 48 mg, or about 60 mg, or about 72 mg. or about 84 mg, or about 96 mg, or about 108 mg, or about 120 mg, or about 132 mg. or about 144 mg, or about 156 mg, oi about 168 mg, or about 180 mg active ingredient Ue, lysate, lysate fraction, and or cell w all fraction, oj combination thcicof) pes day. oi muse as needed in some embodiments, the pharmaetd formulations of the disclosure are administered at a dosage level and frequency such that the subject receives a total of about 15 mg, or about 30 mg, or about 45 mg, or about 60 mg, or about 75 mg, or about 90 mg, or about 105 mg, or about 120 mg, or about 135 mg, or about 150 mg, or about 165 mg, or about 180 mg, or about 195 mg, or about 210 mg, or about 225 mg active ingredient (Ze, lysate, lysate fraction, and / or cell wall fraction, or combination thereof I per day, or more as needed. In some embodiments, the pharmaceutical formulations of the disclosure are administered at a dosage level and frequency such that the subject receives a total of about 25 mg, or about 50 mg„ or about 75 mg. or about 191»mg. or about 125 nig. or about 150 mg, or about 175 mg, or about 200 nig, or about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, or about 375 mg, or about 41X) mg acme mgtcdieul u; . hrate Iwate frat non. and or cell wall fraction ot ,vimfrnaitontbaeoO per day or more as needed. |0W| Any and all of the above dosage amounts and administration amounts are applicable to bofo monotlierapeutic administration of active ingredients of the disclosure, as well as to embodiments in. which active ingredients of the disclosure are administered in combination with one or more other therapeutic or phannaccutical agents. -21 - 2023251534 20 Oct 2023 Active ingredients f 00911 Active ingredients to be used in the compositions and methods of the disclosure comprise a bacterial lysate, lysate tract ton, or cell wall fraction. Active ingredients may be manufactured, produced, or derived from any Gram-positive or Gram-negative bacterial organism, |0W21 The term “lysate” as used herein refers to a composition prepared from a lysed cell, such ss a bacterial cell. A lysate contains the entire cellular contents as well as, in some embodiments, associated, surface components such as exo-polysaccharide, depending on the precise process conditions used to produce the lysate. 100931 A non-limiting example process for producing an active ingredient according to the disclosure is set forth in Example 1, and in general involves the steps of (1) fermenting a bacterium in growth media; (2) centrifuging the bacterial suspension to harvest the bacteria there-torn, (G cashing and pa^icmtziny the hanested I'.nle / ra (41 d / siepung the cell wails of the bacteria to lyse the bacteria; and (4) lyophilizing the resulting mixture to obtain an active ingredient, such as a bacterial lysate, lysate fraction., or cell wall fmcnon. [00941     Ute structures present in lysates, lysate fractions, andfor ceil wall fractions of the disclosure that ate responsible for TLR activation and oxidative stress reduction are structures common to and consented among ail bacterial microorganisms.. Thus, in principle, any bacterial organism can be used to produce an active ingredient of the disclosure 0.&, lysate, lysate fraction, and / or cell wall fraction). [909S| In sunk- enfoodmionts the hucfcnal mgam^m used to produce .scow myredwms ><f the disclosure is a Gram-possuw baetvnum. In some embodiments, the Gram-positive bacterium is selected from: lactobacillus actekphthts, Lactobcici / lus buchueri, Lactobacilli# casei, Lactobacdlin lateiifiorme. L<utobc.uoiCd ccllohi-iwn, I actobaeiLm; cn^patHs, Lactobacillus ciinKlfus, i uVArfeu7 / / 1 / ¾ delhruedat, Iitctobc'ciBus ch'fbmci.toi subsp bufiaricin, Lctcfobdktlh^ delbrueckii subsp. lactis, lactobacillus hebdiae. l^toKtetlhisjcttseifu, l,aetobacilliis leic / tmawm, Ixtctobacilh# mlnutus, Lactobacillus paracasei, I^toKtotllus plantarum, Lactobacillus rkamiios-us, Lactobacillus ritgosae, Lactobacillus salnattus, Lactobacillus sporogenes (also known as Bacillus' ctwgulantt), Laetobacdlus bivm' 1 actobadlkis gasseri, Lactobacillus / ermemim, .Bifidobacterium actol&sc&tos, Bi / kiobctcteriufn animahs (especially Zf animalis, subspecies anfmabsp Bifidobacterium anguiaium, B^dabacterium bifidum, b‘!>i<tohdk tentun nte>e. Bifid<>bai' / ernmi < .itctmtoiMH. Bijidobik ten;nn Jcuuw, Bifidobacterium criiso / m, Bifidobacterium bfiamis. Bifidobacterium lactis (Bifictobacterium am / milri subsp. Icfcthi, B / fiJ< fiuetertmu bmgimu Bifidobacterium ptontoritm, Bifidobacterium -22- p cZ o & 2023251534 20 Oct 2023 meat extracts, peptones or ammonia salts; a simple sugar or ingredient that contains simple sugars or hydrolyzed carbohydrates that will yield simple sugars, such as but not limited to glucose or lactose (0.5-3%y and minerals (0.05- 0.3%), which may include salts of sodium, manganese, magnesium, calcium and potassium. Surfactant, cysteine HCL, and ribonucleotides f 0 001 dV5%) maybe added to support cell growth. Growth media are adjusted to a pH between 6 and 8. In some embodiments, depending on the particular bacterium being grown, the pH of the-growth media ranges from about 6.0 to 6.5. In some embodiments, the pH of the growth media ranges from about 6.5 to 7.0. In some embodiments, the pH of the growth media ranges from about 7.0 to 7:5. In some embodiments, inoculated media is incubated during fermentation at between 30-50 ”C. In some embodiments, inoculated media is incubated during fermentation at between 30-40 °C. In some embodiments, inoculated media is incubated at around 30 °C, or around 31 °C, or around 32 °C, or around 33 °C, or around 34 ftC, or around 35 °C, or around 36 °C, ar around 37 ;GS or around 38 "C, or around 39 °C, or around 40 °C, or around 45 °C. In some embodiments, inoculated media is incubated at around 30 °C. In some embodiments, inoculated media is incubated at around 33 -’C. In some embodiments, inoculated media is incubated at around 35 ”C. In some embodiments, inoculated media is incubated at around 37 "C In some embodiments, inoculated media is incubated at around 40 °C. In some embodiments, inoculated media is incubated at around 45 °C. 101001 In some embodiments, fermentation is continued from about 6 hours to about 120 hours prior to harvesting the bacteria. In some embodiments, fermentation is continued from about 12 hours to about 48 hours prior to harvesting the bacteria, in some embodiments, fermentation is continued from about 12 hours io about 24 hours prior to harvesting rhe bacteria. In some embodiments, fermentation is continued for about 14 hours, or about 15 hours, or about 16 hours, or about 17 hours, or about 18 hours, or about 19 hours, or about 30 hours, or about 22 hours, or about 24 hours, or about 48 hours. In some embodiments, fermentation is continued until bacterial growth reaches the mid-logarithmic phase, the late-logarithmic phase, the early stationary phase, the mid-stationary phase, or the late stationary phase. In some embodiments, fermmtstiou is continued until the bacteria reach the stationary growth phase. In some embodiments, the fermentation way be held prior to downstream processing using techniques known to those skilled in the art, such as but not limited to, chilling and pH control, for up to 14 days or longer as warranted, After fermentation, the broth is typically chilled and the bacteria harvested by centrifugation. In some embodiments, the broth is chilled post-fennentation w from about -24- 2023251534 20 Oct 2023 IX to about 2SX. In some embodiments, die broth is chilled to about 1 X, or to about 2 °C, or to about 3 X, or to about 4 X, or to about 5X, or to about 6 °C, or to about 7^, or to about 8 X', or to about 10 "C. In some embodiments, the broth is chilled from to about 4 X to about 7 X. |0102|    After chilling, centrifugation is.performed to separate the cells from the surrounding growth .media. Cells are then washed in fresh media, deionized water, water, or other solution m .repeated centrifugations.-and. resuspensions, and then re-suspended in. fresh media or other solution in prcpai atwn tor the pasteurization step. (Ol&H In some embodiments, the washed bacteria are pasteurized. In some embodiments, the bacteria are pasteurized at from about 75 X to about 85 X tor 30 minutes to 60 minutes, hi some embodiments, the harvested bacteria are pasteurized at about 80 X. In some embodiments, pasteurization proceeds for about 30 minutes, or about 45 minutes, or about 61 * minutes. jQ104| Following pasteurization, the cell concentrate is treated to disrupt coll walls and thereby expose TLR agonists. Disruption of the cell walls may be accomplished by using chelating agents, detergents, surfactants, and hydrolytic enzymes. Examples of hydrolytic enzymes that may be used include, but are not limited to, lysozyme, such as chicken (hen) egr whim     me <foi example, iNOVIXR % IA SO' AC R. DFLVOZ\ MF % LYSOVIY R. or LYSOBAQ-'C hsuw, cudolysms, and In (Judases In some embommems. lysozyme is added to the pasteurized bacterial cell suspension to a final concentration of 0.01-4% by volume In some embodiments, lysozyme is added to the pasteurized bacteria! cell suspension to a final concentration of about 0.5%, or about i" u, or about 2%. or about 3 '<>, ot about 4% by volume. In some embodiments, treatment of the pasteurized bacterial suspension with lysing enzymes continues from about 1 to about 10 hours, or from about 6 to about. 8 hours, or for about 5 hours, or for about 6 hours, or for about 7 hours, or for about 8 hours, or for about 9 hours, or for about 10 hours. In some embodiments, treatment of the pasteurized bacterial suspension with lysing enzymes is performed at a temperature of from about 25 X to about SOX, or from, about 30 X to about 45 X, or at about 35 X, or atabout 37 X, or at about 40 X, or at about 42 X, or at about 45X. After lysis, the lysate is typically frozen and lyophilized. |0105| In some embodiments, and as is described in. more detail below, the lyophilized material is then blended with a promoter, such as N-acetyl D glucosamine HCI (NAG). Optionally, other formularion excipients may be added to generate a solid form pill or powder, as appropriate. 2023251534 20 Oct 2023 J0106| In some embodiments, the particular TLR or TLRs that are activated or stimulated by a particular lysate can be altered by changing raw materials, process materials, or process conditions. As used herein, the term “TLR specificity” refers to the particular TLR or TLRs that are activated by a given composition of (he disclosure comprising a bacterial lysate, lysate fraction, and / or cell wall fraction. In some embodiments, TLR specificity is altered depending on the density to which bacterial cells are grown during fermentation. In some embodiments, the particular bacterial species or subspecies from which the active ingredient is produced also results in differences in TLR specificity. In some embodiments, the particular enzyme used to lyse the bacterial cells following pasteurization results hi differences in TLR specificity. [0107} As used herein, the terms “activation ” ’"stimulation / ' “targeting,” and “agonism,” when used in relation to a receptor or other biomolecular target, are interchangeable and refer to the binding to and activation of a receptor, such as a toil-like receptor, such that the signaling cascade downstream of the receptor is altered, modulated, or otherwise affected. [01081    It will be understood that the cells can be fractionated prior to lysis or that the lysate as produced above can be fractionated by well-known biochemical procedures, including, for example, differential centrifugation or column chromatography, such as gelpermeation chromatography, ion exchange chromatography, chromatography over hydrophobic media, or precipitation, and the like. In some embodiments, lysate fractionation produces fractions with differing TLR specificities; for example, fractions may be produced that are targeted to a smaller number of TLRs than a complete lysate. [0109} In some embodiments, ingredients comprising exo-polysaccharides may be combined with the lysates, lysate fractions, and / or cell wall fractions of the disclosure. Exopolysaccharides are able to activate TLRs. Thus,:for example, xanthan gum, which is:derived from Xanthonwws eampestris, may be used in combination with the lysates, lysate fractions, and / or cell wall fractions of the disclosure to increase TLR activation and / or alter the TLR specificity of a composition. In some embodiments. xanthan gum is itself a lysate fraction, for example, in embodiments where xanthan gum is derived from a lysate produced from fermentation of Xanthomonas eampestris, such as by fractionation of a Xamhomonas eampestris lysate. Other ingredients and delivery forms [0110} The therapeutic compositions of the present disclosure may further and optionally comprise one or more promoters, to assist in the therapeutic delivery of the active agent across a biological membrane. The promoter useful in accordance with the present disclosure -26- 2023251534 20 Oct 2023 can be amino acid, N-alkylated peptide, sugar, amino sugar or amino sugar chelate. An amino sugar chelate comprising one or more amino sugar ligands, one or more -saturated hydroxylated carboxylic acid ligands, and a nutritionally acceptable metal, wherein at least one of the one or more amino sugar ligands is glucosamine, and wherein the metal is selected from the group consisting of manganese, magnesium, sodium, potassium, and zinc, and wherein the one or more saturated hydroxylated carboxylic acid ligands is gluconic acid, and wherein the glucosamine ligand to nutritionally acceptable metal ratio is 2:1, wherein the nutritionally metal is nonferrous, [M11| In accordance with one aspect of the present disclosure, the therapeutic formulations may include one or more, acetylated or deacetylated amino sugars selected from the group consisting of NAG, galactosamine, N-acetylgaiactosamine, mannosamine, and N-acetylmannosamine in the form of monomers, oligomers, and / or polymers thereof including chitin, and human glueosaminoglycans, as well as derivatives thereof. The term “derivatives thereof ’ used herein with reference to amino sugars means derivati ves of the amino sugars having the same or essentially the same ability to form cytotoxic degradation products during sterilization. In accordance with select further aspects of the present disclosure,, the promoter is a member selected from the group consisting m'poh-L-lysinc. glucosamine, poly-L ammine gahetosamme, N-acetyhnaimosammc f\ AM, N-Ac-Man), N-l* acertlglucosamme (NAG; N- Ac-Glc), N,N’-diacetylglucosajnine (NAG-NAG; NN'-diaeetylchiiobiose), N,N’, N”, N’M“ tetraacetylglucosammc (NAG-NAG-NAG-NAG; NN^N’lN’”-tetraacetyichitotetraose), and mi Mmes thereof [Ml 2]    Optionally, and equally acceptable, the promoter may be an acylated glycosyloxy sugar or an optionally acylated oiigoglyeosyloxy sugar moiety of 2 to 12, a-1, 2 and or a-1, 6 linked sugars, wherein the sugars) are selected from the group consisting of D-mannose, D-galactose, D-glucose, D~g! ucosamine, N-acetylghwosamine, and 6-deoxy-I,-mannose, wherein an oiigoglyeosyloxy sugar moiety may comprise the same or different sugars. [M 13| In another embodiment, the compositions of the present invention are in a dosage form selected from the group consisting of a lozenge, a chewing gum, a chewable tablet, and a dissolving tablet such as a slow-dissolving, tablet, a quick-dissolving tablet or a controlled-release tablet or other suitable controlled-felease formulation, [M 14|    In an embodiment, the active agent of the present disclosure is delivered across an oral mucosa of a subject, the oral mucosa being selected from the group consisting of the sublingual mucosa, the buccal mucosa, and a combination thereof. The composition can be 2023251534 20 Oct 2023 administered sublingually so that Ike active ingredient is delivered across the sublingual mucosa. 115| In another embodiment, the carrier is typically a solid, semi-solid, or liquid such as a binder, a gam base, or combinations thereof. Suitable, binders for use in the compositions of the present invention include, without limitation, sugar alcohols such as mannitol, sorbitol, and xylitol; sugars such as lactose, dextrose, sucrose, glucose, and powdered sugar; other substances such as inositol, molasses, makodextrin, starch, cellulose, mjcrocrystalline cellulose, polyvlnylpwolidone, acacia gum, guar gum, tragacanth gum. alginate, extract of bisk moss, panwar gum, ghatti gum, mucilage of isabgol (psyllium) husks, VEEGUM®, larch arabogalactan, gelatin, methylceilulose, ethylcelhdose, carboxymethylcelhdose, hydroxypropyhnetbylcellulose,polyacrylic acid(e.g., Carbopoll calcium silicate, calcium phosphate, dicalcium phosphate, calcium sulfate, kaolin, sodium chloride, polyethylene glycol: and combinat ions thereof. Suitable gum bases for use in the compositions of the present invention include, for example, materials selected from among the many waterinsoluble and saliva insoluble gum base materials known in. the art. In certain instances, the gum base comprises at least one hydrophobic, polymer and at least one hydrophilic polymer. Non “limi ting examples of suitable hydrophobic and hydrophilic polymers for gum bases include both natural and synthetic polymers such as elastomers, rubbers, and combinations thereof. Examples of suitable natural polymers include, without limitation, substances of plant origin such as chicle, jelutong, gutta percha, crown gum, and combinations thereof. Examples of suitable synthetic polymers include elastomers such as butadiene-styrene copolymers, isobutylene and Isoprene copolymers (e.g... "butyl rubber”), polyethylene, poh isobutx lene. pohx myksier (e.g., polyvinyl acetate and polyvinyl acetate phthalate), and combinations thereof. In other instances, the gurn base comprises a mixture of buty l rubber (i,e,, isobutylene and. isoprene copolymer), polyisobutylene,, and optionally, polyvinylacetals (e.g., having a molecular weight of approximately 12,000)- |0116| In yet another embodiment, the compositions of the present invention can further comprise a sweetening agent, a flax oring agent, a protecting agent, a plasticizer, a wax, an elastomeric solvent, a filler material, a preservative, or combinations thereof. In still yet another embodiment, the compositions of the present invention can further comprise a lubricating agent, a wetting agent, an emulsifying agent, a solubilizing agent, a suspending agent, a coloring agent, a disintegrating agent, or combinations thereof In an embodiment, the average particle size of the drug m the compositions described herein is abou t 20 micrometers, as compared to a ivpical avvmge drug particle sue of from about 75 io about -28- 2023251534 20 Oct 2023 I Ou nucji'iHUcu in another cmbodnncni the avctage partide size of the dmg in the compositions described herein is less than or equal to the average particle size of the carrier ingredients (e.g., gum base, binders, etc.).

[0117] In one aspect of the present disclosure, the therapeutic composition may optionally include a buffer system to raise the pH of saliva to a pH of from about 8.0 to about 11, irrespective of the starting pH of saliva in the oral cavity of the subject to be treated. Suitable therapeutic agents for use in the present invention are described above. Suitable carbonate salts and bicarbonate salts for use in rhe buffer systems of the present invention are also described above. In certain instances, composition further comprises a nombiologic therapeutic agent, such as an NSAID.

[0118] Suitable citrate, phosphate, and borate salts include, without limitation, any salt of citric .acid, phosphoric acid, or boric acid known in the art. For example, in some embodiments, the citrate salt is selected from the group consisting of sodium citrate, potassium citrate, calcium citrate, magnesium citrate, and ammonium citrate. [9119|    In other embodiments, the phosphate salt is selected from the group consisting of monobasic sodium phosphate, dibasic sodium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, monobasic calcium phosphate, dibasic calcium phosphate, monobasic magnesium phosphate, dibasic magnesium phosphate, monobasic ammonium phosphate, and dibasic ammonium phosphate. In yet other embodiments, the borate salt is selected from the group consisting of sodium borate, potassium borate, calcium borate, magnesium borate, and ammonium borate. In certain instances, the buffer system comprises a carbonate salt, a bicarbonate salt, and / or a citrate salt. In certain other instances, the buffer system comprises a carbonate salt, a bicarbonate salt, and / or a phosphate salt. In further instances, the buffer system comprises a carbonate salt, a bicarbonate salt, and / or a borate salt. [0120| In addition to a buffer system comprising a carbonate salt, a bicarbonate salt, and / or a metal oxide, other buffer systems arc suitable for use in the compositions of the present invention. For example, in an alternative embodiment, the ternary buffer system comprises a carbonate salt, a bicarbonate salt, and. a citrate, phosphate, or borate salt. In another alternative embodiment, the buffer system comprises a carbonate salt or a bicarbonate salt and. two or more buffering agents selected from the group consisting of a metal oxide, a citrate salt, a phosphate salt, and a borate salt. In yet another alternative embodiment, the buffer system is a binary buffer system comprising a carbonate salt or a bicarbonate sah and a metal oxide. In still yet another alternative embodiment, the buffer - 29 - 2023251534 20 Oct 2023 system' is a binary buffer system' comprising, a carbonate salt or a bicarbonate salt arid a citrate, phosphate, ar borate salt. In a further alternative embodiment, the buffer system is a binary buffer system comprising a metal oxide and a citrate, phosphate, or borate salt. In still yet another alternative embodiment, the buffer system is a binary buffer system comprising a carbonate salt and a bicarbonate salt. Delivery forms [01211    The therapeutic compositions of the present invention may take the form of solid, semi- solid, lyophilized powder, or liquid dosage forms, such as. for example, tablets (e.g., chewable, slow-dissolving, quick-dissolving), pills, capstiles, lozenges, candies, gums, powders, solutions, suspensions, emulsions, aerosols, or the like The dosage form can be a chewing gum, quick- dissolving tablet, candy, or lozenge. |0122| As used herein, the term “dosage form” refers to physically discrete units suitable as unitary dosages for human subjects, mammals, and other non-mammalian animals, each unit containing a predetermined quantity of therapeuti c agent calculated to produce the desired onset, tolerability,, and therapeutic effects, in association with one or more suitable pharmaceutical excipients such as carriers. Methods for preparing such dosage forms are known or will be apparent to those skilled in the art. For example, in some embodiments, a chewing gum dosage form of the present invention can be prepared according to procedures standard, in the industry. In other embodiments, a tablet, lozenge, or candy dosage form (e.g,, a sucker or lulhpop * of the present invention can be prepared according to the procedures set foirh m foi sample RemmgtouT'The Science and Practice of Pharmacy, '!)th Fd ” [Lippincott, Williams & Wilkins (2003); and, ' Pharmaceutical Dosage Forms, Volume I: Tablets,” 2nd Ed., Marcel Dekker, Inc., New York, N.Y. (1 °S9||. The dosage form to be administered will, in any event, contain a quantity of the active therapeutic agent in a therapeutically effective amount for relief of the condition bcmg treated when administered in accordance with the teachings of this invention. [91231 As used herein, the term “carrier” refers to a typically inert substance used as a diluent or vehicle for a drag such as a therapeu tic agent. The term also encompasses a. typically inert substance that imparts cohesive qualities to the composition. Suitable carriers for use in the compositions of the present invention include, without limitation, a solid, semisol id, or liquid such as a binder or a gum base. Examples of binders are known by one of ordinary skill m the art. Binders can be pre-processed to improve their flowability and taste by methods known in the art such as freeze drying [see. e.g,, “Fundamentals of FreezeDrying,” Pharm, Biotechnol, Vol. 14, pp. 281-360 (2002); “Lyophilization of Unit Dose -30- GQ of the acti ve therapeutic agent (in whatever chosen form., measured as per its free base form), and more typically from about 1.0% to about 5.0%. One skilled in the art understands that the foregoing percentages will vary depending upon the particular source of active therapeutic agent utilized, the amount of the active therapeutic agent desired in the final formulation, as well as on the particular release rate of the active therapeutic agent desired. The buffer system & %' g o a '^’ as c 9* 2023251534 20 Oct 2023 fester than slow-dissolving 'tablets, which are typically dissolved gradually rather than rapidly by a subject’s saliva. In an embodiment, the slow-dissolving or quick-dissolving tablet delivers the therapeutic agent across the sublingual mucosa over a period of time greater than about I minute. |0U6| In certain other embodiments, the tablet is a chewable tablet that is chewed by a subject and formulated to dissolve either rapidly or gradually. For example, a chewable tablet placed on the subject’s tongue can be used for buccal delivery of the therapeutic agent. During chewing, the chewable tablet can. be moved around within the mouth and can sometimes be parked between the gums and the cheeks or underneath the tongue. As a result, at least a portion of the therapeutic agent contained within a chewable tab let may also he delivered sublingually (i.e., across the sublingual mucosa). Typically, the chewable tablet is formulated to dissolve within about 1 to about 15 minutes, within about 2 to about 10 minutes and not less than I minute, e.g., within about 2, 3,4, 5, 6, 7, 8, 9, or 10 minutes, following administration. [01.27} As described above, the dissolving and chewable tablets of the present invention are typically formulated to dissolve within about 1 to 15 minutes following administration, and not less than about 1 minute after administration. However, while these time frames are amenable to maximum exposure of the therapeutic agent to the oral mucosa (e.g., to the sublingual and / or buccal mucosa), they are not always amenable to user compliance (e.g., users may swallow too frequently and, therefore, hinder maximal transmucosal absorption). Concequendy m certain instances n tn ay be desirable to strtkn a balance between pauent compliance and maximum exposure time of the therapeutic agent to rhe oral mucosa. This can be accomplished, for example, by reducing fee tablet size (e.g., from about 700-800 mg to about 200-300 mg) wi thout reducing the concentration or amount per unit dose of the buffer system or the therapeutic agent. In addition, subtle changes to the tablet formulation such as, for example, replacing one flavoring agent for another (e.g., chocolate for spearmint) or replacing one binder or sweetening agent for another (e.g., lactose for mannitol or sorbitol) may be used to reduce salivation. Cotnbinalkms with other pharmaceutical agents

[0128] Many phanmaceutically active agents generate detrimental side effects, which are driven by ROS feat are produced as the active agent proceeds through biochemical and other metabolic reactions. Thus, rhe compositions described herein arc attracme candidates for foe treatment of oxidative stress and oxidative stress-related diseases and conditions and can. be combined with one or more pharmaceutical agents known in fee art, such as any -32- 2023251534 20 Oct 2023 pharmaceutical agent listed m the Physician's Desk Reference (available at http: / / mw.pdi-.tiet). |0129 |    In some embodiments, the .active ingredients of the disclosure are combined wi th known pharmaceutical agents tha t target oxidative stress, inflammation, the immune, response, and / or oxidative stress-related diseases or conditions, or they can be combined with pharmaceutical agents drat produce oxidative stress as a side effect. Where the pharmaceutical agent targets some other disease state but produces oxidative stress as a side effect, combination with the inventive compositions reduces damage ca .sed b\ oxidative stress and also enhances the effectiveness of the pharmaceutical agent b\ al ov ing higher doses without prohibitive damage caused by oxidative stress. It will be appreciated that optimum, results with a particular combination may require adjustmen t of the lysates to optimally target the correct TLRs in the presence of the added pharmaceutical agent. 10130) Thus in one aspect, the disclosure provides methods for reducing or alleviating one or more oxidative stress-related side effects associated with administration of a pharmaceutical agent, the methods comprising administering a lysate, lysate fraction, and / or cell wall fraction of the disclosure in combination with the pharmaceutical agent. In some embodiments, the pharmaceutical agent and lysate composition are administered simultaneously or in any order, and through the same or different routes of administration. In some embodiments, the pharmaceutical agent is any pharmaceutical agent with one or more oxidative stress-related side effects, such as any pharmaceutical agent listed in die Physician's Desk. Reference tavailable at hnp' wwm ndt nett with one or more oxidative stress-related side effects. In some embodiments, the pharmaceutical agent is selected from the group consisting of anti-rhemnatic drugs, anti-intiannnatory agents, chemotherapeutic agents, radiotherapeutics, immunosuppressive agent, interferons, interferon-based chemotherapeutics, and cytotoxic dregs. In some embodiments, the oxidative stress-related side effects are selected from aceruloplasminerma, arterhl / systemic hypertension, arthritis, asthma, atherosclerosis, atopic dermatitis, cancer, bladder cancer, leukemia, uterine cancer, cervical cancer, dizziness, nausea, vomiting,, constipation, diarrhea, insomnia, drowsiness, lightheadedness, reduced libido, blackouts, shakes, jaundice, arrhythmia, increased heart rate, decreased heart rate, hives, depression, clinical depression, brain ischemia, bronchopulmonary dysplasia, cardiovascular diseases, cataract, cellulitis, chemotherapeutic side-effect, chronic fatigue syndrome, colitis, coronary artery disease, dyslipidemia, eclampsia, erectile dysfunction, ataxia, headache, heart failure, hemodialysis side effects, hepatic cirrhusis, hypcrcholesteioiemia, hyperhomoeystetnemia, hyperlipidemia, interstitial - 33- 2023251534 20 Oct 2023 lung disease, lung ihjury, macular degeneration, male infertility, mild -cognitive impairment, myocardial infarction, myocarditis, myopathy, neuropathy, obesity, osteoarthritis, osteoporosis, pancreatitis, periodontal disease, peritoneal dialysis side effects, post-traumatic stress disorder, preeclampsia, psoriasis, psoriatic arthritis, pulmonary hypertension, .radiotherapy side, effects, reactive arthritis, respiratory distress syndrome, rhabdomyolysis, rheumatic disease, sepsis, sleep apnea, stroke, suicidal thoughts, amyloidosis, throinbophily, tauopathics, unstable angina, uremia, or venous insufficiency. [01311 In some embodiments, the pharmaceutical agent having one or more oxidative stress-related side effects is selected from the group consisting of Antispasmodics selected from the group consisting of atropine sulphate, dicycfoverinc hydrochloride, hyoseme butylbromine, propantheline bromide, al venue citrate, and mebeverine hydrochloride; Motility stimulants selected from the group consisting of meioclorpramide and domperidone; H2-Receptor antagonists selected from the group consisting of Cimetidine, famotidinemzatidiiie, and ranitidine; Amimuscarmics: Chelates selected from the group consisting of Tripotassium dicitratbismuthate and sucralfate; Prostaglandin analogues; Aminosalicylates selected from the group consisting of balsazlde sodium. mesalazine, olsalazme, and sulphasaiazme; Corticosteroids selected from the group consisting of bedometasone dipropionate, budenoside, hydrocortisone, and prednisolone; Affecting immune response selected from the group consisting of cielosporin, mercaptopurine, methotrexate, adalimumab, and infliximab; Stimulant Laxatives selected from the group consisting of bisacodyl, dantron docusate and sodium picoculfhre’ Drugs affeenng biliary composition and flow; Bile acids sequcstTan.es selected from the group consisting of colestyraminc. Oxypheneychmine, Camyiofm, Mebeverine, Trimebutine, Rociverine, Dieycloverine, Dihexyverine, Dife^ Piperidolate, Benzilone, Mepenzolaie, Pipenzolate, Glycopyrronium, Oxyphenoniw, Penthienate, Meihantheliue, Ihopantheline, Otilonium bromide, Tridihexethyl, Isopropami.de, Hexocyclium, Poldine, Bevonmm, Dipheman.il, Tiemonium iodide. Prifinium bromide, Timepidium bromide, Fenpiverinium, Papaverine, Drotaverine, Moxaverine, 5-HT3 W 5-HT4 agonists, Fenpiprane, Diisopromine, Chlorbenxoxamme, Pinaverium, Fenoverine, Idanpramine, Proxazole, Alveriue, Trepibutone, Isometheptene, Caroverine, Phloroglucinol, Silicones, Trimctiiyldiphenylpropylamine, Atropine, Hyoscyamine, Scopolamine, Butyfccopolamitie, Mcthvlreopolamiue, Methylatropine, Femcnium, Cmretropium bromide, and primarily dopamme antagonists:’. Proton pump inhibitors selected from the group consisting of Omeprazole, lansoprazole, pantoprazolc, esomeprazole, and rabcprazole sodium; Opioids and - 34 - 2023251534 20 Oct 2023 opioid receptor antagonists; Analgesics selected from the group consisting of Acetaminophen, Diclofenac, Diflumsal, Etodolac, Fenoprofen, Flurbiprofen, Ibuprofen, tedometbac in, Ketoprofen, Ketorolac, Mcclofenamate, Mefenamic Acid, Meldxicam, Nabumetone, Naproxen, Oxaprozin, Phenylbutazone, Piroxicam, Sulindae, Tolmetm, Celecoxib, Buprenorphine, Butorphanol, Codeine, Hydrocodone, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Nalbuphine, Oxycodone, Oxy morphone, Pentazocine, Propoxyphene, and Tramadol; Sleep drugs selected from the group consisting of Nitrazepam, Flurazepam, Loprazolam, Lotmefcazepam, Temazepam, Zaleplon, Zolpidem, Zopiclone, Chloral Hydrate, Triclofbs, Clomethiazole, Quazepam, triazolam, Estazolam, Clonazepam, Alprazolam, Eszopiclone, Rozerem, Trazodone, Amitriptyline, Doxepm, Benzodiazepine drugs, melatonin, diphenhydramine, and herbal remedies; Cardiac glycosides selected from the group consisting of Digoxin and digitoxin; Phosphodiesterase inhibitors selected from the group consisting of enoximone and milrinone; Thiazides and related diuretics selected from the group consisting of bendroflumethiazide, chlortalidone, cyclopcnthiazide, inapamide, metolazone, and xipamide; Diuretics selected from the group consisting of furosemide, bumetanide, and torasemide; .Potassium sparing diuretics and aldosterone antagonists selected from the group consisting of amiloridc hy drochloride, triamterene, weplerenone, and spironolactone; Osmotic diuretics; Drugs for arrhythmias selected from the group consis ting of adenosine, amiodarone hy drochloride, disopyramide, flecatmdc acetate, propafenone hydrochloride, and lidocaine hydrochloride; Beta adrenoreceptor blocking drugs selected from the group consisting of propanafol, atenolol, acebutolol, bisprolol fumarate, carvedilok cdiprolol, esmolol, lebatolol, metoprolol tartrate, nadolol, nehivolol, oxprenolol, pindolol, solato!, and timolol; Hypertension drugs selected from the group consisting of ambrisentan, bosentan, diazoxide, hydralazine, iloprost, minoxidil, sildenafil, sitaxentan, sodium nitroprusside, clomdine, methyldopa, moxonidine, guanethidine monosulphate, doxazosin, indoramin, prazosin, terazosin, phenoxybenzamine, and phentoiamine mesilate: Drugs affecting the renin-angiotensin system selected from the group consisting of Captropril, Cilazapril, Enalapril Maleate, Fosinopril, Imidapril, Lisinopril, Moexipril, Perindopril Erbumme, Quinapril, Ramipril, Traudolapril, Candesartau Cilexeiil, Eprosariau, Irbesartan, Losartan, Olmesartan Medoxomil, Telmisartan, Valsartan, and Miskiren. Nmates, calcium channel Blocked, and antungmal diselected tiom the group consisting of Glyceryl trinitrate. Isosorbide Dinitrate, Isosorbide Mononitrate, Amlodipine, Dihiazem, Felodipine, Isradipine, Lacidipine, Lercamdipine. Nicardipine, Nifedipine, Nimodipine, Verapamil habradinc, Nicorandil, and RanolazuK. Peripheral 2023251534 20 Oct 2023 Vasodilators and related drugs selected from the group consisting of Cilostazol, Inositol Nicounatc. Moxisyh to. XatbdiomrH Oxalate, and Fcntoxifuhne, Sympadu'immcttcs selected from the group consisting of Dopamine, Dopexamine, Ephedrine, Metaraminol, Noradrenaline Acid Tartrate, Norephidrme Bitartrate, and Pheny lephldrine; Anticoagulants and .Protamine selected from the group consisting of Heparin. Bcnnparin, Dalteparin, Enoxaparin, Tinzaparin, Danaparoid, Bivaliradin, Lcpirudm, Epoprostenol, Fondaptinux, W arfarin, Acenocoumarol. Phenindione, Dabigatran Etexilate, Rivaroxaban. and Protamine Sulphate; Antiplatelet Drugs selected from the group consisting of Abeiximab, Aspirin, Clopidogrel, Dipyridamole, Eptifibalide, Prasugrel, and Tirofibair; Fibrinolytic and wifibrindlytic drugs selected from, the group consisting of Alteplasc, Reteplase. Streptokinase, Tencctepki^. I hokmase, Etanisy laic, and Trauexamic Acid; Lipid Regulating Drugs selec ted from the group consisting of Atorvastatin, Fluvastatin, Pravastatin, Rosuvastaim, Simvastatin Cnlesevam, Colesiyramine, Colestipo Ezetimibe, Bezafibrate, Ciprofibrate, Fcnofibrate, Gemfibrozyl. Acipmox, Nictotinic Acid, Omega three fatty acid Compounds, Ethanolamine Oleate, and Sodium Tetradecyl Suphate; CNS Drugs selected from the group consisting of Bcnpcridol, Chlorpromazine, Flupemixol, Haloperidol, Levomepromazine, Pericyazine, Perphenazine, Pimozide, Prochlorperazine, Promazine, Su'pnidt I iitluopuazine, Zvcloptnthj'ol, Amisidptidc Ai ipipuzole, CA / apme, Olanzapine, Paliperidone, Quetiapine, Riperidone, Sertindole, Zotepine, Flupeatixol, Fluphenazine, Olanzapine Embonate, Pipodaziae Palmitate, Risperidone, Zuclopenthixoi Decanoate, Carbamazepine, Valproate, Valproic acid, Lithium Carbonate, Lithium. Citrate, Amitriptyline, Clomipramine, Dosuiepin, Imipramme, Lofepramine, Nortriptyline, Trimipramine, mianserin, Trazodone, Phenelzine, Isocarboxazid, Tranylcypromine, Moclobomide, Citalopram, Escitalopram, Fluoxetine, Fluvoxaminc, Paroxetine, Sertraline, Agomclaunc, Duioxcunc. Fhipctmxo!, Mirtazapine, Rcboxctme, Trytopham Vcnflaxmc, Atomoxetine, Dexameiamiue, Mediylphenidate, Modafinil, Eslicarbazepine, Ocarbazepene, E&osuxhnide, Gabapentin, Pregabalm, Lacosarnide, Lamotrigine, Levetiracetam, Phenobarbital, Primidone, Phenytoin, Rufinamide. Tiagabine, Topiramate, Vigabatrin, Zonisamide, ropinirole, Roiigotine, Co-Beneldopa. Levodopa, Co-Carcldopa, Rasagiliue, Selegiline, Entaeapone, Tolcapone, Amantidine, Orphenadrine, Procyclidine, Trihexyphenidyl, Halopetidol, Piracetam, Riluzole, Tetrabenazinc, Acamprosatc, Disulfiram, Bupropion, Vmohiciline, Buprenorphine, Lofcxidine, Donepezil, Galantamine, Memantine, and Rivastigimine: Antirinfectives selected from, the group consist ing of Benzylpenicillin, Phcnrrxymethyipcnicillm, Flucioxacillin, Temocillin, Amoxicillin, Ampicillin, Co & S‘ o 2023251534 20 Oct 2023 composition that includes a pharmaceutically acceptable carrier. Such compositions comprising additional therapeutic agents can be in any suitable form (depending upon the desired method of administering it to a patient). In some embodiments, the acti ve ingredients of the disclosure are co-administered with one or more additional therapeutic agen ts, though are not necessarily combined into a single formulation with the one or more additional therapeutic agents. In some embodiments, the acti ve ingredient^) of the disclosure are administered via one route of administration, whereas the co-administered additional therapeutic agentfs) are administered via a second route of administration For example, the active ingredients of the disclosure might be administered orally, mucosally, sublingually, buccally, etc., whereas the co-administered one or more additional therapeutic agents are administered parenterally, intravenously, ete. [0133| Examples of compounds that can be combined with the inventive compositions include anti-rheumatic drugs, anti-inflammatory agents, chemotherapeutic agents, radiotherapeutics. immunosuppressive agent, interferons, interferon-based chemothcrapeutics, or cytotoxic drugs. j0134| Anti-rheumatic drugs inchide, but are not limited to, auranotm, azathioprine, chloroquine, D-pemciIla.mme, gold sodium thiomalate hydroxycMotoqmne, Myocrism and sulfasalazine methotrexate. |0135| Anti-inSammatory agents include, but are not limited to, dexamethasone, pentasa, mesalazine, asacol, codeine phosphate, benoryiate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen, as well as other non-steroidal and antiinflammatory agents (NSAIDS). [01M| Chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic agents, which includes any agent that is detrimental to the viability of cells, agents, and liposomes or other vesicles containing; chemotherapeutic compounds Examples of suitable chemotherapeutic agents include but arc not limited to 1 -dehydrotestosteroue, 5-.fluorouracU decarbazme, 6-mercaptopurine, 6-thioguarnne, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, akretamine, amifostine, amistrozole, anrhramyem {AMO), anti-mitotic agents, cis-dichiorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracyclmes, antibiotics, antimetabolites, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicahitamide, bleomycin sulfate, busulfan, calcium leucoyprin, calicheamicin, capecitabine. carboplatin, lomustme (CCNU), carmustine (BSNU), Chlorambucil, Cisplatin, Cladribine, Colchicm, conjugated estrogens, 2023251534 20 Oct 2023 Cyclophosphamide, Cyekithosphamide, Cytarabine, Cytarabine, cytochalasin B, < smsim, Daearbazine, Dactinomycin, dactinomycin (formerly actinomycin), daunirubicin HCL, daunorucbicin citrate, demleukm diftitox, Dexrazoxane, Dibromomanmtol, dihydroxy anthracin dioue, Docetaxel, doiasetron mesylate, doxorubicin HCL, dronabinol, E. coli L~ asparaginase, emetine, epoetin- .alpha.. Erwinia L-asparaginase, esierified estrogens, estradiol, estramustine phosphate sodium, ethidium bromide, ethinyl estradiol, etidronate, etoposide citrovorum factor, etoposide phosphate, filgrastim, lloxuridine, fluconazole, fludarabine phosphate, fluorouracil, Eutamide, folinic acid, gemcitabine HCL, glucocorticoids, goserelin acetate, gramicidin D, gramsetron HCL. hydroxyurea, idarubicih HCL, ifbsfemide, mferfetdp .alpha ~2b, irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate, ievamisole HCL, lidocaine, lomustine, maytansinoid, mechlorethamine HCL. medroxyprogesterone acetate, megestol acetate, melphalau HCL, mercaptopurine, mesna. med ton exate, methyltestosterone. mithramycin, mitomycin C, mitotane, mitoxantrone, nihnamide, octreotide acetate, ondansetron HCL. paclitaxel, pamidronate disodium, peutostatin, pilocarpine HCL, plhm-Jn, polifeprosan with carmustinc implant, porttmer sodium, procaine, procarbazine HCL. propranolol, rituximab, sargramostun, streptozotocin, tamoxifen, laxol, temposide, tenoposide, testo lactone, tetracaine, thioepa, chlorambucil rhioguanme. thiotepa. ropotccan HCL, rommifene citrate, trastuzumab, tretinoin, valntbicin, vinblastine sulfate, vinuisuuc sulfate, and vinorelbine tartrate. J0137J In yet other aspects of the disclosure, active ingredients of the disclosure are administered in combination with a TNF~u antagonist or an anti-TNF- u antibody. Examples of such IMF- a antagonists include, but are not limited to, soluble TNF- a receptors; etanercept tENBRELir; Immunex) or a fragment, derivative or analog thereof; infliximab (REM Ik ADE#; Ceutacor) or a derivative, analog or antigen- binding fragment thereof; Adahmumab (Humira and Exemptla >, IL-lQ, which is known to block TN'F-a production w interferon-y-activated macrophages, TNFR-lgG; the murine product TBP-1; the vaccine CyioTAb (Pmthericsi. atmsense molecule IO4S3S the peptide RDP-5X <SangSMt). thalidomide (Celgene); CDC-S01 (Celgene); DPC-333 (Dupont); VX-745 (Vertex): AGLX-4207 (AtheroGenics); ITF-2357 (Italfanriaco); N.PL13021-31 (Nereus); SCIO-469 {Sciosi; TACE targeier (Immunix / AHP); CLX-120500 (Calyx); Thiazolopyrim (Dynavax); auranofin (Ridaura) (SmithKline Beecham Pharmaceuticals); qumacrine (mepaenne dtchlorobydrate); temdap (Enables'): Melanin (Large Scale Biological); and anti-p.3X MAPK agents by Liriach. |0138| In further aspects of the present disclosure, active ingredients of the disclosure are administered in combination with rapamycin, or similar macrocyclic antibiotics. As used - 39 - 2023251534 20 Oct 2023 herein., rapamycin includes rapamyelu and ah analogs, derivatives and congeners thereof. and other immimophllins that possesses the same pharmacologic properties as rapamycin is including inhibition of TOR or mTOR (mammalian target of rapamycin) (e.g., acting as a TOR kinase inhibitor). Other immunosuppressives that can be used as the one or more pharmaceutical or therapeutic agents include, but are not limited to, cyclosporine, tacrolimus (FK-506), azathloprine, and mycophenolate mofetil [01391    Further therapeutic agents that may be combined with the active ingredients of the disclosure include angiogenic agents such as vase? ar endothelial growth factor (VEGF) and fibroblast growth factor (FGF). angiotensin weeper blockers; nitric oxide donors; antisense oligonucleotides and combinations thereof; cell cycle inhibitors, mTOR inhibitors, and growth factor receptor signal transduction kinase inhibitors; retinoids; cyelmlCDK inhibitors; HMG coenzyme reductase inhibitors (e.g,, statins); and protease inhibitors. TNF Inhibitors

[0140] A tumor necrosis factor ( INF) inhibitor, specifically a TNFa inhibitor which is used in the methods and compositions of the invention includes any agent which interferes with TNFaactivity. In a preferred -embodiment, the TNFa inhibitor can neutralize TNFa acth tty, particularly detrimental TNFa activity which is associated with oxidative stress diseases and disorders, such as [see definition], and related complications and symptoms..

[0141] The term “human TN Fa” (abbreviated herein as hTNFa, or simply hTNF), as used herein, is Intended to refer to a human cy tokmc that exists as a 17 kD secreted form and a 26 kD membrane associated form,, the biologically active form of which is composed of a trimer of noneovalently bound 17 kD molecules. The structure of hTNFais described farther in, for example, Pennica, D., el al. (1984) Nature 312'~24-729; Davis, J M , ci al. i N87) Biochemistry 26:1322-1326; and Jones, E, ¥., &al. (1989) Naiure 338:225-228. The term human TNFa re intended to include recombinant human TNFa trbTNFa), which can be prepared by standard recombinant expression methods or purchased commercially (for example, from R & D Systems, Minneapolis, Minn.). TNFa is also referred io herein equivalently as TNF.

[0142] The term “TNFa inhibitor” refers to an. agent which interferes with TNFa activity. The term also includes each of the anti-TNFa human antibodies and antibody portions described he rem as well as those described in U.S. Patent Nos. 6.099 382: 6.258.562' 6.509,015, and in U.S. Patent No 7,223,394). In one embodiment, the TNFa inhibitor used in the invention is an anti-TNFa antibody, or a fragment thereof including infliximab (Remicade*', Johnson and Johnson, described in U.S. Pat. No. 5,656,272, incorporated by -40- 2023251534 20 Oct 2023 reference livtcmi CDPVl ct humanized monecfonal ann-T\F-alphd k<}4 antibodv) COP 870 (a humanized monoclonal anti-TNF-alpha antibody fragment), an anti-TNF dAb IPeptech). CNTO 148 (’gohnuimab: Medarex and Centocor, see WO 02 / 12502), and adalimumab (I htmira^ Abbott Laboratories, a human anti-TNF mAh. described in U.S. Patent No 6 090.362 as “D2E~”) Additional TNF antibodies which can he used in the indention ate described in U.S. Patent Nos. 6,503,458; 6,498,237; 6,451,9,83; and 6.448.380, each of which is incorporated by reference herein. In another embodiment, the TNFa inhibitor is a TNF fusion protein, e.g , etanercept (Enbrel^ Amgen; described in WO 91 / 03553 and WO 09 / 40076, incorporated by reference herein). In another embodiment, the TNFa inhibitor is a recombinant TNF binding protein (r-TBP-I) (Serono). |0143| The term “antibody”, as used herein, is intended to refer to immunoglobulin molecules comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds Each heavy chain is comprised of a heavy chain variable region (abbrev iated herein as HCVR cr VH) and a heavy chain constant region. The heavy chain constant region is comprised of throe domains. CHI, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL ■ and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions ofhypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Lach VH and VL is composed of three CDRs and four FRs, arranged from amino-tetmmns to carboxy-terminus in the following order FR1, CDRi. FR2. CDR2, FR3 CDR3, FR4. The antibodies of the invention arc described in farther detail In U.S. Patent Nos 6.WU.382; 6.258,562. and 0,509,()15, each of which is incorporated, herein by reference m its entirety. [0 H4j    The term “human antibody”, as used herein, is intended, to include antibodies having variable and constant regions derived from human gcrmlmc immunoglobulin sequences. The human autd >4 vs of the invention may include amino acid residues not encoded by human germhi u munoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in. vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term “human antibody”, as used herein, is not intended to include antibodies in which CDR sequences deri ved from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. 2023251534 20 Oct 2023 [0145) The term “recombinant human antibody”, as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host ceil f described further below), antibodies Isolated horn a recombinant, combinatorial human antibody library (described further below?, antibodies isolated from an animal (e g , a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et ah (19^21 Wef. Adds Xes. 20 0287} or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis? and thus the amino acid sequences of the-VH and VL regions of the recombinant antibodies arc sequences that, while derived from and related to human germlinc VH and VI.. sequences, may not naturally exist within the human antibody germline repertoire in vivo. [0146) In one embodiment, the term “TNFu inhibitor” excludes infliximab. In one embodiment, the term “TNFa inhibi tor” excludes adaiimumab. In another embodiment, the term “TNFa inhibitor” excludes adaiimumab and infliximab, [0147) In one embodiment, the term "TNFa inhibitor’'’ excludes etanercept, and, optionally, adaiimumab, infliximab, and adaiimumab and infliximab, [0148) In one embodiment., the term “TNFn antibody” excludes infliximab. In one embodiment, the term "TNF« anti body" excludes adaiimumab. In another embodiment, the term "TNFa antibody” excludes adaiimumab and infliximab, [0149) In one embodiment, die in vention features uses and composition for treating Or determining the efficacy7 of a TNFa inhibitor for the treatment of Crohn's disease, wherein the TNFa antibody is an isolated human antibody, or antigen-binding portion thereof, that binds to human. TNFa with high affinity and a low off rate, and also has a high neutralizing capacity. Preferably, the human antibodies used in the invention are recombinant, neutralizing human. anti-hTNFa antibodies. The most preferred recombinant, neutralizing antibody of the invention is referred to herein as D2E7, also referred to as HUMERA* or adaiimumab (the ammo acid sequence of the D2E7 VL region is shown in SEQ ID NO: 1; the ammo acid sequence of the D2E~ VH region is shown in SEQ ID NO: 2). T he properties of D21.7 ■ adaiimumab Hl XHRA5') h.n c been dcscnbed m. and, w Kick arc each incorporated by reference herein. The methods of the invention may also be performed using chimeric and & s SV* s S' s a a S a o S3 2023251534 20 Oct 2023 absorption of the composition; and (iii) an optional carrier for increasing a volume of the composition; and (b) making measurements of a bodily fluid of the sub ject to detect changes in oxidative stress levels. In 'some embodiments, the TLR agonist activates at least three different TLRs. In some embodiments, the TLR agonist comprises lysate(s) and / or lysate fractions) and or ceil wall fraction!s) from a single species of bacteria. In some embodiments. the TLR agonist comprises lysatets) and-or lysate fractionfsl from at least two species or strains of bacteria. [01541 In some embodiments, making measurements of a bodily fluid assesses changes in isoprostane concentration in the subject. In some embodiments, changes in isoprostane concentration are measured indirectly bv methods including but not limited to gene expression in the subject In some embodiments, the subject is a .mammal. In some embodiments, the mammal is a human. In some embodiments, the subject is an animal other than a mammal, such as, but not limited to. fish, fowl., crustaceans, and insects, such as Drosophila In some embodiments, the oxidative stress in the human is related to post-traumatic stress disorder.

[0155] In another aspec t, the disclos ure pro vides methods of decreasing the amount of isoprostane in the urine or blood of a subject, the method comprising the steps of: (a) determining the level of isoprostane in the urine or blood of the subject; (b) administering to the subject an vtlectisc amount of a conipusmon composing i t) .t mil- hkc receptor {TL R > agonist comprising at least one bacterial lysate and / or lysa te fraction from a bacterium, wherein the TLR agonist activates at least one or more TLRs or NLR\; and (ii) an optional promoter for enhancing absorption of the composition; and (c) continuing administration of the composition until the level of isoprostane in the urine or blood of the subject is decreased.

[0156] In another aspect, the disclosure provides compositions comprising: (a) a bacterial lysate and / or lysate fraction capable of activating at least one or more toll-like receptors (TLRs) or Nod-like receptor (NLR); (b) an optional promoter for enhancing absorption of the composition; and (c) an optional carrier for increasing a volume of the composition,

[0157] In another aspect, the disclosure provides pharmaceutical formulations comprising any of the compositions disclosed herein. In some embodiments, the pharmaceutical formulations are formulated for buccal or sublingual administration. In some embodiments, the pharmaceutical formulations are formulated to dissolve in not less than 1 minute after administration 2023251534 20 Oct 2023

[0158] In another aspect:, the disclosure provides methods of producing a bacterial lysate, die method comprising the steps of: (a) fermenting a Grain-positive or Gram-negative bacterium in a growth medium to the stationary growth phase to produce a fermentation broth, (b) hancsting bacteria from the fermentation bioth; ic) pasteurizing the harvested bacteria; and (d) lysing the pasteurized bacteria with a lysozyme to produce a bacterial lysate. In some embodiments, the lysate is harvested at different times of rise growth cycle after beginning any particular fermentation.. In some embodiments, the bacteria are fermented in a characteristically defined media.

[0159] In another aspect, the disclosure provides bacterial lysates produced according to a process, the process comprising the steps of (a) fermenting a Gram-positive or Gramnegative bacterium in a growth medium to the stationary growth phase to produce a fermentation broth; (b) harvesting bacteria from the fermeniatiou broth; (c) pasteurizing the harvested bacteria; and (d ■ lysing rhe pasteurized bacteria with a lysozyme to produce a bacterial lysate. In some embodiments, the lysate is harvested at different times of the growth cycle after beginning any particular fermentation. In some embodiments, the bacteria are fermented in. a characteristically defined media,

[0160] In another aspect, the disclosure provides methods for alleviating one or more oxidative sti'css-related side effects associated with administration of a pharmaceutical agent, the method comprising administering in combination with the phannaceuucal agent a therapeutically effective amount of a composition comprising: (a) a lysate and or Ssate fraction of a bacterium; (b) an optional promoter for enhancing absorption of the composition: and (cl an optional carrier for increasing a volume of rhe composition; wherein the pharmaceutical agent and lysate composition are administered simultaneously or in any order, and through the same or different routes of administration, In some embodiments, the lysate and / or lysate fraction activates at least one or more TLRs or NI,Rs. In some embodiments, the lysate and / or lysate fraction activates at least two TLRs and / or NLRs. In some embodiments, the lysate and / or lysate fraction activates at least three TLRs and or NLRs,

[0161] In some embodiments, the one or more oxidative stress-related side effects are selected from the group consisting of: aceruloplasuunemia, arteriai / systemic hypertension, arthritis, asthma, atherosclerosis, atopic dermatitis, cancer, bladder cancer, leukemia, uterine cancer, cervical cancer, dizziness, nausea, vomiting, constipation, diarrhea, insomnia, drowsiness, lightheadedness, reduced libido, blackouts, shakes, jaundice, arrhythmia, increased heart rate, decreased heart rate, hives, depression, clinical depression, brain ■■ 45 - 2023251534 20 Oct 2023 ischemia, bronchopulmonary dysplasia, cardiovascular diseases, cataract, cellulitis, chemotherapeutic side-effect, chronic fatigue syndrome, colitis, coronary artery disease, dyslipidemia, eclampsia, erectile dysfunction, ataxia, headache, heart failure, hemodialysis side effects, hepatic cirrhosis, hypercholesterolemia, hyperhomocysteinemia, hyperlipidemia, interstitial lung disease, lung injury, macular degeneration, male infertility, mild cognitive impairment, myocardial infection, myocarditis, myopathy, neuropathy, obesity, osteoarthritis, osteoporosis, pancreatitis,, periodontal disease, peritoneal dialysis side effects, post-traumatic stress disorder, preeclampsia, psoriasis, psoriatic arthritis, pulmonary hypertension, radio-therapy side effects, reactive arthritis, respiratory distress syndrome, rhabdomyolysis, rheumatic disease, sepsis sleep apnea, stroke, suicidal thoughts, amyloidosis, thrombophily, iauopathi.es, unstable angina, uremia, and venous insufficiency. |0162| In another aspect, the disclosure provides methods for treating oxidative stress-related diseases or coudinous m a subject, the methods comprising administermg io the subject a therapeutically effective amount of a composition comprising: ta) a bacterial lysate and / or lysate fraction capable of activating at least one or more toil-like receptors (TLRs) or Nod-like receptors (NLRst (b) an optional promoter for enhancing absorption of the composition; and u) an optional carrier for increasing a volume of the composition |01631    In some :fembo^hten^, the oxidative stress-related condition is aceruloplasmmemia, acute and chronic alcoholic liver diseases, acute autoimmune myocarditis, acute chest syndrome of sickle cell disease, acme pancreatitis, acute respiratory distress syndrome, alcoholic liver disease, Amyotrophic Lateral Sclerosis, arterial / systemie hypertension, asbestosis. asthma, ataxia telangiectasia, atherosclerosis, atopic dermatitis, brain ischemia, bronchopulmonary dysplasia, burns, some cancers, cardiopulmonary bypass, cardiovascular diseases, cataract, cellulitis, chemo therapeutic side-effect, chronic fatigue syndrome, chronic Hepatitis C, chronic kidney disease, chronic obstructive pulmonary disease, chronic renal failure, colitis, coronary artery disease Creutzfeldt-Jakob disease, Ciohn's disease, cutaneous leishmaniasis. c\sttc tibtosis, diabetes mc'htus type 1. diabetes mellitus type 2, dyslipidemia, Down5s syndroms, eclampsia, end-stage renal disease, erectile dysfunction, Friedreich ataxia, headache, heart failtirc. Hehcabacterpylori ittfection / inflammation, hemodialysis side effects, hepatic cirrhosis. Human Immunodeficiency Virus infection, Huntington disease, hyperbaric diseases, hypercholesterolemia, hyperhomocyste inemia, hyper! ipidemia, idiopathic pulmonary fibrosis, interstitial lung disease, isdiemifeeperfusi.on injury, juvenile chronic arthritis, kidney transplantation failure, leukemia, lung cancer, lung injury, macular degeneration, 2023251534 20 Oct 2023 male infertility, Meniere’s syndrome, meningitis, mild cognitive impairment. Multiple Sclerosis, myelodisplastic syndr&mes, myoeardial infection, myocarditis. neonatal bjorxhopuhronatj d^sphs.a, obesav cotcomrmittrt oeteopoios oanc^at Us Parkinson s disease, periodontal disease, peritoneal dialysis side effects, pfetoageing, post-traumatic stress disorder, preeclampsia, primary biliary cirrhosis, broncopulmonary diseases, progeria, psoriasis, psoriatic arthritis, pulmonary hypertension, radio-therapy side effects, reactive arthritis, renal cell carcinoma, respiratory distress syndrome, retinopathy of prematurity, retrolenticolar fibroplasy, rheumatic disease, rheumatoid arthritis, sarcoidosis, sepsis, sickle cell disease, sleep apnea, spherocytosis, spinal cord injury, stroke, Syuuctemopathies, systemic amyloidosis, systemic lupus erythematosus-, systemic sclerosis (scleroderma), thrombophily, tauopathies, traumatic stress tubercolpsis, unstable angina, uremia, venous insufficiency, Werner syndrome, or Zellweger syndrome. 1'0164) Ik another aspect, the disclosure provides methods for reducing oxidative stress in a subject, the methods comprising: (a) determining the level of oxidative stress in the subject by measuring the amount of isoprostane in the urine or blood of the subject; (b) admimsicimg to the subject an clkxmxc amount of a composHfun composing tn a i<>H-siKv receptor (TLR) agonist comprising at least one lysate and / or lysate frac tion from a Gramnegative or Gram-positive bacterium, wherein the TLR agonist activates at least one or more different TLRs or NLRs; and (ii) an optional promoter for enhancing absorption of the cornposition; and (c) continuing administration of the composition until the level of oxidative stress is reduced, as determined by a decreased amount of isoprostane in the urine of the subject. [0165j In some embodiments, of any of the above aspects, administration of the bacterial lysate is continued until the amoun t of isoprostane in the urine of the subject is less than about. 3 pg per mg creatinine, less than about 2 ng per mg creatinine, less than about 1 ng per mg creatinine, or less than about o 5 ng per mg of creatinine. |0166| In another aspect, the disclosure provides pharmaceutical formulations comp' wiry the combination 0' (at a hsak composition comprising vj a back rial Ksarc and / or lysate fraction capable of activating at least one or more toll-like receptors (TLR) or Nod-like receptors (NLR); (ii) an optional promoter for enhancing absorption of the composition; and (iii) an optional carrier for increasing a volume of the composition; and (b) one-or more pharmaceutical agents. In some embodiments, the one or more pharmaceutical agents are selected from the group consisting of: an antispasmodic, a motility stimulant, an. H2-Receptor antagonist, antimuscarmic^ a chelate, a prostaglandin analog, an 2023251534 20 Oct 2023 aminosalicylate, a corticosteroid, an. drag affecting immune response, a stimulant laxative, a drug affecting biliary composition and flow, a bile acids sequestrate, a dopamine antagonist, a proton pump inhibitor, an opioid, an opioid receptor antagonist, an analgesic, a sleep drug, a cardiac glycoside, a phosphodiesterase inhibitor, a thiazide, a diuretic, a potassium sparing diuretic, an aldosterone antagonist, an osmotic diuretic, a drug for arrhythmia, a bbeta adrenoreceptor blocking drug, a hypertension drug, a drug affecting the renin-angiotensin system, a nitrate, a calcium blocker, an anti anginal drug, a peripheral vasodilator, a sympaihomijnetic, an anticoagulant. a protamine, an antiplatelet drug, a fibrinolytic drug, an antifibrinolytic drug, a lipid regulating drug, an omega three fatty acid compound, a CMS drug, an anti-infective, or another drug selected from the group consisting ^ procyclidine, biperiden. Amantadine, Bromocriptine, Pergohde, Eutacapoue, Tolcapoue, Selegeline, Pramipexole, budesonide, formoterol, quetiapine fumarate, olanzapine, pioglitazohe, montelukast, Zolcdromic Acid, valsartan, latanoprost, Irbesartan, Clopidogrel, Atomoxetine, Dcxamfctemme, Methylphenidate, Modafinil, Bleomycin, Dactinomycin, Dauuorubiein. Idarubkin, Mitomycin, Mitoxantrone, Azacitidine, Capecitabiue, Cladribine, Ch'farubmv. Cytarabine. Fiudiuubinc, Flow outsell, Gemcitabine, mcrcaptopuunc. methotrexate. Ndarabmc. Pcrnclrexcd, Raititrcxed, Thioguanine. Apomorphinc, Betamethasone, Cortisone, Peflazacort, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisolone, Triamcinolone, Ciciosporine, Sirolimus, Tacrolimus, Interferon Alpha, and Interferon Beta. |9I671    In another aspect, the disclosure provides formulations, such as pharmaceutical formulations. comprising.’ (a) a Is safe composition comprising (i) a bacterial lysate and / or lysate fraction capable of activating at least one or more toll-like receptors (TLRs) or Nodlike receptors (NLRs); (ii) an optional promoter for enhancing absorption of the composition, and (m) an optional carrier fm increasing a x ohmic of rhe composition: and an isolated human. anti-TW     antibody or antigen-binding fragment thereof or INF inhibitor. In some embodiments, the human anti-TNFalpha antibody or antigeii-bmding fragment thereof is adalimmnab. In some embodiments, the disclosure provides uses of the combination formulations of this aspect in the manufacture of a medicament for the treatment of rheumatoid arthritis (RA) or late-onset RA in a subject. In some embodiments, the disclosure provides methods for the treatment of rheumatoid, arthritis (RA) or late-onset RA m a subject, the method comprising administering to the subject a therapeutically effective amount of the combination formulation of this aspect, and as disclosed herein. In some embodiments, the subject is over 50 years old. In some embodiments, the human anti-■■ 48 - 2023251534 20 Oct 2023 TNFalpha antibody or antigen-binding fragmen t thereof is administered to the subject in a biweekly dosing regimen. In some embodiments, the human anti-TNFalpha antibody or antigen-binding fragment thereof is administered to the subject in a dose of 30 mg or greater. In some embodiments, the TNFalpha inhibi tor a TNFalpha fusion protein. In some embodiments, the TNFalpha fusion protein is etanercept. In some embodiments, the auti-TNFalpha. antibody or antigen-binding fragment thereof is infliximab or golimumab. In some embodiments, the anti-TNFalpha antibody or antigen-binding fragment thereof is adalimumab. [01681    hi another aspect, the disclosure provides methods for inhibiting oxidative stress- related disease or disorder progression in a human subject having an oxidative stress-related disease or disorder associated with a disorder in which TNFa activity is detrimental, the method comprising: administering to the subject having an oxidative disease or disorder a lysate, lysate fraction, and / or cell wall fraction of the disclosure, and an isolated human anii-TNFa antibody, or antigen-binding portion thereof, such that oxidath c stress disease progression is inhibited in the subject, ’wherein the human ami-TNFu antibody, or an antigen-binding portion thereof, neutralizes human TN'Fa cytotoxicity in a standard w wW L929 assay with an IC^of I lb M or less, hr some embodimems, the lysate of the disclosure and the human anti-TNFa, or antigen-binding portion thereof, ate administered at different times under different dosing regimens. In some embodiments, the human anti-TNFa antibody is golimumab, or an. antigen-binding portion thereof. In some embodiments, the human anti-TNFa antibody is adalimumab, or an antigen-binding portion thereof. In some embodiments, the human ann-TNF« antibody, or antunn-bmdmg portion thereof, is administered to rhe subject on a biweekly dosing regimen In some embodiments, the methods further comprise administering an additional therapeutic agent to the subject. In some embodiments, the lysate of the disclosure is administered for a period of at least 24 weeks. In some embodiments, the anti-TNFa antibody, or antigen-binding portion thereof, is administered tor a period of al least 24 weeks, hi some embodiments, the lysate of the disclosure, the anti-TNFu antibody, or antigen-binding portion thereof, or both, repairs or prevents oxidative damage to the subject by a combination of one or more different mechanisms.

[0169] In some embodiments of any of the methods or compositions disclosed herein, the bacterium is a Gram-positive or Gram-negative bacterium. In some embodiments of any of the methods or compositions disclosed herein, the Gram-positive bacterium is selected from the group consisting of a bacterium of iMcfrtbacillaceae family, a bacterium of - 49 - 2023251534 20 Oct 2023 family, a bacterium of Bfifafaaeteritee&e family, and a bacterium of Bacilfaceae family. In some embodiments, the .Gram-positive bacterium is selected from die group consisting of Bacillus coagufans, LactobaciUus spmogewy, Streptococcus thermophilus, Bifidobacterium animate. Bifidobacterium. animate, subspecies animate. Bifidobacterium infante. Bifidobacterium longum, Bifidobacterium breve, Lactobacillus acidophilus, Lactobacillus,plantarum,LaciobcKdlhis cosei, Lactohaeillte delbrtfeckii. Lactobacillus delbmeckii subspecies bulgaricus, Lactococcus facte. Ixictococcus facte subspecies facte, Streptococcus facte, Streptococcus thermophilus, Bifidobacteriurn facte. Bifidobacterium breve, Pedibcoccus acidifabtid, -didLactobdcilfas helvetibus. JOI70J    In some embodiments of any of the methods or compositions (including, formulations) disclosed herein, foe Gram-negative bacterium is selected from foe group consisting of a.bacterium, of Pseudomonas genus. Klebsiella genus, Xanihomonas genus. Shigella genus, and hfaten / baeter genus In some embodiments, the Gram-negative bacterium is selected from the group consisting of Klebsiella oxytocia. Shigella flexneri, Xanihomonas campesiris. and Pseudomonas fiourescens. JO 1711    In. some embodiments of any of the methods or compositions (including formulations) disclosed herein, the TLR agonist,- lysate, lysate fraction, or cell wall fraction activates at least one or mere of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NODI, andNOD2. In some embodiments, the TLR agonist, lysate, lysate fraction, or cell wall fraction activates two or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NOD 1, and NOD2. In some embodiments, the TLR agonist, lysate, lysate fraction, or cell wall fraction actn arcs TLR 2 and TLR 4. In some embodiments, the TLR agonist, lysate, lysate fraeOon, or cell v. all fraction activates three or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NOD I , and NOD2, (0172J    In some embodiments of any of the methods or compositions (Including; formulations) disclosed herein, foe promoter is selected from the group consisting of amino acids, ammo sugars, and sugars. In some embodiments, the earner is selected from die group consisting of a binder, a gum base, and combinations thereof. In some embodiments, foe gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer. In some embodiments, the binder is selected from the group consisting of a sugar, a sugar alcohol, and combinations thereof. In some embodiments, the sugar alcohol is selected from the group consisting ol mannitol, soibitol. xv litol, and combinations rhe-cof j0173| In some embodiments,. the compositions are manufactured as a dosage form selected from the group consisting of a lozenge, a chewing gum, a chewable tablet, a candy, - 50 - - 51 - |0177| Active Ingredient. The active ingredient was derived from a bacterial fermentation and cell isolation process as described below.             iMbmec&ib ssp. busmens (referred to herein as L. bulgaricifs) was the organism used in this example, but the bacterial organism may be any Gram-positive or Gram-negative bacterium, or both. |0178| Lactobacillus. delbrueckii ssp bulgartous was 'fermented in growth media Example 1: Preparation of active ingredient for TLR agonist compositions |0176|    An. example of how to formulate the composition includes the following process. 0Q S3 2023251534 20 Oct 2023 accomplished using chicken egg white lysozyme at a concentration of 3% by wt, for 7 hours at 40 X, The resulting lysate was frozen and lyophilized. |0 1811 The lj ophibzed material was blended With a promoter, such as N-acetyi D glucosamine HC1 s NAG). io form a mixture of lysed Lactobacillus delbmeckit subsp. Sulgaricus and NAG. Optionally, other formulation excipients to generate a solid form pill or powder were added, as appropriate. This product was then used in the following screening tests. Example 2: TER screening assay |0182|    Toll-1 ike receptor (TLR) stimulation was tested by assessing NF-KB activation in HEK293 cells expressing a given TLR or Nod-like receptor (NLR). The activities o f the samples were tested on seven different human TLRs: TLR2,3, 4, 5,7, 8 and 9 (Invivogcn, San Diego, € A), and on two different hunian NLRs, nucleotide-binding oligomerization domain-containing proteins I and 2 (NODI and NOD2) Each ligand was tested at a final concentration of 1 / 100 of the stock solution on the TLR. or NLR cells, and compared to control ligands, as described below. This step was performed in triplicate. |0183| The control ligands, control cell lines, and sample product used in the examples were as shown in Table I. Table 1: Control ligands and control cell line information used in ligand screening tests. | ILR2. HKLM I heat-killed /                       at i(F 1 celLvmL TLR3: Poly(l:C) at 1 pg / mL TLR4: E cob KI2 LPS at WOngZmL XV      .     * V *         A j TLR5. S' lyffhunwutm ihgcllm at 100 ng ml Control Ligands TLR7: CL097 at 1 pg / mL | TLR8: CLO75 at 1 p^mL | TLR9: CpG ODN 2006 at 1^0 ng / mL NODI: C12iEDAP at 10 ug'mL NOD2; LIX-MDPm IPOng / mL | HEK293 / NulH: TNF-alphaat 1 pg mL {control for human TLR 2, 3, 5. 8, 9 and NOD P> Control Cell Lines HEK293 / Nulll-k: TNF-alpha at 1 gg / mL 1 {control for human TLR7) Sample HEK293 / Null2: TNF-alpha at 1 pg / mL 1 (control for human TLR4 and NOD2) Exhale <>f / ou.vwvu.Ws <A         subro bulgai'h 1 {l / l 0 dilation prepared in sterile, endotoxin-free water) <Z! •   ¢1 4ft K W ft. Ou SW ’>1 The screening results of these experiments are shown graphically in Figure 2. These results show that a typical lysate produced as described above is a strong agonist for at least TLR2 (and TLR4 to a lesser extent) and NOD2. Example 3: Effects of changes in process variables on TLR signaling |018€|    Through observations of the effects, >f certain process changes on TLR signaling, o MW ya. Q W O & iZi rs sc. -¾            Hi &   % gj % However., A iaetis, although a different morphology than L bulganci<$ gave a similar IXR pattern. Them was little similarity in the TLR pattern across the Gram-posili ve rod cultures of / hLii'HK i<\ I nciJcpbih^, / , i>lcif!tiu> / fn ft. subliia I hjliutiLW produced a ILR pattern similar to ihe TER pattern of L.            L. aeidopMIus-, although lower in signal strength ptodiKcd resues smi’lur to the patterns produced by the cocci. L acidaplnlus did not 5' ri c n p H sr <3 ? ST o 8 Cu r> to Sr* n v> to sr p 2023251534 20 Oct 2023 and                             grown using Tryptic Soy Broth in-shake flasks, Ki nxymtefo £. col£ and & flexneri were incubated at 37 °C and 250 rpm while P. fjuuniscens Xanthamanas campextris were incubated at 30 °C and 250 rpm. Xanihomonos campesirix was grown using a yeast extract / glucose media supplemented with calcium carbonate at 1%. Prior to harvesting, the CaCOs was removed by centrifugation at 500x g for 3 minutes. Harvest of the cultures from the fermentation broth followed foe lysate production process of Example I. Surprisingly and unexpectedly , the TER sigua! pattern of foe lysate from Gram-negative-organisms, including E. aPk when tested at similar concentrations, were much lower in signal strength than the lysates of Gram-positive organisms, except for TLR 5 and 9. In general, the Gram-negative bacteria membrane / cell wall is easier to break than that of Gram-positive bacteria,, which may explain foe higher TLR 9 signal. Al ary / ocm and X rwm / M-s / rvh was observed to produce EPS during fermentation and also produced relatively high act'd alien of TLR 3, 4 and 9. A', osyzocrtr produced the highest TLR2 and NODI activation of rhe strains tested. EPS appears to alter the TLR signal pattern as compared to non-EPS producing strains <5 / / expert} Interestingly, all Gramnegative bacteria had significant activation of the NF-kappaB of the Null cells in the TLR assay. This NF-kappaB activity was subtracted from foe TLR signal and explains the slightly negative activities for TLR 7 and NOD2 for P. flpurescefa |019IJ Lastly, Figure 7 shows TLR signaling for a lysate composition comprising xanthan gmn, These data demonstrate that foe lysate produced from the strain well as xanthau gum itself, the FPS produced by the stmin.A7?n / lwHm^ campeslns, both produce TLR activation. There is strong stimulation by both the strain and foe EPS xanfoan gamut TLR5 and moderate activity at TLRs 4 and 9. These data suggest that the lysate from a given bacterial strain, as well as the corresponding EPS from that strain (e,g„ xanthan gum ip this example) can both be used in or blended into a formulation for a targeted TLR acl i\ its |Q192| Surpusmglx and unexpectedly, these data demonstrate that the TLR signal pattern resulting from a given lysate, as well as the strength of the TLR signal, Is dependent on the mamifaeturing process as well as choice of raw materials, including, but not limited to, media and microorganisms. These data, demonstrate that TLR activation specificity can be altered and tailored by changing process, bacterial organism, raw material, and reagent parameters. Example 4: Oxidative stress, cognitive and quality of life indicators in post-traumatic stress disorder (PT SD)-diagnosed combat veterans -55- 2023251534 20 Oct 2023

[0193] PTSD is an oxidative stress-related disease or condition,. The purposes af the study were four-feid: (I) to evaluate the effectiveness of the inventive composition in quantitatively reducing levels of fee oxidative stress marker isoprostane in PTSD-diagnosed combat veterans; (2) to evaluate the effectiveness of fee inventive composition m qualitatively reducing levels of nitric oxide in PTSD-diagnosed combat veterans; t 3) to evaluate fee effectiveness of fee ms emu e composition m improving word finding and word recall in Pl SD-diagnosod combat veterans; and 14) to evaluate the effectiveness of the inventive composition in improving quality of life parameters in PTSD-diagnosed combat veterans.

[0194] Emerging evidence-based literature supports the link between oxidative stress and post-traumatic stress disorder (PTSD). Oxidative stress occurs m fee body and on fee cellular level as a result of an imbalance between circulating oxidants and anti-oxidants. Many studies have shown that tins cellular ox-dame stress results from the effect of free radicals on the body’s neurophysiology . Nitric oxide has been implicated as playing an important role in protecting against oxidative stress.

[0195] Word-finding is often affected in individuals who suffer from Traumatic Brain Injury as well as in combat veterans. Closed Head Ihjury / Traumulk- Brain Injury (CHVTB1) and PTSD are frequently co-morbid conditions.

[0196] Criteria^ xittyect wferfew,

[0197] The anticipated n umber of participants in fee study was a mfeimum of 10 and maximum of 15.

[0198] The anticipated gender distribution was as close to 50”6 male and 50% female as possible. Due to fee larger numbers of male veterans diagnosed wife PTSD, it was possible that there could be a slightly larger male percentage in the participant pool.

[0199] Pregnant women were not allowed to participate in the study.

[0200] Die only age restriction was due to the military recruitment minimum age, 18 years old, so the anticipated age range for the study was from 18 to approximately 80, with the upper limit dictated level of health. [0201 ]    There were no racial or ethnic origin restrictions. The intended percentages based on race mirrored those of fee greater Houston area, from which fee participants were recruited. These percentages are roughly; 44% Hispanic, 26% white, 23% African America, 6% Asian, I % other.

[0202] Inclusion and Exclusion criteria are outlined in Table 2 below'. 2023251534 20 Oct 2023 Table 2. Inclusion and exclusion criteria for Example 3. Inclusion Criteria Exclusion Criteria combat or military veteran pregnant females resides in the greater Houston area any psychiatric hospitalization within the past 16 months PTSD diagnosis from the Veteran Health Administration of the U.S. Department of Veterans Affairs current probiotic use life-threatening medical condition unstable physical health children or participants under the age of 18 classification as “other traditionally defined vulnerable subjects such as prisoners" lack of adequate capacity to render informed consent {0203}   Methods and procedures. [0204} Under mfurmvd consent pattieipants were evaluated to assess levels of cellular oxidative stress, nitric oxide levels, language / word-finding ability, levels of anxiety and depression, and current quality of life parameters. [0205} Participants were provided with 15 days of the composition, which is hypothesized, to reduce oxidative stress, as indicated specifically by a reduction in urinary Isoprostane levels Two ¢2) 12-mg product tablets were taken sublingually two 12} tmu-s per day, for a total of48 mg daily. |020d} To minimize measurement fluctuation no placebos were-used, and subjects served as their own measurementcontrols. All subjects were assigned, to the same study group mid received the same procedure.

[0207] Oxidative stress was measured via urinalysis of isoprostane using a commercially available assay (Oxford Biomedical Research). Samples collected were normalized creatine using a creatinine assay kit (Oxford Biomedical Research) to control for differences in the level of concentration of the urine. [0208} Each participant had his / her urine tested for isoprostane levels, at a minimum, on days I and 15. A consistent subset of individuals were asked to submit urine samples each of the 15 days of the study to establish data points as a means of examining possible isoprostane Er p emailed io him / her every mommg at 4:00 am. In order to familiarize each participant with die QOL Survey format and to establish a stronger baseline of data, each individual began recording his / her scores on the QOL Survey a minimum of four (4) days prior to beginning his / her use of product [02121 ZWa (inafysis and cia'a g ex* e-os 2023251534 20 Oct 2023

[0218] The study used a convenience sample, the method of recruiting participants being based largely on personal and professional contacts of the investigators.

[6219] capacity

[0220] If the individual was deemed Co lack adequate capacity to consent, they were not allowed to participate in the study. There were no minors involved in this study, and no one who required an assent form or legal representative present, [0221 ]         erw / wtemd#

[0222] To assess that adequate comprehension has taken place, the participant was required to explain the study back tv the individual doing the consent process before they were allowed to enroll in the study. The subject confirmed that all their questions were answered adequately.

[0223] Resi^Rs

[0224] te the study, effects of the supplement were assessed by measuring / analyzing: 1) isoprostane levels; 2) quality' of life survey results; 3) Zung Z psychological survey results; and 4) speech language results.

[0225] As shown in Figure 8, treatment with the supplement caused a decrease in the levels of urinary isoprostane. Isoprostanes are prostaglandin-like compounds formed 1» from rhe free ladical-catalyzed perox tdahen of essential fau\ acids {primarily amclndoiuc aval) without the direct action, of cyclooxygenase (COX) enzymes usually involved in piosiagiandin production. These compounds are accurate markers of lipid peroxidation in both .tmuisl and human models of oxidative stress. At day 15, most subjects displayed decreased isoprostane levels. By day 70. all subjects displayed isoprostane levels lower than at day 1. [0226| As seen in Table 3A and Table 3B, treatment with the armposition resulted in marked decreases in the amount of isoprostane alter just 15 days of treatment Table 2A displays the raw data from me study, while table 3B display® the results following calculation of percentage reduction and percentage improvement of oxidati ve stress marker . In Tables 3A and 38, “PTSD*” is a participant who was diagnosed with PTSD. “PTSD is a participant not diagnosed with PTSD. 'TX+-’ is a participant who used the composition. prior to the study. ‘TX-” Is participant who was naive to theeomposition.

[0227] As seen in Tabic 3B. subjects displayed over a 66% reduction in isoprostane levels after 15 days of treatment followed by an additional 3.18% of reduction in isoprostane lex cis after "0 days ol treatment in addition, subjects displayed oxer a 469% improxement m levels of oxidative stress biomarker after 15 days of treatment followed by an additional 2023251534 20 Oct 2023 53.19% improvement In levels of oxidative stress biomarker (isoprostane) after 70 days of treatment Table 3A: PTSD Oxidative Stress Study Raw Data Day I isoprostane (ng / mncreatinine) Day 15 Isoprostane (ng / mg creatinine) Day 70 Isoprostane (ng / mg creatinine) PTSD+ / TX- P00la 0.897 0.320 0.564 mn- L\-P002a 1.736 0.956 0.4294 PTSD+ / TX- P004a 1.667 0.470 0.4068 PTSD+ / TX- P005a 1.365 1.456 0.3997 PTSD+ / TX-P006a 3.2154 0.759 0.3514 PTSD+ / TX-P007a 3.923 0.177 0.2156 PTSD+ / TX- P008a 0.851 0.195 0.3407 PTSD+ / TX+ P009a 0.566 0.834 0.483 PTSD- / TX+P010a 1.471 0.401 0.499 PTSD- / TX- POlla 2.542 0.507 0.441 PTSD- / TX- P012a 1.002 1.348 0.360 Table 3B: PTSD Oxidative Stress Study Data Day 1 to Day 15 Dax 15 to To Difterenc e %Rc<h iCtsO n %Improvemen I Different' e %HcdU<.UO n ‘Mmproveinen t PTSD+ / TX- POOla -0,577 -64.30 -180.12 0.243 75.96 43.17 PTSD-h TX-1’0023 -0.78 -44,94 -81.62 -0.53 -55.07 -122.57 PTSD+ / TX-P004a -1.198 -71.85 -255.20 -0.06 -13.33 -15.38 PTSD+ / P005?) 0.0909 6..66 6.24 -1.06 -72.55 -264.24 PTSD < TX-P006a -2.455 -76.39 -323,55 -0.41 -53.69 -115.95 minimal, discomfort and pain from neuropathy symptoms as compared io day ]. At day 70, all patient except for one (P03) showed cither minimal discomfort and pain from neuropathy symptoms or......in the case of P94.....no difference in discomfort (note that P04 indicated minimal discomfort and pain from neuropathy symptoms at the onset of the study) as compared to day 1. % improvement Oxidative Stress Biomarker {PISD-kfx-> 4« Reduction Oxidative Stress Biomarkcr iPTSlfo Tx-) PTSD-,TX-POI2a P1SD-rx- P01 la v(i I nd •’■XI -asid PTSD 6 TX; P009a & ft J* >4 w?" "X 3» rs ' / ■»> a rt PTSD+ / TX-POOka PTSD+ / TX-P007a :¼ ’•z4 > fas 69c’O 1- w tri -3.746 N> •4 ■■3 S -4 -95.49 5-Z< '4 fat o 14 1 -2116.18 -0.99 -0.07 0.097 -0.35 &■ 0.039 59.19% 3.18% -73.31 -13.06 24.48 9071- 1 74.62 i 21.81 -274.66 -15.02 19.54 -72.60 fai 17.30 CT 2 8 g stiffness and pain) on a scale of 1-10, where a value of I corresponded to a low level of satisfaction and a value of 10 corresponded to a high level of satisfaction. As seen in Figure 13, at day 15 all subjects (except for P03 and P<M> displayed improved levels of satisfaction with, their joints as compared to day 1. This trend continued at day 70. j0233| Subjects w ere asked to sdf-asscss and rate their overall satisfaction with their 5' 2 g_ o ra I# B 3 32 JO n c S ft s ft 15. At day 70, all subjects completing the study (except P03) displayed decreased day-time sleepiness as-compared'to day 1, j0238| Subjects were asked to self-asscss and rate their overall level of satisfaction w ith their life on a scale of 1-40, where a value of 1 corresponded to a low level of satisfaction and a value of 40 corresponded to a high level of satisfaction. As seen in Figure 18, at day 15 ail g S3'’ Q g 6 S' (D) Day 13., patient begins using 75 mg bid. lysate to address headaches; (E) Days 18 to 89, headaches now resolved and continue to be resolved; (F) Day 30, new impact event playing football, headache for 18 hours with visual and neurological disturbances; (G) Day 81, situational stress eny showing cic\ area FPlsoP kn els. bur did not result m headache: (H) Days I to K9, trend line of isoprostanc showing 98% reduction over 8$ days. Overall, these '•-A s $8 O' >-*■ c 2023251534 20 Oct 2023

[0244] A randomized Phase III study of adalimumab is studied in patients with active PsA (>3 swollen and >3 tender joints) who had failed NSAID therapy. Randomization is centrally stratified by methotrexate (MTX) use and extent of psoriasis (<3% or >3 % body ■surface area (BSA|) at baseline. Patients completing Week 24 will be eligible to continue in an open-label extension study. (02451 Patients rue included if they have a history of psoriasis; are over 18 years; >3 swollen and >3 tender joints; and inadequate response to NSAID therapy. Exclusion criteria includes prior auti-TNF therapy; alefacept within 12 weeks prior to study entry; other biologies within 6 weeks prior to study entry; DMARDs (except MTX) within 4 weeks prior to study entry; systemic therapies for psoriasis within 4 weeks prior to study entry; and phototherapy and topicais within 2 weeks prior to study entry. [0246( Patients are stratified by incthoticxatc use (ves no) and degree of psoriasis (■- 3% and >3% BSA involvement) and receive lysate 20-50 trig orally on a daily basis, in combination with adalimumab, 40 mg every other week or placebo for 24 weeks,

[0247] Efficacy measures to be used include: ACR response criteria (co-primary endpoint: ACR20 response at Week 12); Psoriasis Area and Severity Index (PASI) in patients with significant psoriasis at study entry (d-P’ - BSA): ami Physician’s Gfobal \ssvssincnt (PGA) of psoriasis. The study examines patients according to the severity of psoriasis at baseline: PASKI0 vs. PASI>1()

[0248] Thus, efficacy measures in patients with psoriasis affecting >3% BSA at baseline include PASI, PGA of psoriasis, and DLQI. ACR response criteria are also used as an efficacy measurement. A post-hoc analysis is conducted for patients with baseline PASI-10 vs. those with PASI>1(). PASI analyses are by NRI, and PGA and DLQI scores are calculated as LOCF.

[0249] The treatment group receiving co-administered lysate experiences amelioration of injection site reactions (such as pain, redness, or irritation) and less overall oxidative stress-related side effects, which will aifow for increased adherence and compliance with treatment, ■which in turn allows a greater opportunity for ameliorating the primary disease. Example 7: Lysate / stetm / ACE inhibitor combinations are effective for treatment of hypertension

[0250] A human subject being treated for hypertension and receiving a combination of 20 mg QD pravastatin and 20 mg QD lisonopril was experiencing oxidative stress-related side effects of skin rash and insomnia. 2023251534 20 Oct 2023

[0251] When the patient was additionally administered. 45 nig bid of a lysate encompassed by the disclosure herein, the skin rash and insomnia side effects resolved within 60 days, Example 8: Lysate / SSRI combination is effective for treatment of clinical depression

[0252] A human subject being treated for depression and receiving 60 mg QD duloxetine (CYMBALTA®) was experiencing oxidative stress-related side effects of anorgasmia, dizziness, numbness, and irritability.

[0253] When the patient was additionally administered 45 mg bid of a lysate encompassed by the disclosure herein, anorgasmia resolved within 10 days, dizziness resolved within 7 days, numbness resolved within 1.0 days, and irritability resolved within 5 days. Example 9; Lysate / hormtme combination is effective for treatment of hypothyroidism

[0254] A human subject being treated for hypothyroidism and receiving 150 mcg QD of levothyroxine (SYNTHS was experiencing oxidative stress-related side effect of hair loss.

[0255] When the. patient was additionally administered 75 mg bid of a lysate encompassed by the disclosure herein, the hair loss side effect resolved within 180 days. Example Mb I ysate / reverse transcriptase inhibitor combination is effective for treatment of HIV infection

[0256] A human subject being treated for HIV (non-AIDS) and receiving one tablet QD of efavirenz / emtricitabiheAenbfdvir disoproxil fumarate (ATRIPLA®) was experiencing oxidative stress-related side effects of erectile dysfunction, neuropathy, insomnia, and brain foe. 'S-'

[0257] When the patient was additionally administered 45 mg bid of a lysate encompassed by the disclosure herein, erectile dysfunction resolved within. 10 days, neuropathy resolved within 10 days, insomnia resolved within. 3 days, and brain fog resolved within 3 days. Example 11: Lysate / direct-acting antiviral drug combination is effective for treatment of hepatitis C 2023251534 20 Oct 2023

[0258] A human subject being treated for Hepatitis C and receiving one tablet QD of ledipasvirAofbsbuvir (HARVOM u } u as experiencing oxidative stress-related side effects of brain fog, headache, and arthritis.

[0259] When the patient was additionally administered 75 mg bid of a lysate encompassed by the disclosure herein, brain fog resolved within 3 days, headache resolved within 10 days, and arthritis resolved within 14 days. Example 12: Lysate / anti-cancer drug combination is effective for treatment of cancer

[9260] A human subject being treated for cancer and receiving a biweekly dose of topoisomerase 1 inhibitor / vmca alkaloids / alkyhttng amineaplastic (IRINOTECAN®, V1NCRISTIN®, TEMODAR®) was experiencing oxidative stress-related side effects of brainfag, malaise, insomma, and rash.

[0261] When the patient was additionally administered 75 nig bid of a lysate encompassed by the disclosure herein, brum fog resort ed within 3 days, malaise resolved within 5 days, insomnia resolved within 5 days, and rash resolved within 14 days. Example 13: Lysate / msulm analog combination is effective for treatment of type 2 diabetes

[0262] A human subject being treated for type 2 diabetes and receiving a daily dose of the ubuhu analog msulm gkugtne JlANTbS«) was expvirencmg oxidative stress-related side effects of rash (injection sire), irritability, and headache.

[0263] When, the patient was additionally administered 45 mg bid of a lysa.le encompassed by the disclosure herein, irritability resolved within 5 days, headache resolved within 7 days, and rash (injection site) resol ved within 10 days. Example 14: Lysate / antibmtic combination is effective for treatment of rheumatoid arthritis

[0264] A human subject diagnosed with rhemnatoid arthritis and being treated with an TNF inhibitor was also being treated with antibiotics that caused Grade 3 diarrhea as determined by National Cancer Institute t NCI > standards for the prior ten months. Concurrently the subject was receiving additional antibiotics in order to combat a Clostridium difficile infecrioa due to the severe diarrhea. Without changing current pharmacologic therapies, the subject was additionally administered 45 mg lysate twice a day. Diarrhea began to resolve within. 2 weeks and improved to an NCI Grade 2 standard in one month, -67- 2023251534 20 Oct 2023 Example IS: Lysate / radiation eombi»atMm is effective for treatment of cancer {0265| A human subject was being treated for prostate cancer and received radiation treatments increasing in intensity and for duration over the course of 40 days of prescribed therapy as follows: 8 sessions at 180 cGy (IcGy ~ I rad) during week day on nine points in two bursts one at 8 seconds one at 5 seconds; 8 sessions at 180 cGy with bursts of 12 and 9 seconds; 9 sessions at 180 cGy with bursts of 1.4 and 10 seconds on the right 2 quadrants and then 12 and 9 seconds on the left; and 16 sessions at 200 cGy two continuous foil circumference passes for 80 seconds and every other session being two ■complete continuous, full circmnference passes in opposite directions. The radiation dose change was always on a Monday and the patient was seen by a physician each subsequent Tuesday to assess side effects. Each increase resulted in 3 hrs. of nausea, occurring approximately 2 hrs. post treatment and resolved completely in no more than 6 hrs after any treatment session. In combination with the radiation treatment* the patient was administered a lysate of the disclosure at a dose of 75 mg, three times a day. The patient was not administered any other treatment for nausea, vomiting or bleeding. On a Quality of Life scale of I to 10 CT’ being the worst. ’ Rf the best) the patient reported an 8 through commencement of the final escalation of exposure.. The patient reported nausea to be no worse than a 7 at the greatest exposure and continued to function daily in bis work duties throughout treatment. |9266| Given the \ ariety of mechanisms of action of rhe above drugs u uh which the lysate composutons of the disclosure are coadministered, and given rhe mechanism of action of the lysate itself, the lysate compositions disclosed herein can be reasonably extrapolated to provide beneficial adverse-effeetweduemg results with most any drag. For example, with HUM1RA®, an injectable a-TNF, co-adntimstration wifo lysate produces amelioration of injection site irritations. Per package insert this drug is identified as causing arthritis as is seen in the Direct Acting Antiviral. HARVONIOV. When a patient uses a lysate of the disclosure in conjunction with a prescribed BCV medication such as HARVONllv, side effects are diminished during treatment and do not persist post treatment i0267j It should be understood the arrangements and functions described herein are presented for purposes of example only , and that numerous variations are possible. For instance, elements can be added, omitted, combined, distributed, reordered, or otherwise modified. The following claims ate thus to be understood to include what is specifically -68- to.

Claims

1. A method of regulating redox status in a subject, the method comprisingadministering to the subject a composition comprising:a Toll-like receptor (TLR) agonist comprising at least one lysate and / or lysate fraction of an inactivated bacterium comprising the entire cellular contents of the bacterium cell, wherein:the TLR agonist activates TLR 2 and TLR 4 in the subject; andthe bacterium is inactivated by a heat treatment of the bacterium followed by a lysozyme treatment of the bacterium;wherein administration of an effective amount of the composition to the subject measurably reduces oxidative stress levels in the subject and decreases the amount of isoprostane in the urine or blood of the subject.

2. Use of a composition comprising a Toll-like receptor (TLR) agonist comprising atleast one lysate and / or lysate fraction of an inactivated bacterium comprising the entire cellular contents of the bacterium cell in the manufacture of a medicament for regulating redox status in a subject, the bacterium is inactivated by a heat treatment of the bacterium followed by a lysozyme treatment of the bacterium;wherein administration of an effective amount of the composition to the subject measurably reduces oxidative stress levels in the subject and decreases the amount of isoprostane in the urine or blood of the subject.

3. The method according to claim 1 or the use according to claim 2, wherein the heattreatment is pasteurization at a temperature from about 75 °C to about 85 °C for about 30 minutes to about 60 minutes.

4. The method according to claim 1 or 3 or the use according to claim 2 or 3, whereinthe lysozyme treatment is conducted at a temperature from about 25 °C to about 50 °C for about 1 hour to about 10 hours.

5. The method according to any one of claims 1 or 3-4 or the use according to any oneof claims 2-4, wherein the TLR agonist also activates (a) at least one TLR other than TLR 2 or TLR 4, or (b) a Nod-like receptor (NLR).2023251534   28 Aug 20266.     The method or the use according to claim 5, wherein the TLR or NLR is TLR 3,TLR 5, TLR 7, TLR 8, TLR 9, NOD1, or NOD2.

7. The method according to claim 1 or the use according to claim 2, wherein thebacterium is:a Gram-positive bacterium selected from the group consisting of Lactobacillus delbrueckii subspecies bulgaricus, Pediococcus acidilactici, Bacillus coagulans, Streptococcus thermophilus, Lactobacillus helveticus, Lactobacillus acidophilus, Lactobacillus plantarum, Bifidobacterium animalis subsp lactis, Bacillus subtilis, or a Gram-negative bacterium selected from the group consisting of Escherichia coli, Klebsiella oxytocia, Shigella flexneri, Pseudomonas flourescens, and Xanthomonas campestris.

8. The method according to claim 1 or the use according to claim 2, wherein thecomposition comprises an absorption promoter, wherein the absorption promoter assists in the delivery of the composition to the subject and enhances absorption of the composition; and wherein the absorption promoter is selected from the group consisting of amino acids, amino sugars, and sugars.

9. The method according to claim 1 or the use according to claim 2, wherein thecomposition comprises a carrier for increasing a volume of the composition that is selected from the group consisting of a binder, a gum base, and combinations thereof.

10. The method or the use according claim 9, wherein the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer.

11. The method or the use according to claim 9, wherein the binder is selected from the group consisting of a sugar, a sugar alcohol, and combinations thereof.

12. The method or the use according to claim 11, wherein the sugar alcohol is selected from the group consisting of mannitol, sorbitol, xylitol, and combinations thereof.

13. The method according to claim 1 or the use according to claim 2, wherein the composition is manufactured as a dosage form selected from the group consisting of a lozenge, a chewing gum, a chewable tablet, a candy, and a dissolving tablet.

14. The method or the use according to claim 13, wherein the dosage form delivers the TLR agonist to an oral mucosa.2023251534   28 Aug 202615. The method or the use according to claim 14, wherein the oral mucosa is selected from the group consisting of sublingual mucosa, buccal mucosa, and a combination thereof.

16. The method or the use according to claim 1, wherein the composition is administered in combination with a pharmaceutical agent to enhance activity of the pharmaceutical agent.

17. The method or the use according to claim 1, wherein the composition is administered in combination with a pharmaceutical agent so as to reduce a side effect of the pharmaceutical agent.

18. The method or the use according to claim 17, wherein the side effect of the pharmaceutical agent is oxidative stress.

19. The method according to claim 1 or the use according to claim 2, wherein the subject is a mammal.

20. The method or the use according to claim 19, wherein the mammal is a human.

21. The method according to claim 1 or the use according to claim 2, wherein the subjectis a non-mammal.

22. The method or the use according to claim 21, wherein the subject is a fish or fowl.

23. A pharmaceutical formulation comprising the composition as recited in claim 1 and one or more pharmaceutical agents.

24. The pharmaceutical formulation of claim 23, wherein the pharmaceutical formulation is formulated to dissolve at an oral mucosa of the subject in not less than 1 minute after the composition is delivered to the oral mucosa.

25. The pharmaceutical formulation of claim 23, wherein the one or more pharmaceutical agents are selected from the group consisting of:an antispasmodic, a motility stimulant, an H2-Receptor antagonist, antimuscarinic; a chelate, a prostaglandin analog, an aminosalicylate, a corticosteroid, an drug affecting immune response, a stimulant laxative, a drug affecting biliary composition and flow, a bile acids sequestrant, a dopamine antagonist, a proton pump inhibitor, an opioid, an opioid receptor antagonist, an analgesic, a sleep drug, a cardiac glycoside, a phosphodiesterase inhibitor, a thiazide, a diuretic, a potassium sparing diuretic, an aldosterone antagonist, an2023251534   28 Aug 2026osmotic diuretic, a drug for arrhythmia, a bbeta adrenoreceptor blocking drug, a hypertension drug, a drug affecting the renin-angiotensin system, a nitrate, a calcium blocker, an antianginal drug, a peripheral vasodilator, a sympathomimetic, an anticoagulant, a protamine, an antiplatelet drug, a fibrinolytic drug, an antifibrinolytic drug, a lipid regulating drug, an omega three fatty acid compound, a CNS drug, an anti-infective, or another drug selected from the group consisting of Benztropine, procyclidine, biperiden, Amantadine, Bromocriptine, Pergolide, Entacapone, Tolcapone, Selegeline, Pramipexole, budesonide, formoterol, quetiapine fumarate, olanzapine, pioglitazone, montelukast, Zoledromic Acid, valsartan, latanoprost, Irbesartan, Clopidogrel, Atomoxetine, Dexamfetamine, Methylphenidate, Modafinil, Bleomycin, Dactinomycin, Daunorubicin, Idarubicin, Mitomycin, Mitoxantrone, Azacitidine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Fludarabine, Flourouracil, Gemcitabine, mercaptopurine, methotrexate, Nelarabine, Pemetrexed, Raltitrexed, Thioguanine, Apomorphine, Betamethasone, Cortisone, Deflazacort, Dexamethosone, Hydrocortisone, Methylprednisolone, Prednisolone, Triamcinolone, Ciclosporine, Sirolimus, Tacrolimus, Interferon Alpha, and Interferon Beta.

26. The pharmaceutical formulation of claim 23, wherein the one or more pharmaceutical agents are selected from the group consisting of:Antispasmodics selected from the group consisting of atropine sulphate, dicycloverine hydrochloride, hyoscine butylbromine, propantheline bromide, alverine citrate, and mebeverine hydrochloride;Motility stimulants selected from the group consisting of metoclorpramide and domperidone;H2-Receptor antagonists selected from the group consisting of Cimetidine, famotidinenizatidine, and ranitidine;Antimuscarinics;Chelates selected from the group consisting of Tripotassium dicitratbismuthate and sucralfate;Prostaglandin analogues;Aminosalicylates selected from the group consisting of balsazide sodium, mesalazine, olsalazine, and sulphasalazine;Corticosteroids selected from the group consisting of beclometasone dipropionate, budenoside, hydrocortisone, and prednisolone; Drugs affecting immune response selected2023251534   28 Aug 2026from the group consisting of ciclosporin, mercaptopurine, methotrexate, adalimumab, and infliximab;Stimulant Laxatives selected from the group consisting of bisacodyl, dantron, docusate, and sodium picosulfate;Drugs affecting biliary composition and flow;Bile acids sequestrants selected from the group consisting of colestyramine, Oxyphencyclimine, Camylofin, Mebeverine, Trimebutine, Rociverine, Dicycloverine, Dihexyverine, Difemerine, Piperidolate, Benzilone, Mepenzolate, Pipenzolate, Glycopyrronium, Oxyphenonium, Penthienate, Methantheline, Propantheline, Otilonium bromide, Tridihexethyl, Isopropamide, Hexocyclium, Poldine, Bevonium, Diphemanil, Tiemonium iodide, Prifinium bromide, Timepidium bromide, Fenpiverinium, Papaverine, Drotaverine, Moxaverine, 5-HT3 antagonists, 5-HT4 agonists, Fenpiprane, Diisopromine, Chlorbenzoxamine, Pinaverium, Fenoverine, Idanpramine, Proxazole, Alverine, Trepibutone, Isometheptene, Caroverine, Phloroglucinol, Silicones, Trimethyldiphenylpropylamine, Atropine, Hyoscyamine, Scopolamine, Butylscopolamine, Methylscopolamine, Methylatropine, Fentonium, Cimetropium bromide, and primarily dopamine antagonists;Proton pump inhibitors selected from the group consisting of Omeprazole, lansoprazole, pantoprazole, esomeprazole, and rabeprazole sodium;Opioids and opioid receptor antagonists;Analgesics selected from the group consisting of Acetaminophen, Diclofenac, Diflunisal, Etodolac, Fenoprofen, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Meclofenamate, Mefenamic Acid, Meloxicam, Nabumetone, Naproxen, Oxaprozin, Phenylbutazone, Piroxicam, Sulindac, Tolmetin, Celecoxib, Buprenorphine, Butorphanol, Codeine, Hydrocodone, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Nalbuphine, Oxycodone, Oxymorphone, Pentazocine, Propoxyphene, and Tramadol;Sleep drugs selected from the group consisting of Nitrazepam, Flurazepam, Loprazolam, Lormetazepam, Temazepam, Zaleplon, Zolpidem, Zopiclone, Chloral Hydrate, Triclofos, Clomethiazole, Quazepam, triazolam, Estazolam, Clonazepam, Alprazolam, Eszopiclone, Rozerem, Trazodone, Amitriptyline, Doxepin, Benzodiazepine drugs, melatonin, diphenhydramine, and herbal remedies;Cardiac glycosides selected from the group consisting of Digoxin and digitoxin;2023251534   28 Aug 2026Phosphodiesterase inhibitors selected from the group consisting of enoximone and milrinone;Thiazides and related diuretics selected from the group consisting of bendroflumethiazide, chlortalidone, cyclopenthiazide, inapamide, metolazone, and xipamide;Diuretics selected from the group consisting of furosemide, bumetanide, and torasemide;Potassium sparing diuretics and aldosterone antagonists selected from the group consisting of amiloride hydrochloride, triamterene, weplerenone, and spironolactone;Osmotic diuretics;Drugs for arrhythmias selected from the group consisting of adenosine, amiodarone hydrochloride, disopyramide, flecainide acetate, propafenone hydrochloride, and lidocaine hydrochloride;Beta adrenoreceptor blocking drugs selected from the group consisting of propanalol, atenolol, acebutolol, bisprolol fumarate, carvedilol, celiprolol, esmolol, lebatolol, metoprolol tartrate, nadolol, nebivolol, oxprenolol, pindolol, solatol, and timolol;Hypertension drugs selected from the group consisting of ambrisentan, bosentan, diazoxide, hydralazine, iloprost, minoxidil, sildenafil, sitaxentan, sodium nitroprusside, clonidine, methyldopa, moxonidine, guanethidine monosulphate, doxazosin, indoramin, prazosin, terazosin, phenoxybenzamine, and phentolamine mesilate;Drugs affecting the renin-angiotensin system selected from the group consisting of Captropril, Cilazapril, Enalapril Maleate, Fosinopril, Imidapril, Lisinopril, Moexipril, Perindopril Erbumine, Quinapril, Ramipril, Trandolapril, Candesartan Cilexetil, Eprosartan, Irbesartan, Losartan, Olmesartan Medoxomil, Telmisartan, Valsartan, and Aliskiren;Nitrates, calcium channel Blockers, and antianginal drugs selected from the group consisting of Glyceryl trinitrate, Isosorbide Dinitrate, Isosorbide Mononitrate, Amlodipine, Diltiazem, Felodipine, Isradipine, Lacidipine, Lercanidipine, Nicardipine, Nifedipine, Nimodipine, Verapamil, Ivabradine, Nicorandil, and Ranolazine;Peripheral Vasodilators and related drugs selected from the group consisting of Cilostazol, Inositol Nicotinate, Moxisylyte, Naftidrofuryl Oxalate, and Pentoxifylline;Sympathomimetics selected from the group consisting of Dopamine, Dopexamine, Ephedrine, Metaraminol, Noradrenaline Acid Tartrate, Norephidrine Bitartrate, and Phenylephidrine;2023251534   28 Aug 2026Anticoagulants and Protamine selected from the group consisting of Heparin, Bemiparin, Dalteparin, Enoxaparin, Tinzaparin, Danaparoid, Bivalirudin, Lepirudin, Epoprostenol, Fondaprinux, Warfarin, Acenocoumarol, Phenindione, Dabigatran Etexilate, Rivaroxaban, and Protamine Sulphate;Antiplatelet Drugs selected from the group consisting of Abciximab, Aspirin, Clopidogrel, Dipyridamole, Eptifibatide, Prasugrel, and Tirofiban;Fibrinolytic and antifibrinolytic drugs selected from the group consisting of Alteplase, Reteplase, Streptokinase, Tenecteplase, Urokinase, Etamsylate, and Tranexamic Acid;Lipid Regulating Drugs selected from the group consisting of Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, Simvastatin, Colesevam, Colestyramine, Colestipol, Ezetimibe, Bezafibrate, Ciprofibrate, Fenofibrate, Gemfibrozyl, Acipmox, Nictotinic Acid, Omega three fatty acid compounds, Ethanolamine Oleate, and Sodium Tetradecyl Suphate;CNS Drugs selected from the group consisting of Benperidol, Chlorpromazine, Flupentixol, Haloperidol, Levomepromazine, Pericyazine, Perphenazine, Pimozide, Prochlorperazine, Promazine, Sulpiride, Trifluoperazine, Zuclopenthixol, Amisulpride, Aripiprazole, Clozapine, Olanzapine, Paliperidone, Quetiapine, Riperidone, Sertindole, Zotepine, Flupentixol, Fluphenazine, Olanzapine Embonate, Pipotiazine Palmitate, Risperidone, Zuclopenthixol Decanoate, Carbamazepine, Valproate, Valproic acid, Lithium Carbonate, Lithium Citrate, Amitriptyline, Clomipramine, Dosulepin, Imipramine, Lofepramine, Nortriptyline, Trimipramine, mianserin, Trazodone, Phenelzine, Isocarboxazid, Tranylcypromine, Moclobemide, Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Agomelatine, Duloxetine, Flupentixol, Mirtazapine, Reboxetine, Trytophan, Venflaxine, Atomoxetine, Dexametamine, Methylphenidate, Modafinil, Eslicarbazepine, Ocarbazepene, Ethosuximide, Gabapentin, Pregabalin, Lacosamide, Lamotrigine, Levetiracetam, Phenobarbital, Primidone, Phenytoin, Rufinamide, Tiagabine, Topiramate, Vigabatrin, Zonisamide, ropinirole, Rotigotine, Co-Beneldopa, Levodopa, Co-Careldopa, Rasagiline, Selegiline, Entacapone, Tolcapone, Amantidine, Orphenadrine, Procyclidine, Trihexyphenidyl, Haloperidol, Piracetam, Riluzole, Tetrabenazine, Acamprosate, Disulfiram, Bupropion, Vareniciline, Buprenorphine, Lofexidine, Donepezil, Galantamine, Memantine, and Rivastigimine;Anti-Infectives selected from the group consisting of Benzylpenicillin, Phenoxymethylpenicillin, Flucloxacillin, Temocillin, Amoxicillin, Ampicillin, Co-Amoxiclav, Co-Fluampicil, Piperacillin, Ticarcillin, Pivmecillinam, Cephalosporins,2023251534   28 Aug 2026Cefaclor, Cefadroxil, Cefalexin, Cefixime, Cefotaxime, Cefradine, Ceftazidime, Cefuroxime, Ertapenem, Imipenem, Meropenem, Aztreonam, Tetracycline, Demeclocycline, Doxocycline, Lymecycline, Minocycline, Oxytetracycline, Tigecycline, Gentamicin, Amikacin, Neomycin, Tobramycin, Erythromycin, Azithromycin, Clarithromycin, Telithromycin, Clindamycin, Chloramphenicol, Fusidic Acid, Vancomycin, Teicoplanin, Daptomycin, Linezolid, Quinupristin, Colistin, Co-Trimoxazole, Sulpadiazine, Trimethoprim, Capreomycin, Cycloserine, Ethambutol, Isoniazid, Pyrazinamide, Rifabutin, Rifampicin, Streptomycin, Dapsone, Clofazimine, Metronidazole, Tinidazole, Ciproflaxacin, Levoflaxacin, Moxifloxacin, Nalidixic Acid, Norflaxine, Orflaxacin, Nitrofurantoin, Methenamine Hippurate, Amphotericin, Anidulafungin, Caspofungin, Fluconazole, Flucytosine, Griseofluvin, Itraconzole, Ketoconazole, Micafungin, Nystatin, Posaconazole, Terbinafine, Voriconazole, Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir Disoproxil, Zidovudine, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinair, Nelfinavir, Ritonavir, Saquinavir, Tipranavir, Efavirenz, Etravirine, Nevarapine, Enfuvirtide, Maraviroc, Raltegravir, Aciclovir, Famciclovir, Inosine Pranobex, Valaciclovir, Cidofovir, Gangciclovir, Foscarnet, Valgangciclovir, Adefovir Dipivoxil, Entecavir, Telbivudine, Amantadine, Oseltamivir, Zanamivir, Palivizumab, Ribavirin, Artemether, Chloroquine, Mefloquine, Primaquine, Proguanil, Pyrimethamine, Quinine, Doxycyclin, Diloxanide Furoate, Metronidaziole, Tinidazole, Mepacrine, Sodium Stibogluconate, Atovaquone, Pentamidine Isetionate, Mebendazole, and Piperazine; andOther drugs selected from the group consisting of Benztropine, procyclidine, biperiden, Amantadine, Bromocriptine, Pergolide, Entacapone, Tolcapone, Selegeline, Pramipexole, budesonide, formoterol, quetiapine fumarate, olanzapine, pioglitazone, montelukast, Zoledromic Acid, valsartan, latanoprost, Irbesartan, Clopidogrel, Atomoxetine, Dexamfetamine, Methylphenidate, Modafinil, Bleomycin, Dactinomycin, Daunorubicin, Idarubicin, Mitomycin, Mitoxantrone, Azacitidine, Capecitabine, Cladribine, Clofarabine, Cytarabine, Fludarabine, Flourouracil, Gemcitabine, mercaptopurine, methotrexate, Nelarabine, Pemetrexed, Raltitrexed, Thioguanine, Apomorphine, Betamethasone, Cortisone, Deflazacort, Dexamethosone, Hydrocortisone, Methylprednisolone, Prednisolone, Triamcinolone, Ciclosporine, Sirolimus, Tacrolimus, Interferon Alpha, and Interferon Beta.

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