AU2016352986A1 - Control of cellular redox levels - Google Patents
Control of cellular redox levels Download PDFInfo
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- AU2016352986A1 AU2016352986A1 AU2016352986A AU2016352986A AU2016352986A1 AU 2016352986 A1 AU2016352986 A1 AU 2016352986A1 AU 2016352986 A AU2016352986 A AU 2016352986A AU 2016352986 A AU2016352986 A AU 2016352986A AU 2016352986 A1 AU2016352986 A1 AU 2016352986A1
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Abstract
Disclosed herein are compositions and methods for regulating redox status and/of 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.
Description
BACKGROUND
J96021 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 estab lish 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 cclis 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 ceil, 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 io as pathogen-associated molecular patterns (PAMPs), Immune cells undergo activation when one of their PRRs recognizes a 'PAMP and in response release inflammatory mediators.
{OO03 J 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, incl uding glyeans and glyeoconjngates. These structures can also be referred to ar. small molecular motifs which are conserved within a class of microbes. They are recognized by Toli-iike receptors {TLRsl and other PRPs m b.»tn plants and animals, |00<Mf TLR'S arc Conserved receptors that recognize structures from haetena, fungi, protozoa, and viruses. Although the ILR receptor is located on the surface of the plasma membrane, binding to the receptor is transmitted transm.emhrane and results in an intercellular signaling response, TLR signaling ultimately leads to the induction or
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PCT/US2016/061247 suppression of genes 'that orchestrate 'the inflammatory response. Activation of a particular TLR, for example. Initiates a series of intracellular events resulting in aa immune response characterized by the production of pro-inflammatory cytokines, TLR signaling originates from the cytoplasmic Toll-interleukin 1 (TIR) domain, conserved among all 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-icB and secretion of pto-inflammatory cytokines. A52R. an immunoregulatory' protein from the vaccinia virus, has previously been Shown to he an intracellular inhibitor of TIR-dependent signaling. When expressed in HFK29i cells, AS^R stiown to inhibitNf-κΒ activation m response to stimulation by a variety of TLRs, including TLR4, TLR5, and the combination of TLR2 and 6, and TLR2 and
1. In addition, A52R inhibited NF-κΒ activation in response to Poly ί 1:0S, a synthetic ligand for TLR3. TLR3 has been implicated in an anti-viral innate immune response )0005) One of the primary responses of activation is to shift the redox status of a ceil Reactive Oxygen species (ROS) can he produced for defensive purposes. The very presence of ROS consumes antioxidants ('reductants) and results in a more oxidative redox status. 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 sulfltydryi groups on certain proteins become oxidized. The oxidized s tate of these proteins is then recognized, leading to acti 1:111011 of specific genes, such as genes controlling redos status and promoting or controlling inflammation, or genes producing aberrant or disease-promoting proteins.
10006) inflammation is part of the complex biological response of body tissues to 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 vessels, and molecular medi ators. 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 inflammatory1 process, and to initiate tissue repair, it is useful to differentiate inflammation from infection conceptual iv, as there are many pathological situations where inflammation is not driven by microbial in vasion or infection, for .example, atherosclerosis, type ill hypersensmuty. nauma, and ischemia, f'here arc afro pathob-gical uituatious where microbial invasion does not .result in classic inflammatory response, for example, as in eosiuophilia, Whereas too little inflammation could lead to progressive tissue destruction by -2WO 2017/083470
PCT/US2016/061247 the harmful “invaders (e.g. bacteria, virus and mutated cells) and compromise the survival of the organism, too much inflammation (as in the case of chronic inflannnaiton) may lead to a host of diseases, such as hay fever, periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer (e.g., gallbladder carcinoma).
[00071 The initiation of a redox change and the resulting inflammatory response to pathogens is a critical comp onent o f the innate immune response designed to control infection. Because the sustained production of inflammatory mediators can lead to chronic inflammation, tissue damage and disease development, inflammation is normally closely regulated. The signaling cascade initiated by PAMP/TLR interactions and culminating in gene activation has been associated with many disease states, including sepsis, autoimmune diseases, asthma, heart disease and cancer. For example, it is hypothesized that sepsis-occurs 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, cellactivation responses contributing to sepsis.
[00081 inflammation (whether chrome or acute) results from and leads io the increased produc tion and release of free radicals and other ROS from damaged and/or inflamed tissues and as a result contributes to or causes oxidative stress. At the same, time, inflammation can result from oxidative stress when ROS damage tissues. As such, infiammation and the various conditions associated with it can also be rcgaided as an oxidative stress-related disease or condition.” Other stresses such as 'psychological stress can also lead to shifts in redox level and resulting oxidative stress and even inflammation. With such a positive feedback loop when the redox status induces a state of oxidative stress, that state may become self-perpetuating. Oxidative redox status and oxidati ve stress is supposed to occur in a defined locus and for a limited time. When the locus of the oxidative redox, status is inappropriate and/or continues for too long, a pathological or disease state exists. A wide range of pathological or disease states are potentiated by inappropriate redox state or oxidative stress brought on by chronic or acute inflammation or vice versa, [0009] Oxidative stress is a pathological form of an oxidative redox state involving the damaging action of abn ormally increased amounts of ROS including free radicals. Free radicals are single atoms or molecules having at least one external electron orbital “occupied by a smglc electron f unpai-ed'T instead o; two electrons (“paired”) The eststenee of an unpaired electron makes free radical compounds-exceptionally reactive. They may spontaneously react with, and thereby damage, a large variety of key cellular molecules. A -3WO 2017/083470
PCT/US2016/061247 certain number of ROS including free radicals are naturally produced by the body due to ceil 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 io 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 acidtc.g.. arachidonic acid), it immediately 'extracts an electron from the target molecule. Due to this effeci--“oxidafion”--thc 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 b\ bee tadwah can ic-'ult in \aty tm- degrees of tissue damage and can cause (or conversely result from) inflammatory responses. An initial or primary site of ROS release may he an appropriate response to an invading microorganism, but the invader is not destroyed or if redox homeostasis is nor 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 inittry (TB1) which leads to localized. inflammation wad 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).
[001.11 There tints exists a need in the art tor compositions and methods for controlling cellular redo x lev els .
SUMMARY
J0012 j lire methods and compositions disclosed herein are not limited to specific advantages or functionality.
[0013[ In one aspect, the disclosure provides toll-like receptor (TLR) agonist compositions for regulating redox status tn a subject, the composition comprising: (a) a TLR ,4WO 2017/083470
PCT/US2016/061247 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, tb) an optional promoter for enhancing absorption of the composition; and (c) an optional carrtct 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..
(00141 In another aspect, the disclosure provides methods of regulating redox status in a subject, the method comprising administering a 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.
(00151 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 m time and consisting of a composition comprising fi) a ioll-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 NL-Rs; (ii) an. optional promoter for enhancing absorption of the composi tion; and (hi) an optional carrier for increasing a volume of the composition; and ilri making measurements of a bodily fluid of the subject to detect changes to oxidative stress levels.
JQOlbj In another aspect, the di sclosure provides methods of decreasing the amount of isoprostane in the urine or blood of a subject, the method comprising tlte steps of: (a) determining the level of isoprostane in the urine of blood of the subject; (b) administering to the subject an effective amount of a composition comprising: (i) a toil-like receptor (TL.R? agonist comprising at least one bacterial lysate and/or lysate fraction from 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.
(00171 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 tire composition..
[0018] In another aspect, the disclosure provides pharmaceutical formulations comprising lysate compositions according to the disclosure, wherein the pharmaceutical formulation is *5WO 2017/083470
PCT/US2016/061247 formulated for buccal or sublingual administration. In some embodiments, the pharmaeeutieal formulations are formulated to dissolve in not less than 1 minute after administration.
[0019 j 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; sod (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 midstationary 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 fermetnation brotlt, to pasteurizing the harvested bacteria; atid id > lysing the pasteurized bacteria with a lysozyme to produce a bacterial lysate. In some embodiments, the bacteria are har\ ested in the mid-logarithmic phase, t re ate -logarithmic phase, the early stationary phase, the mid-stationary phase, or the late stationary phase.
[9021J In another aspect, the disclosure provides methods for alleviating one or more oxidari ve stress-related side effects assoc iated with administration of a pharmaceutical agent, the method comprising administering in combination with the pharmaceutical agent a therapeutical ly effective amount of a lysate composition comprising: (a) a lysate and/ot lysate fraction of a bacterium; (b) an optional promoter for enhancing absorption of the composition: and <c) an optional carrier lor increasing a volume of the composition; wherein the pharmaceutical agent and lysate composition are administered simultaneously or in any order, and through the same or different routes of administration.
[0022[ In another aspect, the disclosure provides methods for treating oxidative stressrelated diseases or conditions in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising: (a) a bacterial lysate and oi lysate fraction capable of activating at least one br more toll-like receptors (TLRs) or Nodhke receptors {Ns Rsf (bran optional promoter for enhancing absorption of the composition; and (c) an optional carrier for increasing a volume of the composition.
[0923| In 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 amount of isoprostane in the urine or blood, of the subject', thl administering to the subject an effective amount of a composition comprising; ft) a toll-like receptor (TLR) *6WO 2017/083470
PCT/US2016/061247 agonist comprising at least one lysate and/or lysate fraction from a baeterium, wherein the TLR agonist activates at least one or more TLRs or NLRs; and (ii) an optional promoter for enhancing absorption of the composition; and fc) 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 (it a bacterial lysate and/or lysate fraction capable of activating at least one or more tofl-hke receptors (TLRs) or Nod-likc receptors (NLRs); in) 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; 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, [002SI in another aspect, the disclosure provides pharmaceutical formulations comprising the combination of ta) a lysate cotnpo»mou compttsmg (it a bacterial Svsate and ot lysate fraction capable of activating at least one or mete toll hke leceptors (TLRs) or Nod-like receptors ; NLRs): iiil an optional promoter for enhancing absorption of the composition; and (i n) an option al 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-Reeeptor antagonist antimuscaiimc; 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 bile acids sequestrant, a dopamine antagonist, a proton pump inhibitor, an optotd, an opioid receptor antagonist, an analgesic, a sleep drag, a cardiac glycoside, a phosphodiesterase inhibitor, a thiazide, a diuretic, a potassium sparing diuretic, an aldosterone antagonist, au osmotic diuretic, a drug lot arrhythmia, a beta adrenoreceptor Mocking drug, a hypertension drug, a drug affecting the renin-angiotensin system, a nitrate, a calcium blocker, an antiangsnal drug, a peripheral vasodilator, a sympathomimetic, an anticoagulant, a protamine, an antipiatelet drug, a fibrinolytic drug, an antifibrinolytic drug, a lipid regulating drag, an omega force fatty acid compound, a. CNS drag, art anti-infective, or another drag selected from the group cotisisfoig ofBenztropiiie, procyelidine, biperiden. Amantadine. Bromocriptine, Rergohde, Esitaeapow, Toicapone, Selegeline, Praniipexole, budesonide, formoterol, quetiapine furaarate, olanzapine, piogfitazorte, montelnkast,
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Zoledromic Acid, valsartao, latanoprost, Irbesartan, Clopidogrei, Atomoxetine,
Dexamfetanhne, Methyipheaidaie, Modafinil, Bleomycin, Daebnomycin, Daunorubicm, Idarubicm, Mitomycin, Mitoxantrone, Azacitidine, Capecitabine, Ciadribine, Clofarabine, Cytarabine, Fludarabinc, Flourouraeii, Gemcitabine, mercaptopurine, methotrexate, Nelarabine, Pemefrexed, Raltitrexed, Thioguanine, Apomorphine, Betamethasone, Cortisone, Deflazacort, Dexamethosonc, Hydrocortisone, MethyiprednisoSone, Prednisolone, Triamcinolone, Ciciosporine, Strolimus, Tacrolimus, Interferon Alpha, and Interferon Beta, [0926] in another aspect, the disclosure provides formulations comprising (a) 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); (it) an optional promoter for enhancing absorption of the composition; and (iii) an optional carrier for increasing a volume of the composition; and (b) an isolated human and-TNFalpha antibody i-;r amigcn-huiduu? fragment thereof or TNF mbibitor. In some embodiments (be human nnriTNFaipha antibody or antigen-binding fragment thereof is adahmumafo in another aspect, the disclosure pro\ ides uses of such formulations in the manufacture of a medicament for the ireatmeni of iheumatoid arthritis (RA), fete-onset RA, or psoriatic arthritis in a subject. In another aspect, the disclosure provides methods for the treatment of rheumatoid arthritis (RAX lafe-onset RA, or psoriatic arthritis in a subject, the method comprising, administering to die subject a dierapeuticaily effective amount of such formulations, [0027] 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 heitw. the Gram-povme bat cerium is selected, from the group consisting of a bacfciuun of / ίΚί<ν\η>'^\ρ.ί.. famifr, a bacterium of SirepffH-occuiXOC-family,, a bacterium of Bi/bobocfermcere family, and a bacterium of ititii-t u > famifr in some embodiments the Gram-positive bacterium is selected from the group consisting of Bacillus eaagi/lans, ί aefnbacdiusi sporogenes, Slreplococcits !t!eni}(>philh\ Pibdabc^feruitti amtftahs. liindchaclcriitf,} οαί-ναίο, subspecies aw/nuhs. Bifklabaciemtrn infantis, Si/idabaeieriar; iangum. /hfidabaeteniun breve, Laefebactihis acidophilus, Lociabcicillns pldritarum, Lactahocillus easel, LaciobaclUas delbrueeku, Laciabacfllas deihrueckii subspecies bulgarieas, Laaacaecus laciis, Laciecoecus laetis subspecies k/ef/v, SVcptouK. cuv bn ns, Sirepiata^ /«> thermophilic·, bifutabe·, ι,ιιμι kieio. Bifidobacterium breve, Pedlaeoeeus aciditaerici, and Laefobaetlbis heivetieus.
[0028] In some embodiments of any of the methods or compositions disclosed herein, the Gram-negati ve bacterium is selected from the group consisting of a baeterium of -8WO 2017/083470
PCT/US2016/061247 /NiWoznonns genus, .K/ebjfi&dct genus, Xundithfibnifs genus, Sb/geRa genus, and Ssfero&aeier genus, in some embodiments, the Gram-negative bacterium is selected from the group consisting of Klebsiella oxytocia, Shigellajfewrnw, XanlhomonaSeampesfriS, and .Pseadamanasfiaureseens.
[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 wail fraction activates two 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 ceil wail fraction activates TLR 2 and TLR 4. In some embodiments, the TLR agonist, lysate, lysate fraction, or cell wall fraction activates three or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NODI, and'NOD2, [9039] 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, sorbitoi, xyhtof and combinations thereof.
[00311 hr 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 I'LR agonist to an oral mucosa. In some embodiments, the oral mucosa is selected from the group consisting of the sublingual .mucosa buccal mucosa, and a combination thereof [09321 I» 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 sablinguai or buccal, delivery. In some embodiments, the compositions are formulated to dissolve in not less than I minute after administration.
[ΘΟ33| These as well as oilier aspects, advantages, and .alternatives, will become apparent to those of ordinary skill in the art by reading the following detailed description, with reference where appropriate io the accompany ing drawings, and taken together with the accompanying claims.
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BRIEF DESCRIPTION OF THE DRAWINGS [0034] Figure 1 shows a diagrammahc representation of a toll-like receptor (TLR) showing various response pathways.
[0035] Figure 2 shows the exemplary stimulator. ei Sects of a composition oi rite present invention on select TLR/NLR cell lines: the values in the graph correspond to an average of three screening experiments, [6636] Figure 3 shows results of TLR stimulation for a Pediococcifs acidilactici lysate as compared to a Lactohacilhts bitigaricits lysate.
[0037] Figure 4 shows results of TLR stimulation for Bacillus coagulant lysates with di tiering tunes of harvest.
[0038] Figure 5 shows results of TLR stimulation for Gram-positive bacterial lysates from Lactobacillus acidophilus, Lactobacillus helviticus, Lactobacillus plaaiartun, and Streptococcus ifterbwphiitus.
10039] Figure 6 shows results of TLR stimulation for Gram-negative bacterial lysates front EschcrP hia coli, Klebsiella oxytocia, Shigella flexneri, XattthomotMS compos tris. and Pseudomonas flouroscens.
[0040] Figure 7 shows the results of TLR stimulation for &Xarohemtvtas campestris lysate as compared to xanthan gum.
[0041} 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.
J9042} Figure 9 shows a decrease in sleep deficits of PTSD-diagnosed combat veterans following administration of a composition of the disclosure.
[6043] Figure 10 shows a decrease in neuropathy symptoms in PTSD-diagnosed combat veterans following administration of a composition of the disclosure, [0044] Figure 11 show s an improv ement m the o\ oral! mood of PTSD-diagnosed combat veterans following administration of a composition of the disclosure,
J9045} Figure 12 shows an increase in overall energy levels in PT SD-diagnosed combat veterans following administration of a composition of the disclosure.
[9046} 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.
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PCT/US2016/061247 (00471 Figure '14 stows an increase in levels of satisfaction of the digestive health of PTSD-diagnosed combat veterans following administration of a composition of the disclosure, }O048J Figure 15 shows a decrease hi levels of irritability of PTSD-diagnosed combat veterans following administration of a composition of the disclosure.
[00491 Figure 16 shows an increase in overall levels of self-reported satisfaction with sexual function of PTSD-diagnosed combat veterans followingadministration of a composition, of the disclosure.
[905θ| Figure 17 shows a decrease in daytime sleepiness of PTSD-diagnosed combat veterans folltiwing administration of a composition of the disclosure.
[00511 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, [9052) Figure 19 shows a decrease in levels of depression hi PTSD-diagnosed combat veterans following administration of a composition of the disclosure, [0053j Figure 20 shows a decrease in isoprostane levels in an individual with a his tory of concussion following administration of a lysate ofthe -disclosure.
DETAILED.DESCRIPTION.
[0054) All publications, patents and patent applications cited herein are hereby expressly incorporated by reference for ail purposes.
|005S| Cellular redox (oxidation-reduction) state varies widely. Oxidation and reduction reactions are key to cellular bioenergetics. Normally when oxidation of food molecules results in election transport and ultimate capture of energy as energy rich molecules such as 'NADP (nicotinamide adenine dinueleotide phosphate) and ATP (adenosine triphosphate), TLRs are activated in such a manner such drat downstream oxidation, reduction reactions are balanced. As used herein, die term “balance” refers- to a homeostatic balance; feat 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 rite host However, there are a number of cellular situations 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. One likely cause for this is the purposeful production of reactive oxygen species (ROS) such as 02' (superoxide radical), OH (hydroxyl radical? and H.O^ ^hydrogen peroxide) (br defensive or similar purposes.
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When 'the redox balance is shifted, oxidative stress way 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 result 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, (0056) 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 “nucleic •acid” means one or wore nucleic acids, f0057$ Fot the purposes of describing and defining this in\ entien it re 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 “subsnnrialfr “ ts aiso utilized herein m represent the degree b\ which a quanrinttve representation can vary from a stated reference without resulting In a change in the basic function of the subject matter at issue.
[β058| As described above, pathogen-associated molecular patterns (PAMPs) can activate innate immune responses by stimulating TLRs. which generally· are activated, by conserved non-seif biochemical structures, thus protecting a host from infection. Bacterial hpopolysaccbaride (LP$) is found on the bacterial cell membrane of some bacteria, and is considered to be the prototypical RAMP I PS ts specifically recognized by TI.R4, a recognition receptor of the innate immune system. Other PAMPs include bacterial flagellin (recognized by TLRS), lipoteichoic acid, peptidoglyean, and nucleic acid variants normally associated with viruses, such as doable-stranded RNA (dsRNA), recognized by TLR3 or uumethylated CpG motifs, recognized by TLR9, jfit)59j In some eases, however,.PAMPs reduce .inflammation. EPS (exo-polysaccharide).
a material that typically stimulates an immune response, has been shown to stimulate
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PCT/US2016/061247 negative regulators of TLRs, thus leading to a reduced inflammatory response. More specifically, EPS has been shown to stimulate expression of immuttoglobin IL-1 related receptor, toll interacting protein, B-cell lymphoma 3-encodcd protein, A20, mitogenactivated protein kinase phosphate-!, and interleukin associate kinase M, and has been shown to lead to the negative .regulation of TLR s and inflammation,
J9960) These seemingly contradictory effects of PAMPs are at least partly explained by the innate immune system’s interaction with the mierobiome. 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 mierobiome. Given the various TLR receptors that are activated are producing a downstream redox state that is in immunologic and metabolic homeostasis, the system issues an “Ail Clear” signal to avoid inadvertent responses which might damage the essential mierobiome constituents. Hence, presenting the-right combination of PAMPs to the ceils of the innate immune system can control the entire redox system, down-regulating or up-regulating it to achieve, or in some eases restore, immunologic arid metabolic homeostasis.
[0061J 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 tire protein is able to conduct signal to the cytoplasmic surface of the membrane through conformational changes that occur when a ligand is bound. At the cytoplasmic surface this signal (arrows) is coupled to a number of different signaling pathways Proliferation differentiation 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 control one pathway or set or pathways and other
TLRs control a different pathway or set of pathways. Io addition, it is likely that one type of TLR controls different pathway s depending on which cell type it is located .in; thus, delivering the eoneet balance of TLR agonists is important for maintaining homeostasis. 19962} The downstream signaling mechantsms mas 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, Ultimateiy ihe phosphorylaied piOtein enters the nucleus (through, the nuclear pores) where the phospborylate 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 - 13WO 2017/083470
PCT/US2016/061247 signaling, and collectively, fee TLRs constitute one of the most pleiottopic yet tightly regulated gateways tor gene modulation.
[6663} One of the-primary responses of TLR activation is to shift the downstream redox •status of fee ceil when warranted. The initiation of a redox change and fee 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 fee increased production and release of free radicals and other ROS from damaged and/or inflamed tissues and as a result contributes to or causes oxidative stress At the same time, hiflamuianon can result from oxidative stress when ROS damage tissues. As such, infiammaiion 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 the specific pathological conditions it induces, ft may generally remain undiscovered, with concomitant damage to the patient, until a clinician suspects its existence and decides to assay for oxidative stress.
[0065} Various common diseases and/or conditions are frequently associated wife oxidative stress. One example is Alzlieinier’s disease. Studies have shown that chronic oxidative stress increases fee levels of tau phosphorylation, a known btomarker of Alzheimer’s disease. Studies have also shown that oxidative stress -results in tau-indueed neurodegeneration in models of Alzheimer’s disease.
[0066} Other known “oxidative stress-related diseases or conditions” include, but are not limited to· iiccrtiloplasmmemta 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/systeinic hypertension, asbestosis, asthma, ataxia telangiectasia, atherosclerosis, atopic dermatitis, brain Ischemia, bronchopulmonary dysplasia, burns, some cancers, cardiopulmonary bypass, cardiovascular diseases, cataract, cellulitis, chemofeeinpeutic side-effect, chronic fatigue syndrome, chronic Hepatitis C, chronic kidney disease, chronic obstructive pulmonary disease, chrome renal failure, colitis, coronary: artery disease, Creutefeidt-Jakob disease, Crohn’s disease, cutaneous leishmaniasis, cystic fibrosis, diabetes mellitus type 1, diabetes mellitus type 2, dyslipidemia, Down’s syndrome, eclampsia, end-stage renal disease, erectile dysfunction, Friedreich ataxia, headache, heart failure, Helicobacter pylori infeeiion/infianrmation, hemodialysis side effects, hepatic cirrhosis. Human
Imuiunodeficiency Vims infection, Huntington disease,'hyperbaric diseases,
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PCT/US2016/061247 hypercholesterolemia, hyperhotnoeysteinemiii, hyperlipidemia, idiopathic pulmonary fibrosis, interstitial lung disease, ischeraia/reporfusion injury, juvenile chronic arthritis,-kidney transplantation failure, leukemia, lung cancer, lung injury, macular degeneration, male infertility, Meniere’s syndrome, meningitis, mild cognitive impairment, Multiple Sclerosis, myelodisplasfic syndromes, myocardial infarction, myocarditis, neonatal bronchopulmonary dysplasia, obesity, osteoarthritis, osteoporosis, pancreatitis, Parkinson’s disease, periodontal disease, peritoneal dialysis side effects, photoageing, post-traumatic stress disorder, preeclampsia, primary biliary cirrhosis, hroncopulmonary diseases, progeria, psoriasis, psoriatic arthritis, pulmonary hypertension, radio-therapy side effects, reactive arthritis, renal cell carcinoma, respiratory distress syndrome, retiaopathy of prematurity. retroieotieolar fibroplasy, rheumatic disease, rheumatoid arthritis, sarcoidosis, sepsis, sickle cell disease, sleep apnea, spherocytosis, spinal cord injury, stoke, synucleinopaihies, systemic amyloidosis, systemic lupus erythematosus, systemic sclerosis (scleroderma), thrombophily, lauopathies, traumatic stress tubercolosis, unstable angina, uremia, venous insufficiency, Werner syndrome, and Zellweger syndrome.
j0067j (XiJativc stress mediates the patiio'ogtval symptoms of a great mam, disorders •and control of redox levels, and control ofredox levels, and hence oxidative stress, will prevent nxueli tissue damage thereby allotting more ready control of the underlying disease where reducing oxidative stress is not sufficient to achieve control of the disease. For example, myocardial infarction is death or damage to heart muscle caused by a vascular blockage. Leaving'· aside the possible role for oxidative stress in -causing vascular blockages, once a blockage has occurred, the affected muscles cells become anoxic and ultimately die. Ikwe'.et tf the blockage is taptdb tevetsed (c g b\ Cot bt!rtmg‘\hugsl vueukiiton is, restored and, in theory, the affected muscle cells: will be saved. However, m many eases, the initial injury provokes an inflammatory response resulting in oxidative stress and muscles ceil damage in spite of the prompt restoration of circulation. Contolling this oxidati ve stress can \ irtually eh minute damage to the heart muscle ceils, in all of these diseases and disorders, regulation of oxidate, e stress might aile\ ;are or treat the symptoms and. or causes of the disease or disorder.
[Θ0&] Changes in redox status can result in oxidation of sulfhydryl groups on key proteins, but these proteins, themselves, are often difficult to measure. However, increased oxidative stress or redox change, either -chronic or acute, can and will alter a number of other cellular constituents either by the previously mentioned oxidation of sulfhydryl groups or by
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PCT/US2016/061247 other chemical oxidative mechanisms, such as peroxidation, that result in the. transfer of electrons.
[OWJj isoprostanes are prostaglandin-like compounds formed is Wvo from the free radical-catalyzed peroxidation of essential fatty acids (primarily arachidonic acid) without the direct action of cyclooxygenase {COX) enzymes, which are the normal mechanism of prostaglandin formatiott, These compounds possess potent biological activity as inflammatory mediators that augment the perception of pain. These molecules are controlled by at least two different pathways. One pathway is mediated by COX enzymes that transform lipids into isoprostanes in response to gene activation and signal molecules. In the alternate pathway, lipids are directly oxidized into isoprostanes in response to a high oxidative redox status. Because isoprostanes are mediators of inflammation they form part of the positive feedback loop that can maintain damaging oxidative redox status.
[0079] Isoprostanes, such as F2-isoprostanes, are thus accurate markers of oxidative redox status in both animal and human models of oxidative stress, and measurement of isoprostanes has emerged as one of the most reliable approaches to assess oxidative stress in vivo due to their inherit stability and their ease of measurement in bodily fluids such as urine and blood. This ease and stability has made measurement of Isoprostanes an important and reliable, tool, to explore the role of oxidative stress in. the pathogenesis of human disease, Isoprostane ievels are directly correlated with oxidative redox status and resulting oxidative stress. Even if the site of oxidative redox status is limited in extent, isopmstanes generated there can be measured in bodily fluids, e.g., urine, remote frem the site of oxidati ve stress and resultant inflammation.
[0071} Other biological compounds that could be oxidized include, but are not limited to, proteins, metalloproreins, enzymes, lipids, fatty acids, carbohydrates, neurotransmitters,
DNA, vitamins, polyphenols, antioxidants, and coenzymes. Thus, constituents such.as, but not limited to, superoxide dismutase (SOD), peroxidases, glutathione, as well oxidized forms of cellular constituents due to exposure to reactive species such as, but not limited to. advanced oxidized proteins, malondiadehyde, k-hydrexydeoyguanosine, are other potential biomarkers for oxidative stress.
[00721 Gi ven the importance of inflammation in the immune response and the harmful .consequences it can cause Wo oxidative stress, oxidative stress-related diseases or conditions and/or other processes, it is important that an organism maintain close control of redox status.
Also, given the intertwined relationship between oxidative stress and inflammation, biomarkers that measure inflammation have been proposed as indirect biomarkers of oxidative stress. These - 16WO 2017/083470
PCT/US2016/061247 biomarkers, such as but not limited to C-reaetive protein, serum amyloid .A, arid cytokines, are limited in their ability to pick up low grade changes in inflammation aid consequently limited in their ability to pick up low grade redox changes. An alternative is to focus on biomarkers, such as isoprostones, to measure redox status, and mechanisms to alter redox status [0Θ73} Redox can be changed either by increasing reducing species t antioxidants) or by decreasing oxidants, There has been little success m coattoiling harmful redox levels through added, antioxidants or antioxidant therapy free T-ίο et ai. Biological markers of oxidative stress: Applications to cardiovascular research and practice, 2013 Redox Biology), There is evidence for the long tern use of dickey anuovdants pedups as pre\entam e agcfiL. ilowtou when the immune system is not. able to achieve or maintain, homeostatic redox levels, added antioxidants: are generally ineffective at correcting the balance, [0074] An alternative route to affecting redox status is to aim at downstream targets: such strategies include the use of aspirin and giueocorticoids to block NF-κΒ activation and the targeting of specific inflammatory mediators such as TNF-»·. Given their role in mediating the innate immune response and inflammation, TLRs present another target tor controlling the innate and inflammatory responses.
|0075j As discussed above, TLRs help mediate the 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 ptwnole or block signal pathways that can induce or suppress genes mediating inflammation. By targeting specific TLRs with specific agems immune responses and inflammatory possesses can be mediated [0076f inhibition of multiple TLR'•dependent responses or acti vation 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-slgnai.ing pathway (e.g., TIR-indnced inflammation), the method comprising the administration of a therapeutically efleetisc amount of a composition as described herein, wherein the TLR affected is one oi more of TLR2:S TLR4, TL.R5, TLR? and T.LR9, [<M>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 hi the subject.
|0078j 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 he effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. The terms -17WO 2017/083470
PCT/US2016/061247 “the product, “die supplement/* and “the composition” are used herein interchangeably in reference to pharntaceutical compositions comprising bacterial lysates, lysate fractions, and/or cell wall fractions of the disclosure,
JW79 j Compositions described herein can be modified to target nidi s dual TLRs or groups of TLRs. By targeting individual TLRs or groups of TLRs, compositions described herein can be used to mediate instances of acute or chronic inflammation. In addition, compositions described herein can housed to curb instances of aberrant inflammation and restore healthy levels of inflammation.
[Wfl| Thus, described herein are compositions and methods for -regulating oxidative stress. The compositions are able to activate various TLRs as assessed by measuring ΝΤ'~κ8 expression in a variety of cell lines. The compositions described herein can also reduce or downregulate the activity of TLRs thus leading to reduced or regulated levels of inflammation \\ hen div po'pc' bakn’cc of TLR activation is achieved, cellular redox status is optimized and o\idari\c stress w reduced, This can he achieved by providing compositions containing PAMPs that simultaneously bind to two or more different types of TLRs. jOOSf l Ια some eases a lysate of a single type of microorganism can act as an agonist to two or more TLRs. As disclosed herein, the precise manner of processing a microorgan ism lysate can affect which TLRs are stimulated by the lysate. In some embodiments, activation of a panel of TLRs may be accomplished by combining -different lysates or fractions from a single type of microorganism or lysates or fractions from more than type of microorganism. R082J There are many different but similar RAMRs that bind to a given TLR type, albeit with different affinities. There are also LAMP molecules that stimulate an entirely different TLR type lion the lysate (fr fraction is processed ean affect die PAMP assemblage present m the final product. Thus, different types of microorganisms present different palettes of PAMPs with which to work. As is disclosed herein, providing a composition that simultaneously stimulates (acts as an agonist for) particular TLR types results in dramatic downregulation of oxidative stress.
[0083} Unexpectedly, stimulating TLRs does not necessarily lead to an increase in oxidative stress. Rather, constant stimulation of TLRs by the micrebiome is the normal situation and does not result in improper redox status and oxidative stress. Part of the explanation may be related, to the location of a given TLR receptor as well as the type of the 1 LR icccptoi Aetreanon of I'LR teeeptom located on mucosa g.vt-s a difreicnt result than activation of the same types of TLR receptors located in intermr tissues of the body . Without being bound to a particular explanation or mechanism, the disclosure provides methods of -18WO 2017/083470
PCT/US2016/061247 applying or augmenting the normal mierobiomc signal, which reasserts homeostasis and “resets” the overall system by mtemrptmg the positive feedback loop that powers abnormal redox status and oxidative stress.
[3084j The therapeutically active compositions of the present disclosure' Include a nonsynthetic biologically active agent, preferably one or more cell wall fractions of one or more microorgauisnis including Gram-positive bacteria. Gram-negative bacteria, or combinations thereof, such as is 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.
j&OSSJ 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 therapeutie agent is alysate, lysate fraction, or cell wail 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 die 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, die. 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 I gut therapeutic agent pci kg body weight. In some embodiments, the acme rherapeutie agents of the disclosure arc administered in a dosage of from about 0.()1 mg therapeutic agent per kg body weight to about 50 tug therapeutic agent per kg body weight. In some embodiments, the active therapeutic agents of the disclosure are administered in a dosage of from about 0,05 ms therapeutic agent per kg body weight to about 30 mg therapeutic agent per kg body weight In some embodiments, the active therapeutic agents of the disclosure are administered ht a dosage of from about 0 'ri mg therapeutic agent 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 weight, or of about 0,5 mg therapeutic agent per kg body weight, or of about 0.6 mg therapeutic agent per kg body weight, or of about 0.7 mg therapeutic agent per kg body weight, or of about 0.8 mg therapeutic agent per kg body weight oi of about 0.9 mg therapeutic agent per kg body weight, or of about 1 mg therapeutic - 79 WO 2017/083470
PCT/US2016/061247 agent per kg body weight, or of about 2 m.g therapeutic agent per kg body weight, or of about 3 rag therapeutic agent per kg body weight, or of about 4 rag therapeutic agent pet kg body weight, or of about 5 mg therapeutic agent per kg body weight, or of about 6 mg therapeutic agent per kg body wei ght, or of abou t 7 mg therapeutic agent per kg body weight, or of about 8 rug 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, die 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, [0086'! As used herein, the terms “therapeutic agent” and “active ingredient” refer to a lysate, lysate fraction, and/or cell wall fraction of the disclosure, or a combination thereof, as opposed to the non-active ingredients in in a composition or formulation.
(01)87 j In some embodiments, foe plwmaceudcal compositions disclosed herein are 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 nig to about 50 rag active ingredient per dose, or of from about 3 mg, to about 30 tug active ingredient pat dose, or of from about 10 to about 30 mg active ingredient per dose, In some. embodiments, the pharmaceutical formulations are formulated and/or administered with about 0.5 mg, or about 1 mg, or about 5 mg, or about 10 mg, or about 15 rag, or about 20 mg, or about 25 rag, or about 30 rag active ingredient per dose. In sonic embodiments, the pharmaceutical compositions of foe disclosure are formulated as tablets, with each tablet comprising about 0.5 mg to about 30 nig active ingredient per tablet In some embodiments, the tablets each comprise about«).5 mg active ingredient, in settle embodiments, the tablets each comprise about 1 mg active ingredient, In some embodiments, the tablets each, comprise about 5 mg active ingredient in some embodiments, foe tablets each comprise about 10 mg active ingredient In some embodiments, foe tablets each, comprise about 15 mg active ingredient. In some embodiments, the tablets each comprise about 25 mg active ingredient In some embodiments, foe tablets each comprise about 4b mg active ingredient. In some embodiments, foe tablets each comprise about 50mg acme 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, (00881 In sonic embodiments the pharmaceutical formulations of foe disclosure are administered from one time per day to three times per day, in some embodiments, foe pharmaceutical formulations of the disclosure are administered once per day. In some embodiments, the pharmaceutical formulations of the disclosure are administered two times per -20WO 2017/083470
PCT/US2016/061247 day. fi» some embodiments, toe pharmaceutical formulations of the disclosure are administered three times per day, [0039-} 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 to abou t .10 gm of active therapeutic agent per day, or a total of from about 1 mg to about 1 gnr of active thempeutic agent per day, ora total of from about 5 mg to about 1 gm of active therapeutic agent pet day, or a total of from about 5 mg to about 500 mg active therapeutic par day, or a total of from about 1.2 to about 375 mg per day, In some embodiments, the pharmaceutical formulations of the disclosure are administered at a dosage level and frequency such drat the subject receives a total of about 1 nig,or about-.2 mg, or about. 3 mg, or about. 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 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 mg active ingredient < /.tr, ivsate, lysate fraction, and/or ceil wail fraction, or combination thereof) per day. or more needed. In some embodiments, the pharmaceutical formulations of the disclosure arc 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 nig, or about 144 mg, or about 156 rag, oi about 168 mg, or about 180 mg active ingredient (i.e., lysate, lysate fraction, and or ceil wall fiacnon. oj combination theiccf) pei day. oi moie as needed in some embodiments, the pharmaceutical formulations of the disclosure are adntinistered at a dosage level and frequency such dial die subject receives a total of about 15 mg, or about 30 mg, or about 45 mg, or about 60 mg, orabout 75 mg, orabout 90 mg, or about 105 mg, or about 120 mg, or about 135 mg, or about 150 mg, orabout 16^ mg ,u a«x>«r thO mg, or about 195 mg. orabout 210 mg, or about 225 mg active ingredient (/.<?., lysate, lysate fraction, and/or cell.wall fraction, or combination thereofJ per day , or more as needed, hr 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 i <.ϋ»mg. or about 125 mg. or about 150 mg, or about 175 mg, or about 200 nig, or abi >ut 225 mg, or about 250 rag, or about 275 rag, or about 300 mg, or about 325 mg, or about 356 mg, or about 375 mg, or about 400 mg arm? rngiedieuf a t , hwite ivsate frat non, ansi or cell wall fraction ot eomfrnano>tthi.ieof) per day or more as needed.
|0990| Any and all of the above dosage amounts and administration amounts are applicable to bofo nionotiierapentic administration of acti ve ingredients of the disclosure, as well as to embodiments in. which active ingredients of the disclosure are administered in combination. with one or wore other therapeutic or pharmaceutical agents,
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Active ingredients [00911 Active ingredients to be used in the compositions and methods of the disclosure comprise a bacterial lysate, lysate if action, or cell wall fraction. Active ingredients may be manufactured, produced, or derived from any Gram-positive or Gram-negative bacterial organism, [0092] The term “lysate” as used herein refers to a composition prepared from a lysed ceil, such as a bacterial cell. A ivsate contains the entire cellular contents as well as, in sonic embodiments, associated, surface components such as exo-polysaccharide, depending on the precise process conditions used to produce the lysate.
[00931 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 iboutom, mi rtaxhntg and pa-aeon/my the hane-ued I'.xteiiu (4) dwiepmig 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 fraction.
[00941 The structures present in lysates, lysate tractions, andfor cell wall inactions of the disclosure that ate responsible for TLR activaifon and oxidative stress reduction ate structures common to and conserved among ail bacterial microorganisms.. Thus, in principle, any bacterial organism can be used to produce an active ingredient ofthe disclosure (i.e, lysate, lysate ifaehon, and/or ceil wail fraction.
[009SJ in sunk- c-mreodimenrs die buftoriaS .nganivn used to produce .sftiw muredtents ,<f the disclosure is a Gram-posmu bacterium. In some embodiments, the Gram-positive bacterium is selected from· I oetadiciHio l-.actobodihts budmeri, Lactobadllus casci,
Lactabacu'iu', <. Aui-to/vcn/uv cellobia.\ti<i, lactobacillus crispatus, Lactobacillus cun’atas, / «vtofen ϊ/ήη dcthntcckti, I ttdobudilus ddbrueckir subsp. huigariam, b.actobai ιία>·> dc'ibnteckii subsp. lactis, I. actobacilhis hefveitcus, lxtct> ibadllas jensemi, Ixtct>)bad/hts idcbm.uwn, lactobacillus mitiutus, Lactobacillus paracasei, lactobacillus piantanan. LacioLacdfus rbaumosus, Lactobacillus rogosoe, Lactobacillus salivarius, Lactobacillus spotvgenes (also known as Baciibts cvagtiiansb lactobadllits brevis, ladobadllus gassed, Lactobacillus fermentum, Bifidobacterium adoleseentis, Bifidobacterium animaiis (especially B. atmtails, subspecies onhwo/rif Bifidobacterium angulatum, Bifidobacterium bifidum,
Htfidobw. tenum btese. Bifidobacterium < .ucttniotiun. Hitidoba<. tcniun Jcntiw.
Blftdobefcterium criksonii: bfiidoboctefium Infanfis. Bijidobacferium lactis tdiftdohocleiiitm aui/nuli'i subsp. lactis t, Bifidobactcria/ii laugum. Buidobactcrauf! plantarum, Bijidobactcruuu -22WO 2017/083470
PCT/US2016/061247 pseriloMitcmtialum, 11 ifdohacteriinn Lepiococcus lactis, Streptococcus lactis (also referred to as lactoeoecus taeiri snhsp. laeirii, rafno&ictis,
Ariclaminococcttsfermetiita, < Vo/>h</gufenttenfans, K/todfo^ax/^mentons, Celhilo/nonas jermenttuns. Aywomonas /nobibs, .Pediocoecus -aeidilactici, or Streptococcus thermophiUts, as well as functionally equivalent variants thereof.
}M%} in some embodiments, fee bacterial organism used to produce active ingredients of the disclosure is a Gram-negative bacterium, in some embodiments, the Gram-negative bacterium is selected from: Aclnetobiu ter S.mma.mhr Aainobapilibts, Acetobacter xylirna\ Bacteroicles theiaioiuotnicron, Bcicteroioc\ ηχγο./ϊ, Bordetdia pertttssri, Brucella abortus,
Catnpylobacierjeftml, CitoMinrfriUndipEnferobactereloacae^nterohociet’sakasakip Cycmobactefia, Erwinia ana ioeora, Irickeriehici coli, Erancricella tularensis, Helieobacler pylori, Haemophilus influenza, Legionella pnemmophikpMoritxellacatarrhalri, Neisseria gonorrhoeae, Proteus mirabiiis, Pseudomonas aeruginosa, Pseudomonas fJoueeseens. Salmonella cn/etttnhs, \ hnoneha bphi, So-ratta mat\ >. ><. t ns, bhtgella dex.nen, 1 tbrio cholera, I ibcio a/genth, Bulstomu a>iundi.ee,mm, Mixobactcrtum mt>cr<.ulo,s^, '/νοΆί< winm icanus'si Elcbsuei/a oxvtocm, and Eict'sie/ia pnemnoma. and Xantlumumas iampeurts. In some emKxhments, the Gmm-ucgato.ebaetcinnn ksselctted from the geucta el Pseudomonas Klch.smlPi. Xattdtomonas, Shigella and Enferobacier. In. some embodiments, the Gram-negative bacterium is one or more of Escherichia coli, Klebsiella oxytocia, Shigella fexneri. Pseudomonas floureseefis, andNanthomonas campesfrri, as well as functionally equivalent variants thereof.
[Θ097] Al! of fee bacteria described above are believed to produce immune-stimulating ceil components, such as but not limited to, EPS (exo-polysaecharide), which is distinct from the LPS (lipopolysaeeharide) found in many bacteria. Other species of bacteria can also be used in the compositions and methods of the disclosure, for example, those disclosed in the state of the art and generally available in culture collections, such as the EC ACC (European Collection of Cell Cultures), ASTM (American Society for Testing and Materials >, ATCC (American. Type Culture Collection), and DSM (German Collection of Microorganisms and Cell Cultures) [0098J With regard to fee fermentation step for producing lysates, lysate fractions, or cell wall fractions according to the d isclosure, acceptable growth media to he used, for fermentation will depend on the particular bacterium being grown. Typical growth media include those which comprise: a nitrogen source (1- 4%), which may include one or more of fee following yeast extract, milk protein and casein hydrolyzates, soy and soy hydrolyzates, -23WO 2017/083470
PCT/US2016/061247 meirt ex tracts, 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%); and minerals (0.05- 0.3%), which may include salts of sodium, manganese, magnesium, calcium and potassium. Surfactant, cysteine HCL, and ribonucleotides ri) 00l 4).75%) may he 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 7:3.
[0099} 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 3(1 °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, or around 37 T, or around 38 C, or around 39 °C, or around 40 °C, or around 45 *€. In some embodiments., inoculated media is incubated at around 30 °C. In some embodiments, inoculated media is incubated at around 33 '’C. la some embodiments, inoculated media is incubated at around 35 ”C. In some embodiments, inoculated media is nieubated 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.
[9100} In some embodiments, fermentation is continued front 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 to about 24 hours prior to harvesting the bacteria. In some embodiments, fermentation is continued for about 14 horns, or about 15 hours, or about 16 hours, or about 17 hours, or about IS hours, or about 19 hours, or about 20 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 lateiogaritbmic phase, the early stationary phase, the mid-stationary phase., or the late' stationary' phase. In some embodiments, fermentation is continued until the bacteria reach the stationary growth phase. In some embodiments, the fermentation may 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 ss warranted, [9101.} After fermentation, the broth is typically chilfed and the bacteria harvested by centrifugation, In some embodimeois, the broth is chilled post-fermentation to uom about -24WO 2017/083470
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T’C to about'25°C, In some cmbodiinettts, the broth is chilled to about 1 °C, er to about 2 °C, or to about 3 T, or to about 4 Ύ, or to about 5T, or to about 6 °C, or to about 7*C, or to about. 8 or to about 10 l’C, In some embodiments, the broth is chilled from to about 4 C to about 7 %?, |0l92j After chilling, eenirifiigarion is.performed to separate the cells from the surrounding growth media. Ceils are then washed in fresh media, deionized water, water, or other solution v&r repeated centrifugations· and. resuspensions, and then re-suspended in. fresh media or other solution in preparation for the pasteurization step.
(91031 in some embodiments, the washed bacteria are pasteurized. In some embodiments, the bacteria are pasteurized at from about 75 °C to about 85 !>C for 30 minutes to 60 minutes, in some embodiments, the harvested bacteria are pasteurized at about 80 VC. In some embodiments, pasteurization proceeds for about 30 minutes, or about 45 minutes, or about <M* minutes.
(ΘΜΜ] Following pasteurization, the cell concentrate is treated to disrupt cell walls and thereby expose TLR agonists. Disruption of the cell walls may he 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) egg *hite Kroxy me Dot example, tNOVPLRf-. 1A SO* AC R. PF'LVO/\ MF k,
LYSOVIX R. or LYSOBAC-Rri, hsms, eudolvsnis, and hydrolases Sn some embodiments, lysozyme is added to the pasteurized bacterial cell suspension to a final concentration of 9.91-4%» by volume In some embodiments, lysozyme is added to the pasteurized bacterial cell suspension io a final concentration of about 0.5%, or about ί», or about 2%. or about 3%, or about 4% by volume. In some embodiments, treatment of the pasteurized bacterial suspension with lysing etmymes 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 yC to about 59 °C,. or from about 30 Ύ' to about 45 ’’’C, or at about 35 °C, or at about 37 A?, or at about 49 T ot at about 42 VC, or at about 45Ύ After lysis, the Ivsstc ts typically frozen and lyophilized.
(01QS| In some embodiments, and as is described in more detail below, the lyophdized material is then blended with a promoter, such as N-aeetyl I.) glucosamine HCl (bi AG}. Optionally, other formulation excipients may be added to generate a solid form pill or powder, as appropriate.
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PCT/US2016/061247 (0106} Is some embodiments, the partieuiar TLR or TLRs that are activated of 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 the disclosure comprising a bacterial lysate, lysate fraction, and/or eel! 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 in differences in TLR specificity.
(01071 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 toll-like receptor, such that the signal)ng 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 preciphation, 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 s maller number of TLRs than a complete lysate, [0109j 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. Th«s,&r example, xanthan gran, which is: deri ved from Xanihoifiows eampesiris, 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, hi some embodiments, xanthart gum is itself a lysate fraction, for example, in embodiments where xanthan gum is derived from a lysate produced from fermentation ofXanthomonas eampesfris,. such as by fractionation of a Xmw/mmmw campcstris lysate.
Other ingredients and delivery forms (01101 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 -26WO 2017/083470
PCT/US2016/061247 'can be amino acid, N-alkylated peptide, sugar, amino sitgtsr or amino sugar chelate. An amino sugar chelate comprising one or more amino sugar ligands, one or more saturated bydroxyiated carboxylic add ligands, and a nutritionally acceptable metal, therein 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 zine, and wherein fee one or mote saturated hydroxyiated carboxylic acid ligands is gluconic acid, and wherein the glucosamine ligand to nutritionally acceptable metal ratio is 2:I, wherein fee nutritionally metal is nonferrous.
(01.311 In accordance with one aspect of the present disclosure, the therapeutic fortnaiations may include one or more, acetylated or deacetylated amino sugars selected from the group consisting of NAG, gnlactosamine, N-aeetylgalactosumine, mannosamme, and Naeeiylmannosamlne in fee form of monomers, oligomers, and/or polymers thereof including ehitm, and human giueosaminogiyeans, as well as derivatives thereof. The term “derivatives thereof used herein wife reference to amino sugars means derivati ves of the amino sugars having the same or essentially fee same ability to form ey rotoxie degradation products during sterilization, in accordance with select further aspects of the present disclosure, the promoter is a. member selected from the group consisting of poly-t-lysine, glucosamine, poly-L arumme gahetosamme, N-acet>lm,mncsamioc t\ ΛΆ1, \-Ac-\lant, N-i* acctelglueosamtne (NAG; N- Ac-Glc), NN’-diacetylglueosamme (NAG-NAG; Ν,Ν’-diaeetySeIiitobiose), N,N\ N”, N’“- tetraacetylglucosamine (NAG-NAG-NAG-NAG; NiN’,N’’,N’“tetraacetylchijote^iaose), and mixtures thereof.
[0112[ Optionally, and equally acceptable, the promoter may be an acylated glycosy loxy sugar or an optionally acylated ohgoglyeosyloxy 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, Dgalaetose, D-glueose, D~gl ueosami ne, N-acetylgineosamine, and S-deoxy-L-mannose, wherein an ohgoglyeosyloxy sugar moiety may comprise the same or different sugars.
}01131 1» another embodiment, the compositions of die present invention, ate in a dosage form selected from fee 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 eontrolled-release formulation, $0-114 j In an embodiment, fee active agent of foe 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
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PCT/US2016/061247 administered sublingually so that the active ingredient is delivered across the sublingual mucosa, ieitsi In another embodiment, the carrier is -typically a solid, semi-solid, or liquid such as a binder, a gum 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 xylitok sugars such as lactose, dextrose, sucrose, glucose, and powdered, sugar; other substances such as inositol, molasses, maltodextrin, starch, cellulose, mjcrocrystalline cellulose, polyvinylpyrrolidone, acacia gum, guar gum, tragaeanth gum, alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of rsabgol (psyllium) busks, VEEGUM®, larch arabogalactan, gelatin, methylcellulose, ethyiceiluiose, earboxymethylceihilose, hydroxypropylmethylcellulose,.polyacrylic acid (e.g,, Carbopol), calcium silicate, calcium phosphate, dicaicium phosphate, calcium sulfate, kaolin, sodium chloride, polyethylene glycol: and combinations 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 gomba.se materials known in. the art. In certain instances, the gum base comprises at least one hydrophobic polymer and at least one hydrophilic polymer. Non “iimi ting examples of suitable hydrophobic and hydrophilic polymers for gum bases include both natural and synthetic poly mers such as elastomers, rubbers, and combinations thereof. Examples of suitable natural polymers include, without limitation, substances of plant origin such as ch icle, jelntong, guttapercha, crown gum, and combinations thereof. Examples of suitable synthetic polymers include elastomers such as butadiene-styrene copolymers, isobutylene and isoprene copolymers ic.g., butyi rubber’'), polyethylene, polyisobutylene. polyvinykstcr (e.g., polyvinyl acetate and polyvinyl acetate phthalate), and combinations thereof, in other instances, the· gum base comprises a mixture of buty l rubber (i.e.. isobutylene and isoprene copolymer), polylsobutylene. and optionally, polyvinylacetate (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 flaxroring agent, a protecting agent, a plasticizer, a wax, aft. 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 in the compositions described herein, is abou t 20 micrometers, as compared io a typical asetage drug particle sue of from about 75 to about -28WO 2017/083470
PCT/US2016/061247 l Ου tmcji'snUcu In another embodiment the avctage particle mzc of the drug m the compositions described herein is less than or equal to the average particle size of the carrier ingredients (e.g,, gum base, hinders, 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 the buffer systems of the present invention arc also described above. In certain instances, composition further comprises anon-biologic therapeutic agent, such as an NS AID.
[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.
[0119] 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 horn 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 tor use tn 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 WO 2017/083470
PCT/US2016/061247 system is a binary- buffer system comprising, a carbonate salt or a bicarbonate salt arid a citrate, phosphate, or 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 [91211 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., ehewable, slow-dissolving, quick-dissolving), pills, capsules, lozenges, candies, gums, powders, solutions, suspensions, emulsions, aerosols, or the ftke The dosage form can be a chewing gum, quick- dissolving tablet, candy, or lozenge.
[9122} 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 therapeutic 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 lollipop) of the present invention can be prepared according to the procedures set foirh m fs; esample Remmgtnn’c 'The Science and Pmcnee of Pharmacy, hifh Fd [Lippineott, Williams & Wilkins (2003); and, ‘ Pharmaceutieai Dosage Forms, Volume 1: Tablets,” 2nd Ed., Marcel Dekker, foe., New York, N.Y. (1 °S9s}. The dosage form to be administered will, in any event, contain a quantity of the active therapeutic agent in a therapeutically effective amount fbr relief of the condition being treated when administered in accordance with the teachings of this invention.
[9123} As used herein, the term “carrier” refers to a typically inert substance used as a diluent or velucic for a drug such as a therapeutic 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, semisolid, or liquid such as a. binder or a gutn base. Examples of binders are known by one of ordinary skill in the art. Binders can be pre-proeessed to improve their Oowability and taste by methods known in the art such as freeze drying [see, e.g,, “Fundamentals of FreezeDrying,” Fharm, Biotechnol., Vol, 14, pp. 281-360 (2002); “Lyophilization of Unit Dose
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Pharmaceutical Dosage Forms,” Drug, Dev, had, Pharm., Vol. 29, pp..595-602 (2003)}; solidsohition preparation: and lubricant dusting and wet-granuiation preparation with, a suitable lubricating agent (see, e,g„ 'Remington: Tire Science and Practice of Pharmacy, supra). When a binder is included in the formulation, the compositions of the present invention can comprise from about 15% to about 99% by weight of the binder, and from about ?c” > to about 80%. However, one skilled in the art will appreciate that the composi tions of the present invention can be made without any binders, e.g,, to produce a highly friable dosage form.
Tablets )0124} When the dosage form is a tablet such as..a dissolving tablet (i.e., disintegrating tablet) or chewable tablet, the compositions of the present invention comprise a therapeutic agent as described herein derived from, one or more bacteria, or a pharmaceutically acceptable salt thereof a promote), a earner such as a Sunder, and a butfet system, including binary or ternary buffer systems, The tablet composition may further comprise lubricating agents, wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents, flavoring agents, coloring agents, and disintegrating agents. Typically, the tablet compositions of the present invention comprise from about 0.001% to about 10,0% by weigh t 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 thempentic agent desired. The buffer system of the tablet composition provides for a final salivary pH in excess of at least about 8.0, at least about 9,5, and for m the range of from about pH 9.9 to about pH 11.
J012S| hr ceiu r embodiments, the tablet is a dissolving tablet such as a slow-dissolving or quick-dissolving tablet that is dissolved by a subject’s saliva, without the need tor chewing. For example, a dissolving tablet placed on the subject’s tongue can be used for buccal delivery of the therapeutic agent. Alternatively, a dissolving tablet placed underneath the subject’s tongue can be used for sublingual delivery of the therapeutic agent. This type of dosage form may be particularly desirable for pediatric and geriatric patients, since small children and aged mdiv (duals often have difficulty chewing, certain items 1 ypjcaUy, the dissolving 'tablet is formulated to dissolve within about 1 to about 15 minutes, within about 2 to about 1.0 minutes, e.g., within about 2, 3,4, 5, 6,7, 8,9, or 10 minutes, following administration. One skilled in the art will understand that quick-dissolving tablets dissolve
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PCT/US2016/061247 fester than slow-dissolving 'tablets, winch are typically dissolved gradually rather than tepidly by a subject’s saliva. In an embodiment, the slow-dissolving ot quick-dissolving tablet delivers the therapeutic agent across the sublingual mucosa over .a period of time 'greater than about 1 minute.
|O12€1 Is 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 ehewable 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 ehewable tablet may also be. 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 1.0 minutes and not less than I minute, e.g., within about 2, 3,4, 5, 6, 7, 8, 9, or 10 minutes, following administration, [0127 j 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, arid not less than about I 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 al ways amenable to user compliance (e.g,, users may swallow too frequently and, therefore, hinder maximal transmucosal absorption). Concequenriy in certain instances it may be des treble to sink·' a balance between panent compliance and maximum exposure time of the therapeutic agent to the oral mucosa. This can be accomplished, for example, by reducing foe tablet size (e.g., from about '700-800 mg to about 200-300 mg) wi thout reducing foe concentration or amount, per uni t dose of foe buffer system or the .therapeutic agent, to .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., iactose for manmtoi or sorbitol 1 may be used to reduce salivation.
Combiuatiotis with other pharmaceutical agen ts [01281 Many pharmaceutically active agents generate detrimental side effects, which are driven by ROS that are produced as the active agent proceeds through biochemical and other metabolic re3cta-ns. Thus, the compositions described heroin arc atrraetne 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 foe art, such as any -32WO 2017/083470
PCT/US2016/061247 pharmaceutical agent listed in the Physician's Desk Reference (available at http;,'7mvw,pdr,net).
[θ!29| In some embodiments, the active ingredients of the disclosure are combined with known pharmaceutical agents that target oxidative stress, inflammation, (he immune response and/or oxidative stress-related diseases or conditions, or they can be combined with pharmaceutical, agents that .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 ’»\ 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 adjustment of the lysates to optimally target the correct TLRs in the presence of the added pharmaceutical agent.
[013Θ1 Thus, in one aspect, die disclosure provides methods for reducing or alleviating one or more oxidative stress-related side effects associated with administration of a pharmaceutical agent, the methods composing administering a lysate, lysate fraction, and/or cell wall fraction of foe 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 tire same or different routes of administration. In some embodiments, the pharmaceutical agent is any pharmaceutical agent wi th oue or more oxidative stress-related side effects, such as any pharmaceutical agent listed in the Physician's Desk Reference iavailable at htip. ..wwryjxhnet} with one or more oxidative stress-related side effects. In some embodiments, the pharmaceutical agent is selected from the group consisting of auti-rheumatte drugs, antnintlammatory agents, chemotherapeutic agents,.radiofoerapeutics, immunosuppressive agent, interferons, interferon-based chemotherapeuties, and cytotoxic drags, in some embodiments, the oxidative stress-related side effects are selected from aeeruloplasminemia, arterial/systemic hypertension, arthritis.
asthma, atherosclerosis, atopic dermatitis, cancer, bladder cancer, leukemia, uterine cancer, cervical cancer, dizziness, nausea, vomiting, constipation, diarrhea, insomnia, drowsiness, hghtheadedness, reduced libido, blackouts., shakes, jaundice, arrhythmia, increased heart rate, decreased heart rate, hives, depression, clinical depression, brain Ischemia, bronchopuhnonary dysplasia, cardiovascular diseases, cataract, cellulitis, ehemotherapeutte side-effect, chronic fatigue syndrome, colitis, coronary artery disease, dyslipidemia, eclampsia, erectile dysfunction, ataxia, headaehe, heart failure, hemodialysis side effects, hepatic ctrrhosis, hypctcholesieiolemta, hyperhoinocystemeinia, hyperlipidemia, interstitial
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PCT/US2016/061247 iung disease, lung injury, macular degenemriott, male infertility, mild cognitive impairment, myocardial mferetmn, myocarditis, myopathy, neuropathy, obesity, osteoarthritis, osteoporosis, pancreatitis, periodontal disease, peritoneal dialysis side effects, post-frauinaric stress disorder, preeelam.ps.ia, psoriasis, psoriatic arthritis, pulmonary hypertension, .radiotherapy side effects, reactive arthritis, respiratory distress syndrome, rhabdomyolysis, rheumatic disease, sepsis, sleep apnea, stroke, spteidal thoughts, amyloidosis, thromhophiiy, tenopathies, unstable angina, uremia, or venous insufficiency.
[0131 j in some embodiments, the pharmaceutical agent having one or more oxidative stress-related side effects is selected from the group consisting of Andspasmodies selected from the group consisting of atropine sulphate, dicveloverine hydrochloride, hyOScine buiylbromme, propantheline bromide, alverine citrate, and mebeverine hydrochloride; Motility stimulants selected from the group consisting of metoclorpramide and domperidone; H2-Rcceptor antagonists selected from the group consisting of ί 'imetidine, femotidmenizatidine, and ranitidine; Amimuscannics: Cheiates selected from the group
Consisting of Tripotnssium dicitrathismuthate and sucralfate; Prostaglandin analogues;
Aminosalicylates selected from the group consisting of balsazidc sodium, mesalazine, olsaldziae, and sulpbasaiazine; Corticosteroids selected from the group consisting of bedometasone dipropionate, budenoside, hydrocortisone, and prednisolone; Affecting immune response selected from the group consisting of ciclosporin, mercaptopurine, methotrexate, adahmumab, and infliximab; Stimulant Laxatives selected from the group consisting of hisacodyl, dantren docusate and sodium pieosulfore· Drugs affeenng biliary composition and flow; Bile acids sequestrante selected from the group consisting of colestymmine. Oxypheneyelimine, Carayioflu, Mebeverine, Trimebutine, Rociverine,
Dicveloverine, Dibexyverine, Difemermc. fiperidoiate, Beuzilone, Mepenzolate,
Pipenzolate, GlycopynOnium, Oxypheoomum, Penthienate, Msthantbelioe, Ifropantheline,
Otiioniumbromide, Tridihexethyl, lsopropami.de, Hexocyclium, Poldine, Bevoninm,
Diplienianil, Tiemonium iodide. Priturium bromide, Timepidiurn. bromide, Fenpiverimum,
Papaverine, Drotaverine, Moxa'<erines 5-lilT3 antagonists, 5-HT4 agonists, Fenpiprane,
Dusopromine, Chlorbenzoxamine, Pinaverium, Fenoverine, idanprannne, Proxazole,
Alverine, Trepibtstone, isometheptene, Caroverine, Phloroglucmol, Silicones,
Trimethyldiphcnylpropylamhic, Atropine, .Hyoscyamine, Scopolamine, Botylscopolsmine,
Mef wiseopolamine, Methyfatropine, Fentoniu.m, Cimetropium bromide, and primarily dopamme antagonists. Proton pump inhibitors selected from tire group consisting of
Omeprazole, lansopiczolc, pantoprazole, esomeprazole, and rabeprazole sodium; Opioids and - 34 WO 2017/083470
PCT/US2016/061247 opioid receptor antagonists; Analgesics selected from the group consisting of
Acetaminophen, Diclofenac, Difiunisal, Etodolae, Fertoprofen, Flurbiprofen, Ibuprofen, fndomethac m, Ketoprofen, Ketorolac, Meclofenamate, Mcfenamic Acid, Mcloxicam, Nabunietone, Naproxen, Oxaprozin, Phenylbutazone, Piroxicam, Snllndac, Toknetin, Ccleeoxib, Buprenorphine, Butorphanol, Codeine, Hydrocodone, Bydromorplione, Lcvorphanoi, Meperidine, Methadone, Morphine, Nalbuphine, Oxycodone, Oxymorphonc, Pentazocine, Propoxyphene, and Tramadol; Sleep drugs selected from the group consisting of Nitrazepam, Flurazepam, Loprazolam, Ironnetezepam, Temazepam, Zaleplon, Zolpidem, Zopielone, Chloral Hydrate, Trielo&s, Clomethiazole, Quazepam, triazolam, Estazolam, Clonazepam, Alprazolam, Eszopiclone, froze rem, Trazodone, Amitriptyline, Doxepin, Benzodiazepine drugs, melatonin, diphenhydramine, and herbal remedies; Cardiac glycosides selected front the group consisting of Digoxin and digitoxin; Phosphodiesterase inhibitors selected from the group consisting of enoxtmonc and milrinone; Thiazides and roiated diuretics selected from the group consisting of bendrofiumethiazide, chiortalidone, eyclopenthiazide, inapamide, roetoiazone, and xipamide; Diuretics selected from the group consisting of fruoseraide, bumetanide, and torasemide; Potassium sparing diuretics and aldosterone antagonists selec ted from the gr oup consisting of ami bride hydrochloride, triamterene, weplerenone, and spironolactone; Osmotic diuretics; Drugs for arrhythmias selected from the group consisting of adenosine, amiodarone hydrochloride, disopyramide, flecaimde acetate, propafenone hydrochloride, and lidocaine hydrochloride; Beta adrenoreceptor blocking drugs selected from the group consisting of propanafol, atenolol, acebutolol, bisprolol fumarate, carvcdilok ccliprolol.. csmolol, iebatolol metoprolol tartrate, nadolol, nebivoloi, 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, moxonidise, guanethidine monosuiphate, doxazosin, indoramin, prazosin, terazosin, phenoxybenzamine, and phentoiamine mesiiate; Drugs affecting the renin-angiotensin system selected from the group consisting of Captroprii, Ciiazaprii, Enalapri! Maleate, Fosinoprii, Imidaprii,
Lisinopril, Moexipril, Perindopril Erbumiue, Quinapril, Ramipril, Trandolapril Candesartan Cilexetil, Eprosartan, Irbesartan, Losartan, Olmesartan Medoxomil, Telmisartan, Valsartan, and Μ)Άηνη, Nroatcs. calcium channel Brocket v and atuungmaf dross selected from the group consisting of Glyceryl trinitrate, Isosorbide Dmitrate, Isosorbide Mononitrate, Amtodipinc, Diltiazem, Felodipine, Isradipine, Laeidipine, tercanidipine. Nicardipine,
Nifedspmv. Nnnodipinc, Verapamil fr anradinc, Nicorandil, and RanolazuK Peripheral - 35WO 2017/083470
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Vasodilators and related drugs selected from the group 'consisting of Cilostazol, Inositol Nicotinate, \to\isyb, te. \atbdtoiunl Oxalate, and PentoxifCihne, Sympathomimetics selected from the group consisting of Dopamine, Dopexamine, Ephedrine, Meteraminol, Noradrenaline Acid Tartrate, Noreplndrine Bitartrate, and Them leplndrine; Anticoagulants and Protamine selected from the group consisting of Heparin. Bcnnpafin, Daiteparin, Enoxaparin, Tinzapari», Danaparoid, Bivalirndin, Lepiradin, Epoprostenol, Fondaprinax, Warfarin, Aeenoeoumaroi. Phemndsone. Dabigafran Etexilate. Rivaroxaban. and Protamine Sulphate; Antiplatelet Drugs selected from the group consisting of Aheiximab, Aspirin, Clopidogrel, Dipyridamole, Eprifibaiide, Frasngrel, and Tirofibau; Fibrinolytic and antitibrinolytic drugs selected from the group consisting of Alteplase, Reteplase. Streptokinase, Tenecieplast, 1 hokmase, Etamst late, and Tranexamic Acid; Lipid Regulating Drugs selected from the group consisting of Atorvastatin, Flnvastatin, Pravastatin, Rosuvastahn, Simvastatin Coiescvam, Colestyramine, Colestipol, Ezetimihe, Bezafibrate, Ciprofibrate, Fenofrbrate, Gemfibrozyi. Acipmox, Nictotinic Acid, Omega three fatty acid compounds. Ethanolamine Oleate, and Sodium Tetradecyl Sophate; CNS Drugs selected from the group consisting of Benperidol, Chtoipromaztne, Flupentixol, Haloperidol, Levomeptomaztne, Pericyazine, Perphenazine,. Pimozide, Prochlorperazine, Promazine, SJpnidt lnlluopua/me, Adopt nthvol, Nmisulptidc A) ipipmzde, Cto/apme, Olanzapine, Paliperidone, Queiiapine, Rtperidone, Sertindole, Zotepine, FInpentixol, Fiuphenaxine, Olanzapine Erabonate, Pipefraxine Palmitate, Risperidone, Zuelopendfrxol Deeanoate, Carbamazepine, Valproate, Valproic acid, Lithium Carbonate, Lithium Citrate, Amitriptyline, Clomipramine, Dosulepin, imipramine, Lofepmnrine, Nortriptyline, Trimipraraine, mianserin, Trazodone, Phenelzine, Isocarboxazid, Tranylcypromine, Moeiobemide, Gitalepram, Escitalopram, Fluoxetine, Fluvoxaraine, Paroxetine. Sertraline, Agomelattnc, Duioxermc. Ehipemixof, Mirtazapine, Rcboxetine, Iryfophan. Ycnffaxmc. Atomoxetme, Dexameiaraine, Methylphemdate, Modafintl, Esliearbazcpine, Oearbazepene, Eiliosuxitnide, Gabapentfrt, Pregahalin, Lacostunide, Lamotrigine, Levetiracetam, Phenobarbital, Primidone, Phenytoin, Rufmamtde, Tiagabine, Topiramate, Vigabatrin, Zonisamide, ropinirole, Rotigotme, Co-Beneldopa, Levodopa, Co-Careldopa, Rasagiline, Selegiline, Entaeapone, Toleapone, Amantidine, Orphenadrine, Procyclidme, Trihexyphenidyl, Haloperidol, Piracetam, Riluzole, Tefrabenaxine, Acamprosate, Disulfiram, Bupropion, Vareniciline, Buprenorphine, Lofexidine, Donepezii, Galantaminc, Memantine, and Rivasiigimine: Anti-lnfectives selected from, the group consisting of Benzylpenicillin.,
PhennxymethylpenieiSbn, Flucloxacillin, Temocillin, Amoxicillin, AmpiciOia, Co-36WO 2017/083470
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Amoxielav, Co-Fiuampieii, Piperacillin, Tiearcibm, Pivmeoillinam, Cephalosporins, Cefaclor, Cefedroxil, Cefalexin, Ceftxirne, Cefotaxime, Cefradine, Ceftazidime, Cefuroxime, Ertapenem, Imtpenem, Meropenem, Aztreonatn, Tetracycline, Demeciocyelme, Doxocychne, Lymeeyeline, Minocycline, Oxytetraeyeline, Tigccycline, Gentamicin, Amikacin, Neomycin, Tobramycin, Erythromycin, Azithromycin, Clarithromycin, Teiithromycin, Clindamycin, Chloramphenicol, Fusidic Acid, Vancomycin, Teicopianin, Daptomycin, Linezolid, Quinupfistin, Colistin, Co-Trimoxazole, Sulpadiazine, Trimethoprim, Capreomyem, Cycloserine, Ethambutol, Isomazid, Pyrazinamide, Rifabutin, Rifampiein, Streptomycin, Dapsoue, Clofazimine, Metronidazole, Tinidazole, Ciproflaxaeut, Levoftaxacin, MoxifioxaciU, Nalidixic Aeid, Nortlaxine, Orflaxacin, Nitrofurantoin, Methenamine Hippurate, Amphotericin, Anidulafungin, Caspofungin, Fluconazole, Flucytosine, Griseoflnvin, itaeonzole, Ketoeonazole, Micafungin. Nystatin, Posaconazole, Terbinaftne, Voriconazole, Abacavir. Didanosme. Emtrieiiabine. Lamivndme, Stavudinc, Tenofovir Disoproxil. Zidovudine, Atazanavir, Darunavir, Fosamprenavdr, Indinavir, Lopinair, NdfmaUr. Ritonavir. $aqmna\ tr, Ί ipranaur. Efaurenz, Ltravirine. Novarapine, Entmirnde. Maravitoc, Raitegrsvir, Aciclovir, Famciclovir, Inosine Pranobex, Valaciclovir, Cidofovir, Gangciclovir, Foscarnet, Valgangciclovir, Adefovir Diplvoxil, Entecavir, Telbivudme, Amantadine, Oscltammr, Zanamivir, Pahvizumab, Ribavirin, Artemcthcr, Chloroqwoe, Mefloquine, Primaquine, FroguaniL Pyrimethamine, Quinine, Doxyeydm, Diloxanide Futoate, Metronidazioie, Tinidazole, Mepaerine, Sodium Stibogluconate, Atovaquone, Pentamidine Iserionate, Mebendazole, and Piperazine; Other drugs selected from the group consisting of Bcnztropine, proeyclidinc. biperiden, Amantadine. Bromocriptine. Pcrgoltde. Entaeaponc, Toicapone, Selegeline, Pranripexole, bndesonide, ibrmoterol, queflapine fnmarate, olanzapine, pioglitezone, monteluiast, Zoledfomie Aeid, valsartan, lataaoprost, Irbesartan, Ciopidogrei Atomoxetme, Dexamfetamine, M.ethyiphenldate, Modafmil, Bleomycin, Dactinomycin Daunorubicin, idarubicin. Mitomycin, Mitoxantrone, .Azaeitidmc, Capecltabine, Cladribine, Clofitmbine, Cytarabine, Fludarahine, FlourouraciL Gemcitabine, mercaptopurine, methotrexate, Nelambme, Pemetrexed, Raltitrexed, Thioguanine, Apomorphine, Betamethasone, Cortisone, Defiazacort,, Dexamethosone, Hydrocortisone, Methylprednisolone, Prednisolone, Triamcinolone, Ciciosporine, Sirollnms, Tacrolimus, Interferon Alpha, and Interferon Beta.
[0Ί32| Thus, the therapeutic formulations of the disclosure may further comprise one or more aridiiionaLiherapeulie agents, such as any of the therapeutic agents described below. In some embodimen ts, the compositions are supplied as part of a sterile, pharmaceutical -37WO 2017/083470
PCT/US2016/061247 composition that includes a pharmaceutically- acceptable carrier. Such compositions comprising additional therapeutic agents can be in atty suitable form (depending upon the desired method of adminis tering it to a patient). In some embodiments, the acti ve ingredients of the disclosure are eo-administered with one or more additional therapeutic agents, though are not necessarily combined into a single formulation with the one or more additional therapeutic agents, in some embodiments, fee acti ve ing-redient(s) of fee disclosure are administered via one route of administration, whereas the eo-administered additional therapeutic agenf(s) are administered via a second route of administration For example, fee active ingredients of the disclosure might be administered orally, mueosaliy, sublingually, bueealiy, etc,, whereas fee co-administered one or more additional therapeutic agents are administered parenterally, intravenously, etc.
[0133} Examples of compounds feat ean.be combined with the inventive compositions include anti-rheumatic drugs, anti-inflammatory agents, chemotherapeutic agents·, radiotherapeutics. immunosuppressive agent, interferons» interferon-based ehemotherapeunes, or cytotoxic drugs, [0134] Anti-rheumatic dings include, but are not limited to, auranofin, azathioprine, chloroquine, D-penicillanime, gold sodium thiomalate hydroxychloroquine, Myocrisin and sulfasalazine methotrexate.
[9135} Anti-inflammatory agents include, but are not limited to, dexamethasone, pentasa, mesalazinc, asacol, codeine phosphate, benoryiaie, fenbufen, naprosyn, diclofenac, etodolac and indometbaesn, aspirin and ibuprofen, as well as other non-steroidal and antiinflammatory agents (NSAIDS).
[0136) 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-dehydrotestosterone, 5-fiuorouracil decarbazine, 6-mercaptopurine, 6thioguanine, actinomycin D, adriamyem, aldesleukin, alkylating agents, aliopurinol sodium, akretamine, amifostine, anastrozole, anrhramyein {AMO), anti-mitotic agents, cisdichlorodiamine platinum. (II) (DDP) cisplatin), diamino dichloto platinum, anlhracyelines, antibiotics, antimetabolites, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicaintamide, bleomycin, sulfate, busuifan, calcium leucovorin, ealieheamicin, capecitabine, cafboplatin, lomustine (GCNU),, earmustine (BSNU), Chlorambucil, Cisplatin, Cladribine, Colchicia, conjugated estrogens,
-38WO 2017/083470
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Cyclophosphamide, Cyckrthosphamide, Cytarabine, Cytarabine, cyfochalasin B, < \O'\an, Daearbazine, Dactinomycin, dactinomycin (formerly actinomycin), datmirublem HCL, dannoruebicin citrate, denilcukm difhtox, Dexrazoxane, Dibroinomanmtol, dihydroxy anthracin dlone, Docelaxel, doiasetron mesylate, doxorubicin HCL, dronabinol, E. coli Lasparaginase, emetine, epoetin- .alpha., Erwinia L-asparaginase, esierified estrogens, estradiol, estramustine phosphate sodium, ethidium bromide, ethinyl estradiol, etidronate, etoposide citrovomm factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil· flutamide, folinie acid, gemeitabioe HCL, glucocorticoids, goserelin acetate, gramicidin D, gramsetron HCL, hydroxyurea, idarubiein HCL, ifesfamide, interferon .alpha -2b, iriuoteean HCL, ietrozole, leueovorin calcium, leuprolide acetate, levamlsole HCL, lidocaine, lomnstine, maytansinoid, mechlorethamine HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL, niereaptoptirine, mesna. met! ton exam, methyltestosterone. mithmmycin,. mitomycin C, mitotane, mitoxantrone. tulutamide, octreotide acetate, ondansetron HCL. paclitaxel· pamidronate disodium, pentostatin, pilocarpine HCL, phmxdn, polifeprosan with carmustine implant, porSmcr sodium, procaine, procarbazine HCL, propranolol, rhuximab, sargmmostim, stieptozotocln, tamoxifen, taxed, teniposide, tenoposide, testo lactone, tetracaine, thioepa, chlorambucil· thioguanme. thiotepa, ropoteean HCL, loremifenecitrate, trastu/umab, tretinoin, valnthiciu, vinblastine sulfate, vinom-ame sulfate, and vinoreibine tartrate.
) 0137} In yet other aspects of the di sclosure, active ingredients of the disclosure are administered in combination with a TNF-αantagonist or an anti-TNE- a .antibody. Examples of such TNF- a antagonists include, but are not limited to, soluble TNF- a receptors; etanercept i'ENBRE1,-,(-. Inuntmex) or a fragment, derivative or analog thereof; infliximab (RE.MR ADEHfe Cemacor) or it derivative, analog or antigen- binding fragment thereof; Adalsmumab (Husnira and Exemptta), it-1.0, which is known to block TNF~a production via interfemn-y-activated macrophages, TNER-IgG; the murine product TBP-1; the vaccine CytolAb (Pmthenesi. antisense molecule 104S3S tISIS), the peptide RDP-58 tSangSiat). thalidomide (Cclgene); CDC-801 (Celgene); DPC-333 (Dupont); VX-745 (Vertex): AGiX4207 (AtheroGenics); ITF-2357 (italfarmaeo)· NPI-13021-31 (Nereus); SCIO-469 {Sciosi; TACE targeter < Immunix/AHP); CLX-120500 (Calyx); Thiazolopyrim (Dynavax); anranofin (Ridaura) (SmithKline Beecham Pharmaceuticals); quinaerine (mepacrine dicblorobydmte); tenidap (Enables): Melanin (Large Scale Biological); and anti-p38 MARK agents by Hriach. )0138) In further aspects of the present disclosure, active ingredients of the disclosure are administered in combination wi th rapamycin, or similar macrocyclic antibiotics. As used - 39 WO 2017/083470
PCT/US2016/061247 herein, rapamyeiu includes ntpamyein and all -analogs, derivatives and congeners thereof, and other immunophllins that possesses the same phannaeotogie properties as rapamyeio 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 mycophenoiate mofeiil.
[0139} further therapeutic agents that may be combined with the active ingredients of the disclosure include angiogenic agents such as raw far endothelial growth factor (VEGF) and fibroblast growth factor (FGF), angiotensin rccvp.o blockers; nitric oxide donors; antisense oligonucleotides and combinations thereof; celt cycle inhibitors, mTOR inhibitors, and growth factor receptor signal transduction kinase inhibitors; retinoids; eyclmlCDK inhibitors; HMG co-enzyme 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 im cntion includes any agent u Inch interferes with TNF ct activity, in a preferred embodiment, the TNFa inhibitor can neutralize TNFa aetix itv, particularly detrimental TNFa activity winch is associated with oxidative sttess diseases and disorders, such as [see definition). and related complications and symptoms, [914.1} The term “human TNFa” (abbreviated herein as hTHFa, or simply hTNF), as used herein, is intended to refer to a human cytokine that exists as a 17 kD secreted fort» and a 26 kD membrane associated form, the biologically' active form of which is composed of a trimer of noncovalently bound 17 FD molecules. The structure of hTN Fa is described further in, for example. Pennies, D., el at, (1984) Nanire 312‘724-729; Da\ is, ,1 M . a ai. f N87) Biochemistry 26:1322-1326; and. Jones. E, ¥,, ei a/, (1989) Nature 338:225-228, The term human TNFa is intended to include recombinant human TNF« trhTNFu), which can be prepared by standard recombinant expression methods or purchased commercially (for example, From R & D Systems, Minneapolis, Minn.). TNFa is also referred to 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 auti-TNFa human antibodies and antibody portions described herein as welt as those described in U.S. Patent Nos. 6,090.382: 6,258.562: 6.509,015, and in U.S. Patent No 7,223,394). hi one embodiment, the TNFa inhibitor used m the invention is an auti-TNFa antibody, or a fragment thereof* including infliximab (Remieade*', Johnson and Johnson, described in U.S. Pat. No. 5,656,272, incorporated by -40WO 2017/083470
PCT/US2016/061247 inference Uuem) CDPV1 u humanized tnonoefonal aon-TNF-alpha igG4 a»tihod\ ί COP 870 fa humanized monoclonal anti-TNF-alpha antibody fragment), an snfi-TNF dAb fPeptech). CNTO 148 (gohmutnab; Medarex and Centocor, see WO 02.12502), and adalimtunab ί 1 hunfra*' Abbott Laboratories, a human auti-TNF mAb. described in U.S.
Patent No 6 000.3x2 as “D2F”'i Additional TNF antibodies which can be used in the indention arc described in U.S. Patent \cs. 6,593,458; 6.498.237; 6,451.983; and 6.448.380, each of which is incorporated by reference herein. In another embodiment, the TNPa inhibitor is a TNF fusion protein, e.g , etanercept ί Enbrefr) Amgen; described in WO 93/03553 and WO 09/406,476, incorpomied by reference herein), in another embodiment, the TNFa inhibitor is a recombinant TNT binding protein (r-TBP-l) (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 infer-cmineered by disulfide bonds Each heavy chain is comprised of a heavy chain variable region (abbreviatedherein as HCVR or Vid) and a heavy chain constant region. The heavy chain constant region is comprised of three domains. C H1., 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 regto.tr. The light chain constant region is comprised of one domain, CL. The VH and VL regions can befurther subdivided into regions of hypervariabihty, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following; order;
FR 1, CORL FR2. CDR2. FR? CDR3, FR4. The antibodies of the invention arc described in further detail In U.S. Patent Nos 6,090.382; 6.258,562; and 6,509,()15, each of which is Incorporated herein by reference in its entirety.
[0144} The term “human antibody”, as used herein, is intended to include antibodies having variable and constant regions derived from human gcrniltnc immunoglobulin sequences. The human ants! xl cs 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 genuline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
-41 WO 2017/083470
PCT/US2016/061247 (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 cell f described further below S, antibodies isolated from a recombinant, combinatorial human antibody library (described further below.), antibodies isolated from an animal ie « , a mouse) that is transgenic for human immunoglobulin genes (see e.g,, Taylor et al. -(1 tKB \«c/. Acids Res. 20:6287) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human imnnsnogiobulin 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 ate sequences that, while derived from and related to human germline VH and VI.. sequences, may not naturally exist within the human antibody germline repertoire in v/vo.
(0146] In one embodiment, the term “TNFa inhibitor” excludes infliximab, In one embodiment, the term “TNFa inhibi tor” excludes adaiimumab. In another eufeodbnesit, the term “TNFa inhibitor” excludes .adaiimumab and infliximab, }Q147j In one embodiment, the term “TNFa ΐηΙιΠηίοΤ’ excludes etanercept, and, optionally, adaiimumab, infliximab, and adahmuntab and infliximab.
(01481 In one embodiment, the term “TNFa 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, the in vention features uses and composition for treating or determining the -efficacy 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 antt-bTNFa antibodies. The most preferred recombinant, neutralizing antibody of the invention is referred to herein as D2E7, also referred to as HUMIRA* or adaiimumab (the ammo acid sequence of the D2E7 VL region is shown in SEQ ID NO: I; the ammo acid sequence of the D2E7 VH region is shown in SEQ ID NO ?) I he properties of D..’f,7 adahmnmab Hi MIRA *) h,n c been described m, and, w inch are each incorporated by reference herein. The methods of the invention may also be performed using chimeric and 42 WO 2017/083470
PCT/US2016/061247 humanized marine anti-hTNFa antibodies which have undergone clinical testing for treatment oi iheumatoid aithnns free eg hlhort. Yi J. eta! (, 1994', / wnct 344 I125- i id7, fclhot,
M.J.,«;αί. ί f 4441 Lancet 344: ί J05-1110, Rankin. E.C . ¢7 a!. (1995) fir. J. Rhamtaiai. 34:334-342).
[0150} Thus, in cine aspect the disclosure provides toli-lske receptor (TLR) agonist compositions for regulating redox status in a subject, the compositions comprising: (a) a TLR agonist comprising at least one or more lysate and/or lysate fraction of a bacterium, wherein the TLR agonist activates at least one or more TLRs or NLRs; (b) an optional promoter for enhancing absorption of the composition; and (e) an optional carrier 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. In some embodiments the agonist act twites at feast two different TLRs and/or NLRs. in some embodiments, the bacterium is a Gram-positi\ e bacterium or a Gram-negative bacterium, [01S11 In some embodiments, the compositions are administered in combination with a pharmaceutical agent so as to enhance activity of the pharmaceutical agent, la some embodiments, the compositions are administered in combinative with a pharmaceutical agent so as to reduce a side effect of the pharmaceutical agent, in some embodiments, the side effect of the ph armaceutical agent is oxidative stress, [0152} In another aspect, the disclosure provides methods of.regulating redox status in a subject, the methods comprising administering a therapeutically effective amount of any of the lysate or lysate fraction compositions disclosed herein to a subject in need thereof. In some embodiments, redox status regulation is assessed ideally by measuring changes hr isoprostane concentration or by other methods including hut not limited to sene expression in the subject, in some embodiments, the subject is a m&tnmai. In some embodiments, the mammal is a human. In some embodiments the subject is an animal which is not a mammal, such as, but not limited to, fish, fowl, crustaceans, and insects, such as Dr»saphi!a. In some embodiments, the redox status is oxidative and. results in oxidative stress. In some embodiments, the oxidative stress in the human is related to post-traumatic stress disorder.
[0153] in another aspect, the disclosure provides methods of regulating redox stains in a subject, the method comprising the steps of: (a) repeatedly admittistering to a subsect in need thereof doses spaced apart m tunc and consisting of a composition comprising ill a toll-lihe receptor (TLR) agonist comprising at least one Ivsate and/or lysate fraction. wherein the agonist activates at least one or mote different TLRs; (ii) an optional promoter for enhancing -43WO 2017/083470
PCT/US2016/061247 absorption of the composition; and (iii) an optional earner for increasing a volume of tire composition; and (b) making measurements of a bodily fluid of the sub ject to detect changes in oxidative stress le vels, in some embodiments, the TLR agonist activates at least three different TLRs. In some embodiments, the TLR agonist comprises iysate(s) and/or lysate fraetionis) and or eel! wall fraction! s) from a single species of bacteria. In some embodiments, the TLR agonist comprises iysatetsl anchor lysate fraetionis) bom at least two species or strains of bacteria.
[9154} 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 by methods including but stot 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 toposttraumatie stress disorder, [9155} In another aspec t, the disclosure pro vides methods of decreasing the amount of isoprostane in the urine or blood of a subject, the meihod comprising the steps of: (a.) determining the level of isoprostane in the urine or blood of the subject; (h) administering to the subject an etleettsc amount of a composition composing t L a toll- bke receptor {TLR I agonist comprising at least one bacterial lysate and/or lysate fraction from a bacterium, wherein the TLR agonist activates at least one or more 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.
[9156} In another aspect, the disclosure provides compositions comprising: (a) a bacterial lysate and/or lysate fraction capable of activating at least one or more tail-like receptors (TLRs) or Nod-like receptor (MLR); (h) an optional promoter for enhancing absorption of the composition; and (e) an optional carrier for increasing a volume of the composition, [9157} In another aspect, the disclosure provides pharmaceutical formulations comprising any of the composi tions 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 i minute after adm'.'.'matron
- 44 WO 2017/083470
PCT/US2016/061247 (0158J in another aspect, the disclosure provides methods of producing a bacterial lysate, fee method. comprising foe steps of: (a) fomenting a Gram-positive or Gram-negative bacterium in a growth medium to the stationary growth phase to produce a fermentation broth, (h) harvesting bacteria from the fermentation btoth; t e) pasteurizing the harvested bacteria; and (d) lysing the pasteurized bacteria with a lysozyme to produce a bacterial lysate, hi some embodiments, the lysate is harvested at different times of foe growth cycle after beginning any particular fermentation, In some embodiments, the bacteria are fermented in a characteristically denned media.
(0159J 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 foe fermentation broth; (c) pasteurizing the harvested bacteria; and (el) lysing the 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 la a eharacterisdcaliy defined media, (0160( in another aspect, foe disclosure provides methods for alleviating one or more oxidative sfress-related side effects associated wife administration of a phannaceuticai agent, the method comprising administering in combination wife foe pharmaeeineal agent a therapeutically effective amount of a composition comprising: (a) a lysate and or ivsate fraction of a bacterium; (b) an optional promoter for enhancing absorption of the composition : and (c) an optional carrier for increasing a volume of the composition, wherein the pharmaceutical agent and lysate composition arc administered simultaneously or in any order, and through the same or different routes of administration, la some embodiments, the lysate and/or lysate fraction activates at least one or more TLRs or NLRs. In some embodiments, foe 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 foe group consisting of; aeerufeplasnrinemia, arteriai/systemie hypertension, arthritis, asthma, atherosclerosis, atopic dermatitis, cancer, bladder cancer, leukemia, uterine cancer, cervical cancer, dizziness, nausea, vomiting, constipation, diarrhea, insomnia, drowsiness, litthfoeadedness, reduced libido, blackouts, shakes, jaundice, arrhythmia, increased heart rate, decreased heart rate, btves. depression, clinical depression, brain · 45 WO 2017/083470
PCT/US2016/061247 ischemia, bronchopulmonary' dysplasia, cardiovascular diseases, cataract, cellulitis, chemotherapeutic side-effect, chrome fatigue syndrome, colitis, coronary artery disease, dyslipidemia, eclampsia, erectile dysfunction, ataxia, headache, heart failure, hemodialysis side effects, hepatic cirrhosis, hypcrchoieste.role.mia, hyperhomocystememia, hyperlipidemia, interstitial lung disease, lung injury, 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, radio-therapy side effects, reactive arthritis, respiratory distress syndrome, rhabdomyolysis, rheumatic disease, sepsis sleep apnea, stroke, suicidal thoughts, amyloidosis, thrombophily, tauopatiti.es, unstable angina, uremia, and venous insufficiency. [01621 In another aspect, the disclosure provides methods for treating oxidative stressrehued diseases or conditions m a subject, the methods comprising administering to die 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 toll-like receptors (TLRs) or Nod-likc receptors iNLRsi (l«) an optional promoter for enhancing absorption of the composition; ants ιc) an optional carrier for increasing a volume of the composition [fi t 631 In some embodiments, the oxidative stress-related condition is aeeruloplasminemia, acute and chronic alcoholic liver diseases, acute auto immune myocarditis, acute chest syndrome of sickle cell disease, acute pancreatitis, acute respiratory distress syndrome,..alcoholic liver disease, Amyotrophic Lateral Sclerosis, arterial/systemie hypertension, asbestosis. asthma, ataxia telangiectasia, atherosclerosis, atopic dermatitis, brain ischemia, bronchopuhnonary dysplasia, burns, some cancers, cardiopulmonary bypass, cardiovascular diseases, cataract, cellulitis, chemotherapeutic side-effect,, chronic fatigue syndrome, chronic Hepatitis C, chronic kidney disease, chronic obstructive pulmonary disease, chronic renal failure, colitis, coronary artery·' disease Ci un rfeldt-Jakob disease, Ciohn's disease, cutaneous leishmaniasis, cvstie tibiosis. diabetes meUitus type 1, diabetes mellitus type 2, dyslipidemia, Down’s syndrome, eclampsia, end-stage renal disease, erectile dyslnnction., Friedreich ataxia, headache, heart failure. Hejicvbacier pylori iufection/inflammation, hemodialysis side effects, hepatic cirrhosis. Human
Immunodeficiency Virus infection, Huntington disease, hyperbaric diseases, hypercholesterolemia, byperhomocyste 'inemia, hyperlipidemia, idiopathic pulmonary fibrosis, interstitial lung disease, ischemi&freperiusion injury', juvenile chronic arthritis.
kidney transplantation failure, leukemia, lung cancer, lung injury, macular degeneration,
-46 ·
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PCT/US2016/061247 male infertility, Meniere’s syndrome, meningitis, mild cognitive impairment. Multiple Sclerosis, myeSodisplasrie syndromes, myocardial infection, myocarditis, neonatal btortehopuiiroiurj d> sphs.a, obesuv o^tcoasrlnuir, octeopotos ouncreat ti\ Parkmson disease, periodontal disease, peritoneal dialysis side effects, photoageing, post-traumatic stress disorder, preeclampsia, primary biliary cirrhosis, broneopulmonary diseases, progeria, psoriasis, psoriatic arthritis, pulmonary hypertension, radio-therapy side effects, reactive arthritis, renal cell carcinoma, respiratory distress syndrome, retinopathy of prematurity, retroientieolar fibroplasy, rheumatic disease, rheumatoid arthritis, sarcoidosis, sepsis, sickle cell disease, sleep apnea, spherocytosis, spinal cord injury', stroke, Synuclelnopathies, systemic amyloidosis, systemic lupus erythematosus, systemic sclerosis (scleroderma), thrombophily, tanopathies, traumatic stress tubercolosis, unstable angina, uremia, venous insufficiency, Werner syndrome, or Zellweger syndrome.
[0164) In 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) admmMeung to the subtect an eiiecme amount of a eomposumn conipt emig o> a η ·Π-ϊ s\e receptor (TLR) agonist comprising at least one lysate and/or lysate fraction from a Gramnegative or Gram-positive bacterium, wherein the TLR agonist activates at least one or more different TLRs or NLRs; and (it) an optional promoter for enhancing absorption of the composition; and (c) continuing admini stration 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.
(0165.1 to some embodiments, of any ofihe above-aspects, administration of the bacterial lysate is continued until the amount of isoprostane in the urine of the subject is less than about 3 ng per mg creatinine, less than about 2 ng- per mg creatinine, less than about 1 ng per mg creatinine, or less than about <» 5 ng per mg of creatinine.
(0166( in another aspect, the disclosure provides pharmaceutical formulations comp-smg the combination o> tut a t\sak composition comprising to a bacunai bsatc and/or lysate fraction capable of activating at least one or more toll-like receptors (TLR) or
Nod-llke reeeptoi s t N1 .R); (ii) an optional promoter for enhancing absorption of the composition; and in·? an optional carrier for increasing a volumeof the composition; and (h) 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-Recepto.r antagonist, anthnuscarithe; a chelate, a prostaglandin analog, an -47WO 2017/083470
PCT/US2016/061247 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 bheta 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 synjpatbomimetie, 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 drag, an anti-infective, or another drug selected to the group consisting Of Benztropine, proeyciidine, biperiden, Amantadine, Bromocriptine, Bergolide, Bntacapone, Toicapoue, Seleseline, Pramipexole, budesonide, formoterol, quetiapine fumarate, olanzapine, pioglitaz-one, montelukast, Zoiedrontie Acid, valsartan, iatanoprost, Irbesartaa, Clopidogrel, Aiomoxetine, Dcxamfetamine, Mefhylphenidate, Modafinif, Bleomycin, Dactinomycin, Daunorabicin, Idanibicin, Mitomycin,. Miioxantrone, Azaeitidine, Capecitabine, Cladribine, Ciofarubmv. Cytarabine. Fiudautbiue, Flowoumcil, Gemcitabine, mercaptoputmc. methotrexate. Nclarabine. Pcrnctrcxed, Raltttrcxed, Thioguanine. Apomorphinc, Betamethasone, Cortisone, Defiazaeort, Dexamethosone, Hydrocortisone,
Methylprodnisolone, Prednisolone, Triamcinolone, Ciclosporine, Sirolimus, Tacrolimus, Interferon Alpha, and Interferon Beta.
|4H.67| In another aspect, the disclosure provides formulations, such as pharmaceutical formulations, comprising.· (a) a lysate composition comprising (it 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 (in) an optional earner tin increasing a volume of the composition: and (hi an isolated human anti-TNFalpha antibody or antigen-binding fragment thereof or TNF inhibitor. In some embodiments, the human anti-TNFalpha antibody or antigen-binding fragment thereof is adahrnemah, In some embodiments, the disclosure provides uses of the combination formulations of this aspect m 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 in 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-48WO 2017/083470
PCT/US2016/061247 'TNFalpha antibody bf antigcn-bindmg fragmen t thereof is administered to the subject in a biweekly dosing regimen, in some embodiments, the human anti-TNFaipha antibody or antigen-binding fragment thereof is administered to the subject in a dose of 3 b mg or greater. In some embodiments, the TNFalpha inhibitor a TNFalpha fusion protein, in some embodiments, the TNFalpha fusion protein is etanercept. In some embodiments, the antiTNFaipha. atstibody or antigen-binding fragment thereof is infliximab or golimumab, in some embodiments, the anti-TNFaipha antibody or antigen-binding fragment thereof is adalimumab.
[0168 J in another aspect, the disclosure provides methods for inhibiting oxidative stressrelated disease or disorder progression in a human subject having an oxidative stress-related disease or disorder associated with a disorder in which TNFct 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 disdosnre, and an isolated human antiTNFa antibody, or antigen-binding portion thereof, such that oxidatn e stress disease progression is inhibited in the subject, wherein the human anti-TNF'u antibody, or an antigen-binding portion thereof, neutralizes human TNFa cytotoxicity hi a standard w vitro L929 assay with an ICUof 1 16' M or less. In some embodiments, the lysate of the disclosure and the human anti-TNFo, or antigen-binding portion thereof, are administered at different times under different dosing, regimens. In. some embodiments, the human antiTNFu antibody is golimumab, or an antigen-binding portion thereof. In some embodiments, the human anti-INFa antibody is adalimumab, or an antigen-binding portion thereof. In some embodiments, the human anti-TNFu antibody, or antigen-binding portion thereof is administered to the subject on a biweekly dosing regimen. In some embodiments, the methods further comprise administering an additional therapeutic agent to the subject. Ih 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 at least 24 weeks, in some embodiments, the lysate of the disclosure, the anti-INFa 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 j In some embodiments of any of die methods or compos itions disclosed herein, the bacterium is a Gram-positive or Gram-negative bacteri um. 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 l.actnbaciHaceae family, a bactwium of - 49 WO 2017/083470
PCT/US2016/061247
Streptoecccaeeae family, a bacterium ofBifido&a&erteceae -family, and a bacterium of Bacillaceae family. I» some embodiments, the .Gram-positive bacterium is selected from tbe group consisting- of Bacillus caagidans, Lactobacillus sparogeftes, Streptococcus iliermophdus, Bifidobacterium anitnalis, Bifidobacterium. aniinaiis, subspecies anitnalis, bifidobacterium infantis, Bifidobacterium ioiigum, Bifidobacterium breve, Lactobacillus acidophilus, Litaidbacillus.plantaruftti.Lacfobcuti/litscasef Lactobacillus Ad/wech?, Lactobacillusdelbrtteckii subspecies bulgarictis, Lactococcus lactis. Ixtciococcus lucks subspecies lacks, Streptococcus lacks, Streptococcus thermophilus, Bifidabacteriufti lacks. Bifidobacterium breve, Pediocoecus acidilackci, mdl Lactobacillus helvekcus, [0170| I» some embodiments of any of the methods or compositions (including formulations) disclosed herein, the Gram-negative bacterium is selected from the group consisting of a.bacterium, oi'Pseudomonas genus. Klebsiella genus, Xanihomonas genus. Shigella genus, and Pkiei'abactcr gems in some embodiments, the Gram-negative bacterium is selected from the group consisting of Klebsiella oxytocia. Shigella flexneri, Xatkhomonas campesirls, and Pseudomonas fiourcscens.
[017l| Is. some embodiments of any of the methods or compositions (including fonttulations) disclosed herein, the TLR agonist, lysate, lysate fraction, orcell 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, NOD 1, and NOD2. In some embodiments, the TLR agonist, lysate, lysate fraction, or eel! wall fraction activates TLR 2 and TLR 4. In some embodiments, the TLR agonist, lysate, lysate fraction, or cell wall fraction activates three or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NODI, and NOD2, [01721 In some embodiments of any of the methods or compositions (including: formulations) disclosed herein, the promoter is selected from the group consisting of amino acids, ammo sugars, and sugars. In some embodiments, the earner is selected from the group consisting of a binder, a gum base, and combinations thereof, hi 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 oi mannitol, soibitol, \\ 1 itol, and eumbinatjons rhe-eof [0173) In someembodiments,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 WO 2017/083470
PCT/US2016/061247 and a dissolving tablet In some -eiabodlmePtS, foe dosage form delivers the TLR agonist to an oral mucosa. In some embodiments, the oral mucosa is selected from the group consisting of the s u blingual mucosa, buccal mucosa, and a combination thereof*.
[0174) In some embodiments of any of the methods or compositions (including formulations) 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.
EXAMPLES [0175) The Examples that follow are illustrative of specific embodiments of the invention, and various uses thereof. They are set forth: fbr explanatory purposes only, and are not to be taken as limiting the invention.
Example 1: Preparation of active ingredient for TLR agonist compositions [0176) An. example of how to formulate the composition includes the following process. 1.01771 Active Ingredient. The active ingredient was derived from, a bacterial, fermentation and cell isolation process as described below. Lach/f'MiHus defbrtieckit, ssp. bitlgarwus (referred to herein as L hidgariew) was the organism used in this example, but the bacterial organism may be any Gram-positive or Gram-negative bacterium, or both.
10.1781 /.jctiibucidus ijdbntcckff ssp biilyurti w, was fermented tn growth media comprising 1,5% casein hydrolysate, I % yeast extract, 3% lactose, 0,2% sodium acetate, 0,02% sodium formate,4).01 % disodium Stinosinate, 0.03% manganese sulfate, 0,05% magnesium sulfate, and' 0.05% poly-sorbate SO, pH 6;4. Inoculated media was incubated at 37 T until, the fermentation reached stationary growth, as determined by cessation of metabolism. Fermentation broth was chilled to 4 *'C ami harvested by centrifugation at about 4000 - 4500 x g.
(01791 The concentrated cells were washed two sequential times using chilled witter and by running tire cells through the centrifuge again. Washed cell concentrate was pasteurized at 801>C for 45 minutes, [0180) Following pasteurization, the cell concentrate was treated to disrupt ceil wails and thereby lyse the bacteria and expose TLR agonists. Disruption of bacterial cell walls was
- 51 WO 2017/083470
PCT/US2016/061247 accomplished using chicken egg white lysozyme at a concentration of 3% by wt, for 7 hours at 40 *€, The resulting lysate was frozen and lyophilized, g0181g The 1> ophibzed material was blended with a promoter, such as N-acetyl D glucosamine HC11 NA<5). to form a mixture of lysed Lactobacillus delbmeckii subsp. Bulgartcus 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: TLR screening assay [0182[ Toll-like receptor (TLR.) stimulation was tested by assessing NF-KB activation in HEK293 cells expressing a given TLR or Nod-like receptor (NLR). The activities of the samples were tested on seven different human TLRs; TLR2,3, 4, 5, 7, 8 and 9 (luvivogen, San Diego, CA), and on two different human N’LRs, nucleotide-htnding oligomerization domain-containing proteins 1 and 2 (NODI and NOD21 Each ligand was tested at a final concentration of 1/1.00 of the stock solution on the TLR. or NLR ceils, and compared to control ligands, as described below. This step was perfertned in triplicate, [0183 j The control ligands, control cell lines, and sample product used in die examples were as shown in Table I.
Table i: Control Sigar ids and control cell line information used in ligand screening tests.
I ILR2. HKLM (heat-killed/zverw /«ratom n/gtwv at HP cells mL |
TLR3 PoH(LG) at 1 pg/mL |
TLR4: E coli K12 LPS at HlOng/mL |
. ,,. ,. j TLRS. .S', typhtmitrimti flageliin at 100 ng/ml |
v. tMlit tii τι /ί Λ.ν> τ' · *· ” 1 TLR/· CL097 at t pg/nu.. |
j TLR8: CLO75 at 1 pg/mL |
ΓΪΧΙΪΡ: CpG ODN 2006 at H>0 ng/mL |
| NODI: C121EDAP at 10 pg'mL |
1 NOD2; LlX-MDPat IOO ng/ml.. |
| Γ5&Κ293/ΝοΙΙΗ TNF-alpha at I pg mL j (control for human TLR 2, 3, 5, 8, 9 and NOD I) |
„ H£K293/Nulil-k: TNF-alpha at 1 ug/mL j ί control tor Human 5. i..Rz) |
HEK293/NuS12: TNF-alpha at I pg/mL ! (control tor human TLR4 and NOD2) |
,, , Lvsatc of Laciiibaci/hts Jc/brueckii subsp. fwivcu'icus ‘ ’ j (l/SO dilution prepared in sterile, endotoxin-free water) |
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PCT/US2016/061247 (0184( General Procedure. TLR stimulation in the screening is tested by assessing NF&B activation, in the HEK293 ceils expressing a given HR. The secreted alkaline phosphatase reporter is under the control of a promoter inducible by the transcription factor NF-KB. TLR. stimulation in the screening was tested by assessing NF-KB activation in the HEK293 cells expressing a given TLR orNLR. This reporter gene allows the monitoring of siguaimg through me II R\l R, based on the activation of M~kB In a Oo-wcll plate t ?00 pL total volume) containing the appropriate ceils (50,000-75,000 ceils/weil), 20n.L of the Sample (lysate product) or the positive control ligands to the wells. The media added to the wells is designed for the detection of NFKB induced S.BAP (secreted alkaline phosphatase) expression. After a 16-20 hr incubation, the OD (optical density) at 650 nm was read on a Molecular Devices Spectra Max 340PC absorbance detector and recorded.
[0185) 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 TI .R4 ίο a lesser extent) and NOD2.
Example 3: Effects of changes in process variables on TLR signaling [0.186) Through observations of foe effects of certain process changes on TLR signaling, It was noted that TLR. signal pattern could be altered, [0187) Figure 3 shows the difference of the cell morphology' has on the TLR signal for a Gram-positive organism. Lysate from Pcdma/ccus aciiiiiactici. a cocci organism, produced higher TLR4 and lower 19002 signals compared to L. htilgCtriciis, a rod organism, while the TLR 2 signal produced by P. acidiiacttci was only slightly higher than that produced by L. hiilgaricus. NOD2 activation was significantly lower in P. aetetitoctici which is reflective of the lower muratnyl peptides found ia cocci.
[0 .188) TLR signs! patterns were also impacted by the time of culture harvest for a
Bacillus caagulaus lysate, as depicted in Figure 4, Bacillus eoogidnnv was grown using a standard yeast extract glucose media with a pH of 6.5 in shake flasks incubated at 45 °C and 25b rpm. Harvest of the cultures followed the lysate production process of Example I but by varying the time of harvest of bacteria after fermentation according to growth phase: midlogarithmic phase, late-logariihffite phase, early stationary phase, mid-stationary phase, and late stationary- phase as determined by OD, substrate depletion, metabolite production and EPS. In general, these data demonstrate that TLR activation specificity can be altered by changing the time- of bacterial harvest after fermentation.. For example, lysate produced from cultures harvested at the mid-log phase activated all targets tested except for TLR 4 and had - 53 WO 2017/083470
PCT/US2016/061247 the highest signal for TLRs 2, 3, 5, 8, 9 and NODI. TL-R signal strength decreased as the culture left log phase and went into stationary phase, with a complete cessation of TLR signal during Sate stationary. Cell culture was plated at all stages of harvest and cell count was noted to he greater than 5x10s CFUftnl at all time points. No eudospores were noted upon visual inspection of the culture. The TLR effects noted from the lysates were from vegetative cells. A. large amount of EPS was noted on the sidewalls of the late stationary culture.
(0189] Figure. 5 shows TLR signal patterns obtained from Ijvmes of selected Grampositive organisms, Stnpiacoccus ibemiapb’hn', bactabaelllus helvctleus, Lactobacillus acidophilus., Hictobacillus plcuttormi, Bifidobactcriiim anitnolis subsp lacfls, and Baciffiis sabutis were grown on a standard yeast extracLiaetose/casem hydrolyzate, media at pH 6.5 in shake flasks incubated at 37 °C and 110 rpm. Lactobacillus plamarum, Bifidobacterium animatis subsp. foetis /71. lacush and bacillus subtilis were grown on yeast extract media/glueose media at pH 6.5 in shake flasks incubated at 37 C and S!() rpm, whereas A .asbidis was incubated at 37 l,C and 250 rpm. />. laais also had 0.05% cysteine HCL. added to the media. Harvest of the cultures followed the lysate puxiuetion process of Example 1,.? tkertuophilus, a cocci organism, gav c a TLR signal panel n {high TLR 2 and TLR. 4, and low NOD2) that was similar to the other cocci culture P. at. id/ku. nci, as noted in Example 4. However, A laetig although a different morphology than I. bulgaricus gave a similar TLR pattern. There was little similarity in. the TLR pattern across the Gram-positive rod cultures ail hdvuaio, I uadi’philm, I, piantafum cud B subt/b', I beta mens produced a TLR pattern similar to the TLR pattern of I. hulgaricus. L. acidophilus, although lower in signal strength, produced results similar to the patterns produced b\ the coet t /., ot id-plulus did not produce any noticeable EPS when the culture was harvested and concentrated, whereas /,. h«^%?7ejis, L, helviti&ts, and B. kictis all produced noticeable EPS, and all produced similar TLR. signal patterns. I. ptanfwvm lysate had a vety different Tl ,R signal pattern, than the other Gram-positive organisms, in which all TLR signals were muted. This muting of the signal pattern was not obvious from the characteristics of the fermentation, bnt£. plawanau is known to produce numerous metabolites that may account for the reduction in TLR signals, B. subtilis had a similar TLR pattern to the log-phase-harvested culture of B. coagulants, except it produced higher TLR 4 activation. Overall, TLR signal patterns across Gram-positive organisms varied according to the morphology, EPS production, and metabolites of the organisms.
(0-190( Figure 6 shows TLR signal patterns obtained from lysates of selected Gramnegative organisms. Pschci'ichbi cob. KJchPelhi oxytocia. Sklgcibf ilexneri, (’.yciuloiuouas
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Eourcxcetty snd Xaniitomonos easnpestris were grown using Tryptic Soy Broth in-shake flasks. X oxytoteti, £. coli, and &ftexttert were incubated at 37 °C and 250 rpm while P, flotiresccmt and Thiiftiomottas cam/^yMs- were incubated at 30 °C and 250 rpm.
Xtrnihomotios aimpestn’s was grown using a yeast extract / glucose media supplemented with calcium carbonate at 1%. Prior to harvesting, the CaCOa was removed by centrifugation at ,500.x g for 3 minutes. Harvest of the cultures from the fermentation broth followed the lysate production process of Example 1. Surprisingly and unexpectedly , the TLR signal pattern of the lysate from Gram-negative organisms, ineloding E, coli, when tested at similar concentrations, were much lower in signal strength than the lysates of Grant-positive organisms, except for TLR 5 and 9. in general, the Gram-negative bacteria membtane/cell wall is easier to break than that of Gram-positive bacteria,, which may explain the higher TLR 9 signal. A'. oxytocia and Ai campestris was observed to produce FPS during fermentation and also produced relatively high aefri atson of fLR 3, 4 and 9. A' oxyiocta produced the highest TLR2 and NODI activation of the strains tested. EPS appears to alter the TLR signal pattern as compared to non-LPS producing strains <5 f/ew;·/) interestingly, ail Gramnegative bacteria had significant activation of the NF-kappaB of the Null ceils in the TLR assay. This NF-kappaB activity was subtracted from tile TLR signal and explains the slightly negative activities for TLR. 7 and NQO2· for P. flourescens, [9191} Lastly, Figure 7 shows TLR signaling tor a lysate composition comprising xanthan gum. These data demonstrate that the lysate produced from the strain Jftrntho/no/uts’ cowpesiris, as well as xanthan gum itself, the FPS produced by the strain ..Wti/mnronas emnperiwv both produce TLR activation. There is strong stimulation by both the strain and the EPS xanthan gum at TLR5 and moderate acti vity at TLRs 4 and 9. These data suggest that, the lysate from a given bacterial strain, as well as the commanding .EPS from that strain (e.g., xanthan gum in this example) can both he used in or blended into a formulation for a targeted TLR act i\ its [9192} Surpttsingb, 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 manufacturing 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 (FTSDj-diagaosed combat veterans -55WO 2017/083470
PCT/US2016/061247 (0193} PTSD is an oxidative stress-related disease or condition., Tire purposes of the study were four-fold: (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 in qualitatively reducing levels of nitric oxide in PTSD-diagnosed combat veterans: (3) to evaluate the effectiveness of the m\ c no vc composition m improving word finding and word recall m Pi SD-diagnosed combat veterans; and ¢-4) 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-tranmatie stress disorder (PTSD), Oxidative stress occurs in fee body and on the cellular level as a. result of an imbalance between, circulating oxidants and anti-oxidants. Many studies have shown feat tins cellular oxidative stress results from toe efseei of free radicals on the body’s neurophysiology. Nitric oxide has been implicated as playing an important role in protecting against oxidative stress.
(0-195( Word-finding is often affected in individuals who suf fer from Traumatic Brain Injurv as well as m combat veteians, Closed Head Injury Ttaumatic Brain Irtiuiy iCHl'TBl) and PTSD are frequently co-raorbid -conditions.
[0196} Crbena/hr xafe/eef ve/ectiun, [0197} The an ticipated number of participants in fee study' was a minimum of 10 and maximum of 15.
[0198} The anticipated gender distribution was as close to 5070 male and 50‘>» female as possible. Due to the larger numbers of male veterans diagnosed with 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} Tire only age restriction was due to the military recruitment minimum age, 18 years old, so the anticipated age range fbr the study was from 18 to approximately 80, with the upper limit dictated by 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, 2ti% white, 23% African America, 6% Asian, 1% other.
[0202} Inclusion and Exclusion criteria are outlined in Table 2 below'.
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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 10 months |
PTSD diagnosis from the Veteran Health Administration of the 11.S. Department of Veterans Affairs | current probiotic use |
life-threatening medical condition | |
unstable physical health | |
children or participants unde· the age of 18 | |
classification as “other traditionally defined vulnerable subjects such as pnsnncid | |
lack of adequate capacity to renctci minjokd consent |
[0203} Methods and procedures.
[0204} Under mfonncd consent. participants 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 1.5 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 (?) tmx-s per day, for a total of 48 mg daily.
[0206} To minimize measurement fluctuation no placebos were·used, and subjects served as their own measurementcontrols. All subjects were· assigned, to the same study group and 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 die urine, [0208} Each participant had his/her urine tested for isoprostane levels, at a minimum, on days 1 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
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PCT/US2016/061247 'changes over time. A third party (naive to the study goals) was retained to 'conductthe isoprostane assays.
(0209( AU participants had three 13) language tests administered in private rooms on days I and 15. The language tests used were the Receptive One-Word Picture Vocabulary Test,
4th edition. (ROWPVT-4), the Expressive One-Word Picture Vocabulary Test, 4th edition (EOWPVT-4), and the Test of Non-Verbal Intelligence, 4th editiort (TQNR).
(0210( Additionally each participant was asked to complete a'Zung Self-Rating Scale for Anxiety and Depression, a Satisfaction with Life Scale (SW1 Sj and the Eppwonh Sleepiness Seale on days 1 and IS. These forms were filled out in private rooms and were coded using standard methods to mask identifying information of participants.
(0211( Each participant filled out a daily Quality of Life (QOI S Survey which was emailed to him/her even,' morning at 4:00' am. In order to familiarize each participant with the QOL Survey format and to establish a stronger baseline of data, each individual began men! ding his/her scores on the QOL Survey a minimum of four (4) days prior to beginning his/her use of product.
(0212( (i/kt iki<\i iwwi/tirfng (0213( A fter the aforementioned parameters were gathered over 15 days, the study data ncrc analyzed foi fronds tn ideufdxmg oxidatnc stress and mine oxide lex els. word-frod ability, the presence of anxiety/depression, and overall quality of life ratings, The statistical analysis methods used were straightforward as only one quantitative parameter, isoprostane, was assessed. Appropriate multivariate statistical tests were used to analyze the data.
(0214( Riskfbenefit assessment.
(0215( Risk category. The risk category tor this trial was “Minimal.” As such, consent tor htjuty language in the consent form was not necessary, and a cihneal trial agreement (CTA) was therefore not necessary'. The minimal risk category was due to the feet that the product being tested is recognized as a food-grade GRAS compound found in yogurt. Furthermore, there were no invasive procedures being performed as urine and saliva were the only body fluids being collected.
(0216} At the time of data collection, there were approximately 35 individuals taking the product, both male and female. At the time of the study, the longest using individual started the product 17 months prior and reported no negative side effects from use of the product. Of approximately 35 total individuals who were administered the product, no negative side effects were reported.
(0217( Methini <;/ Sub/ci. t Itfenfiiieat/an anti Reerui/me/Ji - 58 WO 2017/083470
PCT/US2016/061247 [0218} The study used-a convenience sample, the method of reertuting participants being based largely on personal and professional contacts of the investigators.
(0219} Subject eapactfy [0220} If the individual was deemed to 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.
(02211 Subject eompre/tensfon [0222} To assess that adequate comprehension has taken place, the participant was required to explain the study back to 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} Results [0224} in the study, effects of the supplement were assessed bv measuring / analyzing: 1) isoprostane levels; 2) quality' of life survey results; 3) Zung / psychological survey results; and 4) speech language results.
[0225} As shown in Figure 8, rieatmenf with the supplement caused a decrease in the levels of urinary isoprostane. Isoprosianes are prostagiandin-iike compounds formed in vim from the flee iadicai-corah/cd perov idat .on of essential fatn acids {primarily amchidcn.e acid) without the direct action of cyclooxygenase (COX) enzymes usually involved in prostaglandin production. These compounds ate accurate markers of lipid peroxidation in both animal 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 fee composition resulted in marked decreases in the amount of isoprostane alter just .15 days of treatment Table 2A displays the raw data from fee study, while table 3B displays the results following calculation of percentage reduction and percentage improvement of oxidati ve stress marker . In Tables 3A and 3B, “PTS'D-ϊ” is a participant who was diagnosed with PTSD. “PTSD ··-” is a participant not diagnosed with PTSD. “TX* *’ is a participant who used fee composition prior to the study. “TX- is participant who was naive to fteeomposition, [0227} As seen in Table 3B. subjects displayed over a 60% reduction in isoprostane levels after 15 days of treatment folio wed by an additional 3.18% of reduction in isoprostane levels after 0 days oi treatment in addition, subjects displayed over a 460'’e unprmement m levels of oxidative stress biomarker after 15 days of treatment followed by an additional
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53.Ί9% improvement in levels of oxidative stress bioraarker (isoprostane) after 70 days of treatment
Table 3A: PTSD Oxidative Stress Study Raw Data
Day I Isoprostane (ng/mg creatinine) | Day 15 Isoprosiane (ng/nig creatinine) | Day 70 Isoprostane (ng/mg creatinine) | |
PTSDriTX- P00la | 0.897 | 0.320 | 0.564 |
PTSD- 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 io Da\ | 15 | Dax I5lo7n | ||||
Difterene e | SRcductio n | %hnpmvesien t | Differenc e | %Rtduuto n | Mioprovetoen t | |
PTSD+/ TX- POOla | -0,577 | -64.30 | -180.12 | 0.243 | 75.96 | 43.17 |
PTSD-i-/ TX- l-’002a | -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+/ τχ- P005a | 0.0909 | 6 60 | 6,24 | -1.06 | -72.55 | -264.24 |
PTSD-·.' TX- P006a | -2,455 | -76.39 | -323,55 | -0.41 | -53.69 | -115.95 |
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PTSD+/ TX- P007a | -3.746 | -95.49 | -2116.18 | 0.039 | 21.81 | 17.30 |
PTSD+/ ΓΧ- P008a | -0.656 | -77:88 | -330.25 | 0. J 46 | 74.62 | 45.7.3 |
Average change 1PW lili!· | *1,312 | *88.98 | *469.52 | |||l|ll| | *59.19 | |
PTSD fr ΊΧ1 P009a | 0,269 | 47.47 | 32.10 | -0.35 | -42.06 | -72.60 |
PTSD- IX- POlda | -TO? | -72.23 | -266.70 | 0.097 | 24.48 | 19.54 |
PTSD- . ΓΧP01 la | -2.035 | -80.06 | -401.50 | -0.07 | -13.06 | -15.02 |
PTSD- ,-TX- POida | 0. 346 | 34,54 | 25.67 | -0.99 | -73.31 | -274.66 |
% Reduction Oxidative Stress Biositarker (PTSD+’Tx-) | 60.483¾ | 3.18% | ||||
% improvement Oxidative Stress Biomarker iP'lSDwTx-} | 4t»>».52'’„ | 59.19% |
[8228j Subjects were asked to self-assess and rate their sleep on a settle of 1 -10, where tt value of I corresponded to a deficit in sleep and a value of 10 corresponded to no deficit in sleep. As sees in Figure 9, by day 70 alt subjects showed decreased deficits ia sleep as compared to self-assessed quality of sleep ra tings at day 1.
j0229j Subjects were asked to seif-assess and rate their neuropathy symptoms between a scale of 1-10, where a value of I corresponded .to great discomfort and pain from neuropathy symptoms and a value of 10 corresponded to minimal discomfort and. pain from neuropathy symptoms. As seen in Figure to, at day j 5 all subjects but two t Rod and PO4, showed minimal discomfort and pain from neuropathy symptoms as compared to day 1, At day 70, all patients except for one (P03) showed cither minimal .discomfort and pain from neuropathy symptoms or......in the case of POA—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.
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PCT/US2016/061247 [0230} Subjects were asked to self-assess and rate their overall mood on a scale of 1-10, where a value of 1 corresponded to a generally unhappy or uneasy mood and a value of 10 corresponded to a general happy or relaxed mood. As seen in Figure 11, at day 15 all subjects but two showed an improvement in overall mood. At day 70, all patients except for one (P04) -showed an Improvement in overall mood as compared to day 1.
[0231} Subjects were asked to self-assess and. rate their overall levels of energy on a scale of 1-10, where a value of 1 corresponded to a low level of energy and a value of IO corresponded to a high level of energy. As seen in Figure 12, at days .15 and 70 all subjects (except P03) displayed an increase in energy levels as compared to day 1, [0232} Subjects were asked to self-assess and rate their overall satisfaction with the health of their joints (as determined by evaluating several factors including flexibility, stiffness and pain! on a scale of 1.-10, where a value of 1 corresponded to a low level of satisfaction and a value of 1ti corresponded to a high level of satisfaction. As seen in Figure
13, at day 15 ail subjects (except for P03 and P04) displayed improved levels of satisfaction w ith their joints as compared to day L This trend continued at day 70.
[0233J Subjects were asked to self-assess and rate their overall satisfaction with then digestive health on a scale of 1-10, where a value of 1 corresponded to a low level of satisfaction and a value of 10 corresponded to a high le vel of satisfaction.. As seen in Figure
14, at day 15 all subjects (except for P01 and P04) displayed improved levels of satisfaction with their digestive health as compared to day I, This tread continued at-day 70.
[0234} Subjects were asked to mlf-asscss and rate rheir overall level of irritability on a scale of IΊΟ, where a value of 1 corresponded to a high level of irritability and a value of 10 corresponded to the lowest level of irritability. As seen in Figure 15, at day 70 all subjects displayed decreased levels of irritability as compared to day 1.
[0235} Subjects were asked to self-assess and rate their overall level, of satisfaction with their sexual function on a scale of 1.-10, where a value of 1 corresponded to a low level, of satisfaction and a value of 10 corresponded to a high level of satisfaction. As seen in Figure 16, at day 70 all subjects (except P04 and POS) displayed increased levels of satisfaction with their sexual performance as compared to day 1.
[0236} Subjects were asked to self-assess and rate their overall level of daytime sleepiness in accordance with the guidelines of the Epworth Sleepiness Scale ( ESS). The ESS is a self-administered questionnaire with 8 questions. It provides a measure of a person’s general, level of daytime sleepiness, or their average sleep propensity in daily life, it has become the world standard method for making tins assessment. The ESS asks people to rate, -62WO 2017/083470
PCT/US2016/061247 on a 4-pomt scale (0 - 3), their usual chances of dozing off of falling asleep in 8 different situations or activities that most people engage in as part of their daily lives, although not necessarily every day. It does not ask people how often they doze off in each situation. That would depend very much on how often they happened io be in those situations. Rather it asks what the chances are that they would doze off whenever they were in each situation. This requires a mental judgment which, it seems, most people are able to make in a meaningful way. The total ESS score is the sum of 8 item-scores and can range between 0 and 34. The higher the score, the higher the person’s level of daytime sleepiness. The total ESS score provides an estimate of a general characteristic of each person—their average level of sleepiness in daily life, [0237) As seen in Figure .17, all subjects displayed decreased daytime sleepiness by day
15. At day 70, ail subjects completing the study (except Pt >3} displayed decreased day-time sleepiness as compared to day 1, [0238j Subjects were asked to self-assess and rate their overall level of satisfaction with 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 all subjects displayed increased levels of satisfaction with their lives as compared to day 1. Tins trend continued to day 70.
[0339) Subjects were asked to self-assess and rate their overall level of anxiety in accordance with the guidelines of ihe Zung Self-Rating depression- scale. The Zung SeifRating- Depression Seale was designed by Duke University' psychiatrist William W.R. Zang MD (1929-1992) to assess the level of depression for patients diagnosed with depressive disorder.
[0240) The Zung Self-Rating Depression Seale is a short self-administered survey to quantify the depressed status of a patient. There are 20 items on the scale that rate affective, psychological, and somatic symptoms.associated with depression. There are ten positively worded and ten negatively worded questions. Each question is scored on a scale of I through 4 (based on these replies: “a little ofthe time”, “some of the time., ‘'good part of the time”, 'most of the time’). Scores on the test range from 2i) through 80. The scores fail into four ranges, where: 20-44 correlates to a aormal range , 45-59 correl ates to a state of mild depression, 60-69 correlates to the state of moderate depression, and 7(R- correlates to a state of severe depression. As seen in Figure 19, at day 15 all subjects except for P01 and P05 displayed decreased levels of depression, as compared to day 1. At day 70, subjects F02, M3,
P04, P06 and P0? all displayed decreased lev els of anxiety as compared to day 1..
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Example 5: Reduction of oxidative stress-related side effects [0241j Reduction of headache. A 17-year-old mole that experienced force concessions in the 1.5 years prior to treatment was administered a lysate of the disclosure at a dose of 45 mg twice daily. At day 14 of treatment. the dosage was increased to 75 mg active ingredient twice daily. Prior to treatment, the patient reported frequent headaches. Pre-treatment F2isoprortnne {F2!$oP} was measured m urine at 2 -I ng per mg creannmc Figure 20 shows a decrease over 85 days in. isoprostane as measured in the patient’s urine, with an average of 0,82 ng isops ostune mg creatinine from days 72 - 85, letters A-H in Figure 20 denote the following events: (A) Days 1. to 3, baseline F2boP levels: (B) Day 3, severe headache af the. 9.99 ng/mg FZIsoP peak; (C) Days 1 to 13, using 45 mg bid. lysate, with daily headaches; (D) Day 13, patient begins using 75 mg bid. lysate to address headaches; ί F) Days 1 k to Sfo headaches now resolved and continue to be resorted, (F) Day 30, new impact event playing football, headaehe for 18 hours with visual and nvutoivgicai disturbances, (G) Day k\ situational stress event, showing elevated FclsoP kre els, but did not result in headache: (H) Days 1 to 89, trend line of isoprostane shov tug 981« reduction o\ et days. Overall, these data.suggest a concomitant decrease in oxidative Mress In response to lysate adminisiraiiou. Additionally,, the subject reported a marked decrease in headaches following.lysate administration, [0242J A patient experiencing one or more side effects associated with administration of a pharmaceutical agent is coadministered a bacterial lysate of the disclosure at a dose of 45-100 mg b.i.d. Prior to beginning co-administration of lysate, F2-isoprystane ievels are measured in blood or urine. Go-administration of lysate produces a continual decrease in F21soP ievels over time, with approximately 50% overall reduction in F21soP levels over about 45 days, and approximately? 955-() reduction in FZIsoP levels over about 9; > days, with concomitant reduction in.drugrelated oxidative stress-associated side effects.
Example 6; Lysate/adafimumab combination is effective for treatment of skin disease in psoriatic arthritis [02431 A study is performed to evaluate foe efficacy of a therapeutic composition comprising adalimtmiab in combination with a bacterial, lysate composition of foe disclosure, administered in conjunetiou or separately., for cutaneous disease in patients with psoriatic arthritis (FsA), an oxidative stress disorder.
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PCT/US2016/061247 [0244) A randomized Phase III study of adalimumab is studied in p at ients wi th 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.
[0245) Patients are 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 anti-INF therapy; alefaeept within 12 weeks prior to study entry; other biologies within 6 weeks prior to study entry; DMARDs (except MIX) within 4 weeks prior io study entry; systemic therapies for psoriasis within 4 weeks prior to study entry; and phototherapy and topicals within 2 weeks prior to study entry.
[0246) Patients are stratified by iuetkotiexate use tves 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 t LiP’·, BSA}; ansi Physician’s Gh-bai \sscssineul (PGA) of psoriasis. The study examines patients according to the severity of psoriasis at baseline: PASKK) vs, PASS>I0 [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 PASH It) vs. those with PASI>H). PASI analyses are by NR1, and PGA and DLQI scores are calculated as LOCF.
[0249) Tire treatment group receiving eo-administered lysate experiences amelioration of injection site reactions (such as pain, redness, or irritation) and less overall oxidative stressrelated side effects, which will allow for increased adherence and compliance with treatment, •which In turn allows a greater opportunity for ameliorating the primary disease.
Example 7: Lysate/stotin/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.
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PCT/US2016/061247 (025ij When the patient was additionally administered 45 mg bid of a lysate encompassed by the disclosure herein, the skin rash and insomnia side effects resolved within 60 days.
Example. 8: Lysate/SSRl 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 0: Lysafe/hormtme combination is effective for treatment of hypothyroidism (0254$ A .human subject being treated for hypothyroidism and receiving 150 meg QD of levothyroxine (SYNTHROID®') was experiencing oxidati ve stress-related side effect of hair loss.
$0255$ When foe. patient was additionally administered 75 mg bid of a lysate encompassed by the disclosure herein, the hair loss side effect resol ved within 180 days.
Example ttb Lysate/ι everse transcriptase inhibitor combination is effective for treatment of Hl V infection (0256) A human subject being treated for HIV (non-AIDS) and receiving one tablet QD of eta virenz-fomtrieitabine/ienofovir dlsoproxil fumarate (ATRIPLA®·) was experiencing oxidative stress-related side effects of erectile dysfunction, neuropathy, insomnia, and brain fos.
-ν' $0257$ 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 1.0 days, insomnia resolved within 3 days, and brain fog resolved within 3 days.
Example 11: Eysaie/dicect-acfiag antiviral drug combination is effective for treatment of hepatitis C
-66WO 2017/083470
PCT/US2016/061247 (02581 A human subject being treated for Hepatitis C and receiving one tablet QD of iedipasvir/sofosbuvir (HARVOM ' } 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/auti-eancer drug combination is effective for treatment of cancer [0269} A human subject being treated for dancer and receiving a biweekly dose of topoisp memse 1 inhi bdor/vinea alkaibids/aikylating antiueoplastie (IRINGTECAN®, VINCRISTINE, TEMODAR®) was experiencing oxidati ve stress-related side effects of brain fog, malaise, insomnia, and rash.
[0261 j When the patient was additionally administered 75 nig bid of a lysate encompassed by the disclosure herein, brain fog resolved 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 tor type 2 diabetes and receiving a daily dose of the tumhu analog msuhu ghagmc vLANTbS-x.) was expciienemg oxidative stress-!elated side effects of rash (injection sire), irritability, and headache.
[0263} When the patient was additionally administered 45 mg bid of a lysate encompassed by the disclosure herein, irritability resolved within 5 days, headache resolved within 7 days, and rash (injection site) resolved within 10 days.
Example 14: Lysate/antibfetic combination is effective for treatment of rheumatoid arthritis [0264} A human subject diagnosed with rheumatoid 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 < NCI ί standards for the prior ten months. Concurrently the subject was receiving additional antibiotics in order to combat a Clostridium difficile in fee tion due to the severe diarrhea. Without changing current pharmacologic therapies, the subject was additionally admimstered 45 mg lysate twice a day. Diarrhea began to resolve within. 2 weeks and improved to an NCI Grade 2 standard in one month, -67WO 2017/083470
PCT/US2016/061247
Example 15: Lysate/radiatian combination is effective for treatmeat of cancer [0265} A human subject was being treated for prostate cancer and received radiation treatments increasing in intensity and 'or duration over the course of 40 days of prescribed therapy as follows: 8 sessions at 180 cGy (IcGy ~ 1 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. 290 cGy two continuous foil eireumfcrence passes for 80 seconds and every other session being two complete continuous, full circumference 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 ly sate of the disclosure at a dose of 75 mg, three times a day. The patient was nor administered any other treatment for nausea, vomiting or bleeding. On a Quality of Life scale of 1 to 10 Γ/l” being the worst. ’ iff’ 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.
[8266} Given the variety of mechanisms of action of the above drugs with which the lysate compositions of the disclosure are coadministered, and given the mechanism of action of the lysate itself, the ivsatc compositions disclosed herein can be reasonably extrapolated to provide beneficial adverse-efieet-redtieing results with most, any drag.· For example, with HUMIRA®, an. injectable a-’TNP, co-administration with 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. HARVONF3P. When a patient uses a lysate of the disclosure in conjunction with a prescri bed HCV medication such as WAR YON IB, side effects are diminished during treatment and do not persist post treatment [0267} 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 tallowing claims are thus to be understood to include what is specifically -68WO 2017/083470
PCT/US2016/061247 illustrated and described above, what is conceptually equivalent, what can be obviously substituted and also what essentially incorporates the essential idea of the invention. Those skilled in the art will appreciate that various adaptations and modifications of the justdescribed embodiments can be configured without departing from the scope of the invention. The exemplified embodiments have 'been set forth only for the purposes of example and that should not be taken as limiting the invention. Therefore, it is to be understood that, within the scope of the appended claims, the invention may be practiced other than as specifically described herein.
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Claims (20)
- WHAT IS CLAIMED IS:I. A toll-like receptor (TLR) agonist composition for regulating redox status in a subject, the composition comprising:(a) a TLR 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;fb) an optional promoter for -enhancing absorption of the composition; and fe) an optional carrier for increasing a volume of the composition, whereto administration of an effective amount of the composition to the subject measurably reduces oxidative stress levels in the subject.
- 2, The composition according to claim 1, wherein the agonist activates at least two different TLRs and/or NLRs.
- 3, The composition- according to claim 1, wherein the agonist activates at least three different TLRs and/or NLRs.
- 4, The composition according to claim 1, wherein the bacterium is a Gram-positive bacterium or a Gram-negati ve bacterium,
- 5, The composition according to ciaim 4, wherein the at least one Gram-positive bacterium is selected from the group consistingof a bacterium of Lactobaeidaceae family, a. bacterium of SpAptoeoeeaeeat' family, a bacterium of R/fMoripemriacwe family, and a bacterium of Bacittaceae familv·, and λherem the at least n»e Gram-negative baetcitum u selected from the gtoup consisting of a bacterium of jPseWowdwas genus, Ktebsiefla genus, A/mihoino/ias genus, Sftigefto genus, and Atwro/wreter genus,
- 6, The composition according to claim 4, wherein fee at least one Oram-positive bacterium is selected from the group consisting of Bad/tus coagfdaw, Lactohaeiilus sporogertes', Streptococcus /ht'rfnophUii't. BuiJnhfciL’riu/ij amwah'., ftijklohactcrium anitfhibs. subspecies -70 WO 2017/083470PCT/US2016/061247 timmohs, /bud- >bacieruan frifanite, Bifidobacterium khighm, Bifidobacterium breve, iaciobact/lus acidophilus, fxfciobac/tlit'tpfaft/ontm, Laeieboeilkts ajser, lactobacillus dclbrttcckii, Lactobacillus delbrueekli subspecies bidgaricus, Locteeoceas lactls, Lactococcus laclis subspecies laciis, Streptococcus l&ctls, Sin.pioa'Lcft'· ihcnnopbih/s. Btf/JobjiUrmif' Dens /ii/ftWuk’nwH bn tv Pediococcus acidilactict, and Laciobacilltts· Mveiicus;. and whereiu the at least one Gram-negative bacterium is selected from the group consisting of Klebsiella oxytocia, Shigellqftexneri, Jfanthomonas campestris, and Ps-eudbmbttdsfiotO'escens.
- 7. The composition .according to claim 1,. wherein the TLR. agonist activates at least one or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NODI, and NOD2.
- 8. The composition according to claim 2, wherein the TLR agonist activates TLR 2 and TLR 4
- 9. The composition according to claim 1, wherein the TLR agonist activates two or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, T LR 9, NOD I, and NOD2.
- 10. The composition according to claim 1, wherein the TLR agonist activates three or more of TLR 2, TLR. 3, TLR. 4, TLR 5, TLR 7; TLR 8, TLR 9, NODI, antiNODT
- 11. The composition according to claim 1, wherein the promoter is selected from the group consisting of amino acids, amino sugars, and sugars.
- 12. The composition according to claim 1. wherein the carrier is selected from the group consisting of a binder, a gum base, and combinations thereof.1.3. The composition according claim 12, wherein, the gum base comprises; at least one hydrophobic polymer and at least one hydrophilic polymer.14, The composition, according to claim 12. wherein the binder is selected from the group consisting of a sugar, a sugar alcohol, and combinations thereof.-71 WO 2017/083470PCT/US2016/06124715. The composition according to claim '14, wherein the sugar alcohol is selected from the group consisting of mannitol, sorbitol, xylitoi and combinations thereof16. The composition according to claim 1, wherein the composition is manufactured as a dosage form selec ted from the group consisting of a lozenge, a che wing gum, a chewable tablet, a candy, and a dissolving tablet.17. The composition according to claim 16, wherein the dosage form delivers the agonist to an oral mucosa.18. The composition according to claim 17, wherein the oral mucosa is selected from the group consisting of the sublingual mucosa, buccal mucosa, and a combination fhewo:19. The composition according to claim 1, wherein the composition administered in combination wi th a pharmaceutical agent so as to enhance activity of the pharmaceutical agent.20. The composition according to claim 1. wherein the composition administered in combination with a pharmaceutical agent so as to reduce a side effect of the pharmaceutical agent.21.. The composition according to claim 20, wherein the side effect of the pharmaceutical agent is oxidative stress.22. A method of regulating redox status m a subject, the method comprising administering a therapeutically effective amount of the composition according to claim I to a subject in need thereof23. The method according to claim 22, wherein redox status regulation is assessed by measuring changes in isoprosfane concentration in the subject.24 The method according to claim 23, wherein the subject is a mammal.-72WO 2017/083470PCT/US2016/06124725. The method according to chum 24, wherein the mammal is a human.26. The method of claim 23, wherein the subject is a non-mammal.27. The method of claim 26, wherein the subject is a fish, fowl, crustacean, or insect.28. The method of claim 21, wherein the insect is Drosophila.29. The method according to claim 25, wherein the redox status is oxidative and results in oxidative stress.30. The method according to claim 29, wherein the oxidative stress in the human is related io post-traumatic stress disorder31. A. method 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 in time and consisting of a composition comprising:(j) a toli-hke receptort 1'1 10 agonist comprising at least one h ^atc 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 composition; 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.32. The method of regulating redox status in a subject accord mg to claim 31, wherein the agonist activates at least two different TLRs and'or NLRs.33. The method of regulating redox status in a subject according to claim 32, wherein the agonist activates at least three different TLRs and/or NLRs.34. The method of regulating redox, status in a subject according to claim. 3.1, wherein the bacterium is a Grimi-positive or Gram-negative bacterium.-73WO 2017/083470PCT/US2016/06124735. The method of regulating redox status in a subject according to claim 34, wherein the at least one Gram-positive bacterium is selected from the group consisting of a bacterium, of ώβαΜίκ» family, a bacterium of Slreptoctxtcaceae family, a bacterium af.Bifidobacteriaceae family, and a bacterium of Baciltaceec family; and wherein the at least one Gram-negative bacterium, is selected from the group consisting of a bacterium QfftW<w»is genus, Klebsiella genus, .Xanthomanas genus, genus, and Lkicrobtieier genus.36. The method of regulating redox status in a subject according to claim. 34, wherein the at least one Gram-positive bacterium ss selected from the group consisting of Baciikis coagtdtms, LaciobacHhet sporogeuc'i, Streptococcus thermophilus, Bifidobacterium ammah$> Bifidobacterium. anunebs, subspecies animalis, Bifidobacterium infaniis. Bifidobacterium loiigum, Bifidobacterium breve, Lactobacillus acidophilus, Lactobacillus pfantarum, Lac tohacllltts cetsei. Lactobacillus delbrueckil, Lactobacillus delbrueckii subspecies bulgericus, Lactoeoccus. lacks, Lactococcus lacks subspecies lac!/\ So epfococcus lacks. Streptococcus thermophilus, Bifidobacterium lacks, Bifidobacterium breve. Pediocoecus acidilactief, and.Lactobacillus helvcth us. and wherein the at least one Gram-negative baetermm is selected from the group consisting oi Klebsiella oxytocia. Shigella <L i,W' Xa/Jtbom-nhh noopt mw and Pseudomonas fiauresceks.37. The method. op regulating redox status in a subject according to claim 31. wherein the TLR agonist au \ tes at least one or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NODI, or NOD2,38. The method of .regui ating redox status in a subject according to claim 3I, wherein the TLR agonist, activates two or more of TLR. 2, TLR 3, TLR 4, TLR 5, TLR 7» TLR .-8, TLR 9, NODI, or NOD2.- 74 WO 2017/083470PCT/US2016/06124739. The method of regulating redox status in a subject according to'claim 31, wherein the TLR agonist activates three or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR :8, TLR 9, NODl,orNOD2.40. The method of rcgolatmg icdox status m a subject aeomdmg to claim v, herein the TLR agonist activates TLR 2 and TLR 4,41. The method of regulating redox states in a subject according to claim 31, wherein the promoter is selected from the group consisting of amino acids, amino sugars, and sugars.42. The method of regulating redox status in a subject according to claim 31, wherein the carrier is selected from the group consist ing of a hinder, a gum base and combinations thereof.43. The method of regulating redox: status in a subject according to chum 42, wherein the gum base comprises at least one hydrophobic polymer and at. least one hydrophilic polymer.44. The method of regulating redox status in a subject according to claim 42, wherein the binder is selected from the group consisting of a sugar, a sugar alcohol, and com b i na r i ons thereof.45. The method of regulating redox status in a subject, according to claim 44, wherein the sugar alcohol is selected from the group consisting of mannitol, sorbitol, xylitol, and combinations thereof.46. The method of regulating redox states in a subject according to claim 31, 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.47. The method of regulating redox status in a subject according to claim 46, wherein the dosage form delivers the agonist to an oral mucosa.-75WO 2017/083470PCT/US2016/06124748. The method of regulating redox status in a snineu according to 'claim 31, wherein the oral mucosa is selected from the group consisting of the sublingual mucosa, buccal mucosa, and a combination thereof'49. The method of regulating redox status in a subject according to claim 31, wherein making measurements of a bodily fluid assesses changes in isoprostane concentration is the subject.50. The method of regulating redox status in a subject according to claim 31, wherein the subject is a mammal.51. The method of regulating redox status m a subject according to claim 5o, wherein the mammal is a human,52. The method of claim 31, wherein the subject is a non-mammal.53. The method of claim 52, wherein the subject is a fish, fowl, crustacean, or insect.54. The method of cl aim 53, wherein the insect is DrvsopMa.55. The method of regulating; redox status in a subject according to claim 54, wherein the oxidative stress in the human is related to post-traumatic stress disorder.56. A method 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;(hj administering to the subject an eficctivc amount of a composition 'comprising:(i) a tolMike receptor (TLR) agonist comprising at least one bacterial lysate and/or lysate fraction from a bacterium, wherein the TLR agonist activates at least one or more different TLRs or NLRs; andVi1 an optional promoter for enhancing absorption of the composit ion;and-76WO 2017/083470PCT/US2016/061247 < c) continuing administration of the composition until the level of isoprostane in the urine or blood of the subject is decreased.57. The method of claim 56, wherein the bacterium is a Gram-positive or Grain-negative bacterium,68. The method of claim 57, wherein, the bacterium is (a) a Gram-positive bacterium selected from the group consisting of: Bacillus eougntens, buctobaedbis sparogeoes, Sireptoeoccus tkermophUus, Biftdohaciermm amtnaiis, Bfidabaeieraim. animalis, subspecies ammaiis, Bifafobaeterfam injantis, Bifidobacterium longimt, ffifidobiKleriun} breve, Lactobacillus acidophilus, Lactobacillus plantarum. Ixtciobacilhts casei, i actobaci/lns detbrueeku. i aeiohncdhis de>brtis’eku subspecies bulgarh ns. Laciacaccus lactis, I actacaccus lactis subspecies birds, Streptococcus lactis. Streptococcus fhermophilus, Biftdoboelermm lactis, bifidobacterium breve, Pedtocvccits acidilactici. and Lactobacillus be/veticit\ or (h) a. Gram-segative bacterium selected from the group consisting of; Klebsiella oxytocia, Shigella flexneri, Aauthomonas campestris, and Pseudomonas flouresceus.59. .A composition camprising:(a) a bacterial lysate and/ατ lysate iraetion capable of activating at least one or more toil-like receptors (TLRs) or Nod-hke receptors (NLRs);(b) an optional promoter for enhancing absorption of the composition; and (c) an optional earlier for increasing a volume of the composition.60. A pharmaceutical fornnsiaiiOn comprising the composition of claim 59, wherein the pharmaceutical formulation is formulated for buccal or sublingual administration.61. The pharmaceutical formulation of claim 60, wherein the pharmaceutical formulation is formulated to dissolve in not less than 1 minute after administration.-77WO 2017/083470PCT/US2016/06124762. The composition of claim 59, wherein the bacterial lysate and/or lysate fraction is aGram-negatit cor Gram-positi\e bacterial lysate and/or lysate fraction.63. The composition of claim 62, wherein the bacterial lysate and/or lysate fraction is:a Gram-positive bacterial lysate and/or lysate.fraction selected from the group consisting of: a Ladobaeidaeeae bacterial lysate and/or lysate fraction, a Strepioeoccaeeae bacterial lysate and/or lysate fraction, a Bifidobaeteriaceac bacterial lysate and/or lysate fraction, or a SadBaceae bacterial lysate and/or lysate fraction; or a Gram-negative bacterial lysate and/or lysate fraction selected from the group consisting of: a Psewrfowmas bacterial lysate-and/or lysate fraction, a ffle&sielkf bacterial lysate and/or lysate fraction, a.Ληη/Λο/κοηη,ν bacterial lysate and/or lysate fraction, a Shigella bacterial lysate and/or lysate fraction, or a Ltaeriibiicter bacteria! lysate and/or lysate fraction.64. The composition of claim 62, wherein the bacterial lysate and/or lysate fraction is;(a) a Gram-positive bacterial lysate and/or lysate fraction selected front the group consisting of: a &«.·///?/? coagidaiis, Ladohacdkis sperogen&L Streptococcus thamopkde··. fbb'Jnbi/c/t.f't/tm aiuundi.s. /h/fJnJwL'nw? auoualo, subspecies animalis, Bifidobacterium inftwbs, Bifidobacterium loogim, Bifidobaelerium breve, I aeiohaddus addophdus, Lcjctohacidus plaoiantm, LoctobadBus cased Laetobacdhis delbrueekd, Loeiobacdhis ddbrueckd subspecies btbgadcus, Laciococc >ts «\κ ns, boctococcus kidis subspecies iaci/p iactis, Streptococcus tbermopbdus, Bd'idobacterium iadiy Bifidobacterium brew, Bediococcus aciddactieb or Lactohacdhis havauao lysate and'or lysate fraction; or (b) a Gram-negative bacterial lysate and or lysate fraction selected from the group consisting of: a BLebsieda oxytocia, ShigeBafiexit&i, .Saudtomouas emnpnwra, or Bseudomonosfiourescens lysate and/or lysate fraction.65. A method of producing a bacterial lysate comprising the steps of:(a) fermenting a bacterium in a growth medium to the stationary grow th phase to produce a fermentation broth;(b) hart csting bacteria from the fermentation broth;-78WO 2017/083470PCT/US2016/061247 < c) pasteurizing the harvested bacteria; and (d) lysing the pasteurized bacteria with, a lysozyme to produce a bacterial lysate,66. The method of claim 65, wherein the bacteria are harvested hi the mid-logarithmic phase, the late-logarithmic phase, the early stationary phase, the mid-stationary phase, or the late stationary phase,67. The method of claim 65, wherein the-bacterium is a Gram-positive bacterium or a Gmm-negati ve bacterium.68 . The method of claim 67, wherein the Gram-positive bacterium is selected from the group consoling of a bacterium of / at tobaciliaeeae family, a bacterium of Streptococeaceae family, a hactctmm of Bit>daba<. uruh <ce funny, and a bacterium ot Baalim ac family, and wherein the Gram-negative bacterium is selected from the group consisting of a bauent m .4 /\(.-«/',ήο>-ι/ι genus, AA/Cvt Co gunis „s.uus, Uuyeba genus, and Etiierobacier genus.69. The method of cl ai m 67, wherein the Gtam-posttive bacterium is selected horn the group consisting ol Bacillus coagu ferns, lactobacillus sporogeuas, b/reptocoecus thermophihis. Bifidobacterium atdmalis, Bifidobacterium. animalis, subspecies munm/7.y Bifidobacterium biftwti.v, Bifidobacterium iof}gi(w.Bifidobaeteriaw breve, Laciobacilhis oeidopkihis, Lactobacifbtspfaudtruf»,LaetobaeiiBis casei, Laciobacdfus deibmeekii, Ιχι&οΚ/ί rl/uv dcibmcckii subspecies bidgariciis, Luetoeoceus iactis, Lactococcus lactis subspecies lactis, Stnf foc>Kcus lactis, Siixp/OkOt,;o ihenuophihtv, B/fitioiuicit'rium !aam Bdidobiu \>t>iw 6rt\c Pediococcus aciddactici, and LaCtahocillus helveticas; and wherein the Gram-negative bacterium is selected from the group consisting of Klebsiella oxytocia, Shigella flexneri, Xditthomouas campestris, and Pimfawm fltwrescens.711 A bacterial, .lysate produced, according to the method of any one of claims 65-69.-79WO 2017/083470PCT/US2016/06124771. A method for alleviating one or more oxidative stress-related side effects associated 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 (e) an optional carrier for increasing a volume of the composition; wherein the pharmaceutical agent and lysate composition are administered simultaneously or in any order, and through the same or different routes of adniimstration.72. The method of claim 71 „ wherein the lysate and/or lysate fraction activates at least one or more TLRs or NLRs.73. The method of claim 71,, wherein the lysate and/or lysate fraction activates at least two TLRs and/or NLRs.74. The method of claim 71, wherein the lysate and/or lysate fraction activates at least three TLRs and/or NLRs.75. The method of claim 71, wherein the lysate andor lysate fraction act· wares at least one or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NODI, and NOD2.76. The method of claim 71, wherein the lysate and/or lysate fraction activates TLR 2 and TLR 4.77. The method of claim 71, wherein the lysate and/or lysate fraction activates two or more of TLR. 2, TLR 3, TLR 4, TLR 5, TLR T TLR 8, TLR 9, NODI, and NOD2.78. The method of claim ? 1, wherein the lysate and/or lysate fraction activates three or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NOD I, and NOD2..-SOWO 2017/083470PCT/US2016/06124779. The method of claim 71, wherein the.bacterium is a Gram-positive bacterium or a Gram-negative bacterium.80. The method of claim 79, wherein the Gram-positive bacterium is selected from the group consisting of a bacterium of fa&Bbodllac&ae family, a bacterium of StrepPicoceaceac family, a bacterium of Sifdobac/eriaccae family, and a bacterium ofBaeiltaceae family; and wherein the Gram-negative bacterium is selected, from the group consisting of a b'luietmro of /hu/dowr na^ genus, K'^sicl/a genus Vund/owmao genus Sluyet.’a genus, and Enterobaaer genus.81. The method of claim 79, wherein the Gram-positne· haeferniiit is selected bom the group consisting of Bacillus coagulant, Lactobacilhrt sporagenes, Strop,peace, us thertnophtb/s. Bifidobacterium atiitnafis, Bifidobacterium. animtrfts, subspecies anitnabs. Bifidobacterium in fauns, Bifidobacterium in/ignm, Bifidobctctefinni 'veve. Lauobacflhp; acidophilus, Loclobacilluspfantatwn, Lactobacillus caset, Lactohaalhis deibruecktf LacPbacillus defim/eeka subspecies buigariciii,I Ui *.»( buns / I'UU·, stiiwp<.e!vS bi, ,'><· S/Ί pt(h.iK<,’iS hail,Sirepiococcus thermopfnh/'i, Bifidobacterium locus, Btfidobacterium breve. Pediocoecus aetdilaeficf and i.oeiobaeiiiux heiveiteus: and wherein the Gram-negative bacterium is selected from the group consisting of Klebsiella oxytocia, Shtgdla flexnetf Xanthomonax campestris, and Pseudomonas flourescens.82. The method of claim 72, wherein the one or more oxidative stress-related side effects are selected from the group consisting of: aceruloplasminerata, arterial/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, depiction, cluneal depiesston. brain ischemia, bronchopulmonary dysplasia, cardiovascular diseases., cataract, cellulitis, chemotherapeutic side-effect, chronic fatigue syndrome, colitis, coronary artery disease, dyslipidemia, eclampsia, erectile -81 WO 2017/083470PCT/US2016/061247 dysfunction, ataxia, headache, heart failure, hemodialysis side effects, hepatic einhosis, hyperchoiesteredemia, hyperhomocysteinemla, 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, thrdmbophily, tauopathics, unstable angina, uremia, and venous insufficiency.83. A method for treating an oxidative stress-related disease or condition in a subject, the method comprising admmistomg to site subject a therapeutically eft'eeme amount of a composition comprising;(a) a bacterial lysate and/or lysate fraction capable of activating at least one or more toll-tike receptors (TLRs) or Nod-like receptors (NLRsj;lb) an optional promoter for enhancing absorption of the composition; and (c) an optional carrier for increasing a volume of die composition.84. The method of claim 83, wherein the oxidative stress-related condition is aceraloplasminemia, acute and chronic alcoholic liver diseases, acute autoimmune myocarditis, acme chest syndrome of sickle cell disease, acute pancreatitis, acute respiratory distress syndrome, alcoholic livet disease, Amyotrophic Lateral Sclerosis, a'tcrtal systemic hypertension, asbestosis, asthma, ataxia telangiectasia, atherosclerosis, atopic dermatitis, brain, ischemia, bronchopulmonary dysplasia, burns, some cancers, cardiopulmonary' bypass, cardiovascular diseases, cataract, cellulitis, chemotherapeutic side-effect, chronic fatigue syndrome, chronic Hepatitis C, chronic kidney disease, chronic obstructive pulmonary disease, chronic renal failure, colitis, coronary artem disease, Crentofeldi-Jakob disease, Crohn’s disease, cutaneous leishmaniasis, cystic fibrosis, diabetes mellitus type 1, diabetes mellitus type 2, dyslipidemia, Down’s syndrome, eclampsia, end-stage renal disease, erectile dysfunction, Friedreich ataxia, headache, heart failure, He/icoboe/er pylori infectron/inflammation, hemodialysis side effects, hepatic cirrhosis. HumanImmunodeficiency Virus infection. Huntington disease, hyperbaric diseases.-82WO 2017/083470PCT/US2016/061247 hs-pemhoiesterolemia, bypcfeomocyste inemia, hyperlipidemia, idiopathic pulmonary fibrosis, interstitial lung disease, isehemia/reperfusion injury, juvenile chronic arthritis, kidney transplantation failure, leukemia, lung cancer, lung injury, macular degeneration, male infertility, Meniere’s syndrome, meningitis, mild cognitive impairment. Multiple Sclerosis, myelodisplasfic syndromes, myocardial infarction, myocarditis, neonatal bronchopulmonary dysplasia, obesity, osteoarthritis, osteoporosis, pancreatitis, Parkinson’s disease, periodontal disease, peritoneal dialysis side effects, photoageing, post-traumatic stress disorder, precd.mpsia, primary biliary' cirrhosis, broncopnlmonary diseases, progeria, pso.-mis, psoriatic arthritis, pulmonary hypertension, i^dio-therapy side effects, reacti ve arthritis, renal cell carcinoma, respiratory distress syndrome, retinopathy of prematurity, retro!enficolar fibroplasy, rheumatic disease, rheumatoid arthritis, sarcoidosis, sepsis, sickle ceh disease, sleep apnea, spherocytosis, spinal cord Injury, stroke, synocieinopathies, systemic amyloidosis, systemic lupus erythematosus, systemic sclerosis (scleroderma),, thrombophily,. tauopathies, traumatic stress tubercolosis, unstable angina, uremia, venous insufficiency, Weiner syndrome, or Zellweger syndrome.85. The method of claim 83, wherein' fee bacterium is;(a) a Gram-positive bacterium selected from the group consisting of Bacillus cemgnkm··;, Laembaeillus sparogenes. $/reptococcns thermophthts, Bifidobacterium animal fi, Bifidobacterium. amtnahs, subspecies animat ri, Bniiii<i>ifi,it.riam u-fanns. fh}i<]<t\u.ic}iu>n h/ngian, Bmdcbactet nan orere. Lactobacillus acidophilus, Ixtetobaeiikis pkmtanmt, Lactobacillus easel. Lactobacillus delhrueckii, Laclohtii. ’d»c delbrifeekit subspecies bhfgaricus, Lactococcus lacks, Laciacoccus kicks subspecies lac ris Streptococcus ktctis, S/repiotmci.K') thcnnopliilwi, Bitijobiicternnn lacto, Bifidobacterium !mc\c. Pediocoecus> a rdi/u m > and lactobacillus heiveticas· or (h) a Gram-negative baeterimn selected from the group consisting of; Klebsiella aw/omo, Slrigdlafexneri, Xantbomonas campas'tris, and Ps&idamanas foureseetM.86. A method for reducing oxidative stress in a subject., the method comprising.'-83WO 2017/083470PCT/US2016/061247 (a) detennining fee level of oxidative stress fe fee subject by measuring fee amount of isoprostane in fee urine or blood of the subject;(b) administering to the subject an effective amount of a composition comprising:(i) a toll-hke receptor (TLR) agonist comprising at least one lysate and/or lysate fraction from a bacterium, wherein the TLR agonist activates at least one or more 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 fee urine of the subject.87. The method of claim 86, wherein administration of the bacterial lysate is continued until the amount of isoprostane in fee urine of fee subject is less than about 3 ng per mg creatinine, less than about 2 ng per mg creatinine, less than about 1 ng per mg creatinine, or less than about 0.5 ng per mg of creatinine,88. The method of claim 86, wherein the bacterium is a Grain-negative bacterium or a Gram-positive bacterium,89. The method of claim 86., wherein the bacterium is:(a) a Gram-positive bacterium selected from the group consisting of; Baed/us coagulant,, /.octobacidas iporogenc^. ΛΟ cytoeaeetiS Biermapkihis', Bifidobacterium antmalis. Bifidobacterium. aiiimi}fi<:, subspecies aidmaliy. Bifidobacterium infantis, Bifidobacterium /ongm-H, /ri/h/ffoov/er/mH fovrm I.K-tnhaci/lus cu n/ttphiiin / uern/'m. /i/jm/w, / t'umLicn'/.’o iui/i, l,ac {abaci Bus delbmeckii, Lactobacillus delbrueckii subspecies Bulgarians,. Laclococcus toctis, Laetoeoeetfs /aeiis subspecies lactis, Sirepioeomts lactis, Streptococcus iherm&philus. Bifidobacterium lactis, .Bifidobacterium breve, Pediococcus acidilactiei,. and Iacfob.u dtus heivelicus; or (b) a Gnm-negathe bacterium selected from the group consisting of. A/cfo'c/G oxytocia, Sfe/ge/fo fiexnefi, λαΜίιαφαααϊααΜρ&ϊ&ϊΐί, &αά .Pseudomonas //iWft’.'U'ffi-84WO 2017/083470PCT/US2016/06124790. The method of claim 86, wherein the lysate and/or lysate fraction activates at least one or more TLRs or .NLRs,91. The method of claim 86, wherein the lysate and/or lysate fraction activates at least two TLRs and/or NLRs,92. The method of claim 86, wherein the lysate and/or lysate fraction activates at least three TLRs and/or NLRs.93. The method of claim 86, wherein the lysate and/or lysate fraction activates at least one or more of TLR 2f TLR 3f TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NODI , and NOD2,94. The method of claim 86, wherein the lysate and/or lysate fraction activates TLR, 2 and TLR 4.95.. The method of claim 86, wherein foe lysate and/or lysate fraction, activates two or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7/TLR 8, TLR 9, NODL and NOD2.96. The method of claim 86, wherein the ly sate and/or lysate fraction activates three or more of TLR 2, TLR 3, TLR 4, TLR 5, TLR 7, TLR 8, TLR 9, NODI, and NOD2.97. A therapeutic combination comprising;(a) a lysate composition comprising (i) a bacterial lysate and/or lysate fraction capable of acti vating at least one or more toll-like receptors (TLRs) ot Nod-like receptors (NLRs);(ii) an optional promoter for enhancing absorption of the composition; and (iii) an optional carrier for increasing a vol ume of the composi tion; and (h) 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-85WO 2017/083470PCT/US2016/061247 the one or more pharmaceutical agents are administered via the same or different routes of administration.98. The therapeutic combination of claim 97, wherein the lysate composition is administered sublingually or buccally.99. A pharmaceutical formulation comprising the combination of:(a) 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 carriei fot increasing a volume of the composition; and (b) one or more pharmaceutical agent.100. The therapeutic combination of claim 9? or the pharmaceutical formulation of claim 99, wherein. the one or more pharmaceutical agents ate selected from the group consisting of:an antispasaiodic, a motility stimulant, an H2-R.ecepior antagonist, antimusearinic; 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 sequesfmnt, 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 remn-angfotettsta system, a nitrate, a calcium blocker, an antianghiai 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 three fatty acid compound, a CNS drug, an anfi-mfective, or another drug selected from the group consisting of Benztropine, procyclidine, htperiden. Amantadine, Bromocriptine, Pergolide, Entaeapone, Tolcapone, Selegehne, Pramipexole, hudesomde, fermoterol. qnstiapine fumarate, olanzapine, pioglitazoue, monte’ukast. Zoicdronuc .Acid, valsartan, latanoptost, Irbesartan,- 86 WO 2017/083470PCT/US2016/061247Ciopidogrei, Atomoxetinc, Dexamfetamine, Metbyiphcnidate, Modafmil,Bleomycin, Dactinomycin, Datmoftibicm, Idarubicin, Mitomycin, Mitoxantrone, Azacitidise, Capecitabine, Cladribine, Clofarabine, Cytarabine, FludarabinC, Flonronracil, Gemcitabine, mercaptopurine, methotrexate, Nelarabine, Pemetrexed, Raltitrexed, Thioguamne, Apomorphine, Betamethasone, Cortisone, Defiazacort, Dexamethosone, Hydrocortisone, Methylpredaisolone, Prednisolone, Triamcinolone, Ciciosporine, Sirolimus, Tacrolimus, Interferon Alpha, and interferon Beta,101. The therapeutic combination of claim 97 or the phararaceutical formulation-of claim 99, wherein the one or more pharmaceutical agents are selected from the group consisting of;Antispasmodics selected from the group consisting of atropine sulphate, dfeyeloverine hydrochloride, hyoseme butylhrnmine. propantheline bromide, alvcrine citrate, and mebeverine hydrochloride;Motility stimulants selected from the group const sting of metoclorpiamide and domperidone;M2 -Receptor antagonists selected from the group consisting of Cimetidine, faraotidinenizatidine, and ranitidine;Anti mnsearin ies;Chelates selected from the group consisting of Tripotassium dieitoathismufhate and sucralfate;Prostaglandin analogues;Aminosalicylates selected from the group consisting of balsazide sodium, mesalazinc, oisabzine, and suiphasabzine;Corti costeroids selected from the group consisting of beclometasone dipropionafe, budenoside, hydrocortisone, and prednisolone; Drugs affecting immune response selected from the group consisting of eiclosporin, meicaptopurine, methotrexate., adrdimatnab, and infliximab;Stimulant Laxatives selected front the group consisting of bisaeodyl, dantron, docusate, and sodium picosnifate;Drugs affecting biliary- composition and flow;Bile acids sequestrants selected from the group consisting of eoiestyramine,Oxyplsencyclimine, Camyiofm, Mebeverine, Trimebutine, Rociverine,.Dicycloverine, Dihexyverine, Difemerme, Piperidoiate, Benziione, Mcpenzobte, -87WO 2017/083470PCT/US2016/061247Tipcnzolate, GlyeopynOtuum, Oxypheuouium, Penthienate, Mcihantheline, Propantheline, Otilonium bromide, Tridihexethyi, Isoproparaide, HexoeycHwn, Poldine, Bevonium, Diphemand, Tiemonium iodide, Prifini ant bromide,Timepidium bromide, Fenpiverimum, Papaverine, Drolaverine, M.oxaverme, 5-HT3 antagonists, 5-HT4 agonists, Fenpiprane, Dtisopromine, Chiorbenzoxamine, Pinaverium, Fenoverine, Manpratnme, Proxazole, Alverine, Trepsbutone, Isometheptene, Caroverine, Phloroglueinoi, Silicones,Trimediyldiphenylpropylamine, Atropine, Hyoscyamine, Scopolamine,Btitylseojiolamme, .Methylseopofemlne, Methyiafropine, Fentoniuro, Gfrttefropium. bromide, and primarily dopamine antagonists;Proton pump inhibi tors selected from the group consisting of Omeprazole, lansoprazole, pantoprazole, esomeprazoie, and rabeprazole sodium;Opioids and opioid receptor antagonists;Analgesics selected from the group consisting of Acetaminophen,Dicloienae, Difiunisal, Etodolae. Fenoprofen. Flurbiprofen, Ibuprofen, Indotnethaciu, Ketoprofen, Ketorolac, Mcclofcnamate, Mefenamlc Acid, Meioxicam, Nabumetone, Naproxen, Oxaprozin, Phenylbutazone, Piroxicam, Sulindae, Tolmetin. Celeeoxlb, Buprenorphine, Butorphanol, Codeine,Hydroeodone, Hydromorphone, Eevorphanol, Meperidine, Methadone, Morphine, Nalbuphine, Oxycodone, Gxymorphone, Pentazocine, Propoxyphene, and Tramadol;Sleep drugs selected from the group consisting of Nitrazepam, Fiurazepam, Loprazolam, Lormetazepam, Temazepam, Zaleplon, Zolpidem, Zopiclone, Chloral Hydrate, Tridofos. Clomethiazole, Quazepam, triazolam, Estazolam, Clonazepam, Alprazolam, Eszopiclone, Rozercm, Trazodone, .Amitriptyline, Doxcpin, Benzodiazepine drugs,.melatonin, diphenhydramine, and .herbal remedies:Cardiac glycosides selected from lire group consisting of Digoxin and digitoxin;Phosphodiesterase inhibitors selected from the group consisting of enox.imone and milrinone;Thiazides and related, diuretics selected from the group consisting of bendroflumedriazide, Chlortalidbne, cyclopenthiazide, inapamide, metolazone, and xipamidc;Diuretics selected from the group consisting of furosenhde, humetanide, and torasemide;-88WO 2017/083470PCT/US2016/061247Potassium sparing diuretics and aldosterone antagonists selected from the group consisting of annioride hydrochloride, triamterene, vepSerenonc, and spironolactone;Osmotic diuretics;Drugs for arrhythmias selected from the group consisting of adenosine, amiodarone hydrochloride, disopyratnide, fleeaimdc acetate, propafenone hydrochloride, and lidocaine hydrochloride;Beta adrenoreceptor blocking drugs selected from the group consisting of propanalol, atenolol, acebutolol, bisproloi futtiarate, earvedilol, eeliproiol, esmoloi, lehatolol, metoprolol tartrate, nadolol, nebivolol, oxprenolol, pindolol, solatol, and tlnrolol;Hypertension drugs selected from the group consisting of amhrisentan, bosenran. diazoxide, hydralazine, iloprost, minoxidil,, sildenafil, sitaxentan·. sodium nitroprusside, clonidhte, mcthyldopa, moxonidinc, guanethidme monosulphate, doxazosin, indoranrin, prazosin, terazosin, phenoxybenzamine, and phentoianune mesilaie;Drugs affecting the reuin-angiotensin system selected from the group consisting of (. aptropnl, Cib/aprd Enalaprd Maleate, tosmopril Imidaptii. Lisinopril, Moexiprsi, Perindopril Brbumine, Quinapril, Ramipril, Trastdolapril, Candesartau CilexetiS, Bprosartan, Irhesartan, Losartan, Olmesartau Medoxotml, Tehnisartan, Vaisartan, and Aiiskiren;Nitrates, calcium channel Blockers, and antianginai drugs selected from the group consisting of Glyceryl trinitrate, Isosorbide Dinitratc. isosorbide Mononitrate, Aralodipine, Diliiazem, Felodipine, Isradipine, Lacidipine, Lercanidipine, Nicardipine, Nifedipine, Nimodipine, Verapamil, Ivabradine, NicorandiL and Ranolazine;Peripheral Vasodilators and related drugs selected from the group consisting of Cilostazoi, 1 nesitol Nicotinate, Moxisylyte, Naftidrofuryl. Oxalate, and Pentoxifylline;Sympathomimetics selected from the group consisting of Dopamine, Dopexamine, Ephedrine, Metaraminol, Noradrenaline Acid Tartrate, Norephitirine Bitartraie, and Phenyiephidrine;Anticoagulants and Protamine selected from the group consisting of Heparin,Bemiparin, Daheparin. Enoxaparin, Tinzaparin, Danaparoid, Bivalirudin, Lepirudm, - 89 WO 2017/083470PCT/US2016/061247EpoprostenoL Fondaprittux, Warfarin, Aeenocoumarol, Phenindione., DahigatrauEtexilate, Rivaroxaban, and Protamine Sulphate;Antiplatelei Drugs selected from the group consisting of Abaximab, Aspirin,Ciopidogrel, Dipyridamole. Eptifibatidc. PrasugrcL and Tiroftban:Fibrinolytic and andfibrinolytic drugs selected from the group consisting of Aiteplase, Reteplase, Streptokinase, Tenecteplase, Urokinase, Etamsylate, and Tranexamic Acid;Lipid Regulating Drugs selected from the group consisting of Atorvastatin, Pluvastafln, Pravastatin, Rosuvastatin, Simvastatin. Colesevam, Colestyramine, Colestipol, Ezetintibe, Bezafibtate, Cipirifsbrafe, Fenofifote, Gemfihrozyi,Aeipmox, Nictodnie Acid, Omega three fatty acid compounds, Ethanolamine Oleate, and Sodium Tetradecyl Suphate;CNS'· Drugs selected from the group consisting of Benperidol, Chiorproniazine, Flupentixol, Haloperidol, Levomepromazine. Pcrieyarinc, Perphenazine, Pimozide, Prochlorperazine, Promazine, Sulpiride, Trifluoperazine, Zuclopenthixol, Amisulpride, Aripipraxole, Clozapine, Olanzapine, Pahpcridone, Quefiapine, Riperidone, .Sertindoie, Zoteplne, Flupenfixol, Fluphenaziue, Olanzapine Embonate, Pipotiazine Palmitate, Risperidone, Ztielopenihixoi Decanoaie, Carbamazepine, Valproate, Valproic acid. Lithium Carbonate, Lithium Citrate, Amitriptyline, Clomipramine, Dosulepin, Imipramine, Lofepramine, 'Nortriptyline, Trimipramine, mianserin. Trazodone, Phenelzine, Isocarboxazid, Tranylcypromine, Moelohemide, Ciialopram, Esciialopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Agomelatine, Duloxetlne, Flupentixol, Mirtazapine, Reboxetine, Trytophan, Venflaxine, Atomoxetine, Dexaineiatnine, Methylphenidaie, Modafinil, F-dtcaibazcpme, Ctearbazepene Fthosuxmnde, Gabapentm, Pregahabn I aeosanude. Lamotrigine, Leveriracefam, Phenobarbital, Primidone, Phenytoin, Rufinamide, Tiagabine. Topiramafe, Vjgabauin, Zonisamtde, ropinirole, Rotigotine, CoBeneldopa, Levodopa, Co-Careldopn, Rasagihne, Selegiline, Entaeapone,Tolcapone, Amantidiue, Orphenadrine, Proeyclidine. Trihexyphenidyl, Haloperidol, Piracetam, Riluzole, Teriabenazine, Acamprosate, Disuifiram, Bupropion, Varcaiciline, Buprenorphine, Lofexidine, Donepezil, Galantamine, Memantine, and Rivastigimine;Anti-Infeetives selected, from the group consisting of BenzsdpenfeiHin,Phenoxymefhylpented (in, FlucloxaeHhn, Temocsllin, Amoxicillin, Ampiesllin, Co-90WO 2017/083470PCT/US2016/061247Amoxielav, Co-Phiampieil, Piperaeiiiin, Tieareiilin, Pivineciliinam, Cephalosporins, Cefaclor, Cefedroxd, Ccfalexin, Cefixime, Cefotaxime, Cefradine, Ceftazidime, Cefuroxinie, Ertapenem, Innpenern,Meropenem, Aztreonam, Tetracycline, Demeclocycline, Doxocycline, Lymeeyciine, Minocycline, Oxytciraeydine, Tigeeycline, Gentamicin, Amikacin, Neomycin, Tobramycin. Erythromycin, Azithromycin, Clarithromycin, Tetithromycin, Clindamycin, Chloramphenicol, Fosidie Acid, Vancomycin, Teieoplanin, Dapiomycin, Linezolid, Qninnpristin, Colistin, Co-Trimoxazole, Suipadiazine, Trimethoprim, Capreomyein, Cycloserine, Ethambutol, Isoniazid, Pvrazinamide, Rifabutin, Rifampiein, Streptomycin,Dapsone, Clofazimine, Metronidazole, Tmidazole, Ciproflaxacin, LevOilaxacin, Moxiftoxacm, Nalidixic Acid, Norflaxine, Orflaxacln, Nitroftirantoin, Methenamine Hippurate, Amphotericin, Anidnla&ngin, Caspofnngin, Fluconazole, Flucytosine, Griseotluvin, Iteaconzole, K.etoconazole, Mieafungiu, Nystatin, Posacoimzole, Terbinafine, Voriconazole, Ahacavir, Didanosine, Emtrieitabine, Lammsdine, Stavudine, Tenofovir Disoproxil, Zidovudine, Atazanavir, Daronavir,Fosatnprensvir, Indinavir, Lopinair, Neifinavir, Ritonavir, Saquinavir, Tipranavir, Efavirenz, Etravirine, Nevarapine, Ettfuvirtide, Marsviroe, Rsitegrsvir, Acidovir, Famddovir, Inosine Pranobex, Valaeiclovir, Cidofovir, Gangciciovtr, Foseamet, Valgangcielovlr, Adefovir Dipivoxii, Entecavir, Tdbivudine, Amantadine, Oseitauuvir, Zanamivir, Pali vizumah, Ribavirin, Artemefeer, Chloroquine, Mefloquine, Primaquine, PrognaniS, Pyrimethamine, Quinine, Doxycyelm, Diloxanide Furoatc. Metronidazioic Tmidazole, Mepacrine, Sodium Stibogluconate, Atovaquone, Pentamidine hetionate. Mebendazole, and Piperazine, andOther drugs selected from the group consisting of Benznopine, procyclidine, biperiden, Amantadine, Bromocriptine, Pergolide, Bntacapone, Tolcapone, Sdegeline, Pramipexole, bndesonide, formoteroh qnefiapinc fumarate, olanzapine, pioglitazone, montdukast, Zoledfomic Acid, valsarian, latauoprost, irbesartan, CiopidogreS, Afomoxetine, Dcxarnfetamine, Metbylphenidate,. Modafinil,Bleomycin, Dactinomycin, Daunorubicin, Idarubicin, Mitomycin, Mitoxantrone, Azaeitidine, Capeeitahine, Cladribine, Ciofiirabine, Cytarabine, Fludarabine, PlonrQuraeil, Gemcitabrne, mercaptopurine, methotrexate, Neiaiabine, Pemetrexed, Raltitrexed, Thioguanine, Apomorpliine, Betamethasone, Cortisone, Deilazaeort, Dexamethosone. Hydrocortisone, Meihyipreduisolone, Prednisolone, Triamcinolone,CiciospOfine, Snohruus, Taemlimus, Interferon Alpha, and Interferon Beta,-91 WO 2017/083470PCT/US2016/061247102, A formulation comprising (a) a ly sate 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 composi tion;and (iii) an optional carrier for increasing a volume of the composition; and (b) an isolated human anh-TNFalpha antibody or antigen-binding fragment thereo f or TNF inhibitor.103. The formulation of claim 102, wherein the human anti-TNFaipha antibody or antigen-binding fragment thereof is adalimumab..104, The use of the formulation of claim 103 in the manufacture of a medicament for the treatment of rheumatoid arthritis (RA), latc-onset RA, or psoriatic arthritis in a subject,105. A. method for the treatment of rheumatoid arthritis (RA), late-onset RA, or psoriatic arthritis in. a subject, the method comprising administering, to the subj ect a therapeutically effective amount of the formulation of claim 102.100. The method of claim 105, wherein the human ant.t-TN'Falpha antibody or antigenbinding fragment thereof is administered to the subject in a biweekly dosing regimen.107, The method of claim 105, wherein the human anti-TNFaipha antibody or antigenbinding fragment thereof is administered to the subject in a dose of 30 mg or greater..108. The method of claim 105, wherein the TNFaipha inhibitor a TNFaipha fusion protein.-92WO 2017/083470PCT/US2016/061247109. The method of claim 108, wherein the TNFalpha· fusion protein is etanercept1 ί 0, The metirod of claim 105, wherein the anti-TNFalpha antibody or antigen-binding fragment thereof is infliximab or golimumab.11.1. The method of claim 105, wherein the anti-TNFaipha antibody or antigen-binding fragment thereof is adahtnnmab.112. The method of c laim 105, wherein the anti-TNFalpha antibody or antigen-binding fragment thereof is adalimutnab.-93WO 2017/083470PCT/US2016/0612471/20LUΟίCL CLTf fii te!CL CL _< Oi a aCL CL
1 ¢4 <C H-t I——> —> o oo <N> QxccxQ psssoxp xfoxcx O—-—'·χιCccccsxjSUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/0612472/20Human TLR/NLR ScreeningFIGURE 2UIU099 Xjisuea |eoRdoSUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/0612473/20FIGURE 33.500o o o o o lh o o o O O lh o o o o o LH cn rsi rsj t—i t—i ό SUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/0612474/20LH CM LH τ—I LH O LH rsi τ-i ό OISUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/0612475/20 cnFIGURE 5SUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/0612476/20 <OLU oiCMLO ω<DQ.= E o ro o o LU X ωc <DO ω, E ±3 c o o *□ ΪCO LO c\iLO O LO o oSUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/0612477/20FIGURE 7SUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/0612478/20FIGURE 8SUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/0612479/20Τ- C\l CO LO CD l·- Ο o o o O O O CL CL CL CL CL CL CL 4mmQuality of SleepC\l O 00 CD C\l oA}i|neoFIGURE 9SUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/06124710/20Τ- C\l CO LO CD l·- Ο o o o O O O CL CL CL CL CL CL CL HHIHNeuropathyO 00 CD C\l oFIGURE 10C\lX»!ienoSUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/06124711/20Τ- CM CO LO CD l·- Ο O o o O O O CL CL CL CL CL CL CL HHHIMoodCM O 00 CD CM OX»!|enoFIGURE 11SUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/06124712/20Τ- CM CO LO CO l·- Ο O o O O O O CL CL CL CL CL CL CL HHHIEnergyFIGURE 12SUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/061247 - 13/20
Τ- C\l CO LO CD l·- Ο o o o O O O CL CL CL CL CL CL CL BBiHJointsFIGURE 13AliienoSUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/061247 - 14/20
Τ- CM CO ^7 LO CO l·- Ο O o O O O O CL CL CL CL CL CL CL Digestive healthO 00 CO ^7 CM OFIGURE 14CMX»!ienoSUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/061247 - 15/20
Τ- C\l CO LO CD l·- Ο o o o O O O CL CL CL CL CL CL CL HHHIIrritabilityFIGURE 15A»!ienoSUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/061247 - 16/20
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Τ- CM CO m CD l·- Ο O o o o O O CL CL CL CL CL CL CL Satisfaction with life scaleCO CO CM CMO >>CDQ m>sCDQ >sCDQ euoog uoijoejsijesFIGURE 18SUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/061247 - 19/20
Τ- CM CO ^7 LO CO l·- Ο O o O O O O CL CL CL CL CL CL CL Zung self-reported depression scale00 h- CO LO CO CM oΓ>>CDQCDQCDQFIGURE 19 euoog uoisseudegSUBSTITUTE SHEET (RULE 26)WO 2017/083470PCT/US2016/061247 - 20/20 ¢18888.>888888888848888888;•^C-X-X-X· σ>ooLO oo * >88888 88888888«88^888888888 «C „ 888888888 88888888 Λ. 88888888«17 y/o Male 3x Concussion in 1.5 Yrs. Isoprostane8888888888888888888888888888888888«8888888888888888888888888888888« oo hhoo hσ>coIDCDCD l·LD coID σ>^ID ^hoo co co σ>CNIDCNCN l·00FIGURE 20 >88888888888888888888^88888888888888888888888888888888888888888888888CQ σ>X-X-X-S^X-X-X-X-X-X-X-X-X-X-X-X-X-SX-X-X-X-X-X-X-X-X-X^ •8888888888888888888888888 88888888jg888888888888888888888888888888888888888888888888« X88888888888888888888888888888<$8888888888888888888888®888888888888888888888888888888888888888888i888888CN O CO CD ’st CN O (βω/βιι) <1SUBSTITUTE SHEET (RULE 26)
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CN108949640B (en) * | 2018-08-22 | 2020-08-04 | 江南大学 | Bifidobacterium breve CCFM1025, fermented food thereof and application thereof |
CN109568320A (en) * | 2018-12-13 | 2019-04-05 | 中国人民解放军总医院 | Etravirine is preparing the application in antibacterial-anti-inflammatory drug |
CN109912598B (en) * | 2019-03-27 | 2022-09-13 | 四川大学华西医院 | Nucleoside derivative for preventing and treating inflammatory reaction and application thereof |
CN110106111B (en) * | 2019-05-06 | 2021-04-02 | 华东理工大学 | Preparation method of pseudomonas preparation, preparation product and application of preparation product |
JP7369992B2 (en) * | 2019-05-13 | 2023-10-27 | 株式会社明治 | Fermented milk for improving autonomic nervous function |
CN110079485B (en) * | 2019-05-31 | 2020-09-25 | 江南大学 | Pediococcus acidilactici CCFM6432 for relieving depression, fermented food thereof and application thereof |
DE112020002996T5 (en) * | 2019-08-05 | 2022-05-19 | Agency For Science, Technology And Research | Polylysine polymers with antimicrobial and/or anticancer activity |
CN110604098B (en) * | 2019-09-23 | 2021-09-07 | 广东省中医院(广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院) | Method for constructing animal model of rheumatoid arthritis combined with interstitial lung disease |
CN111849805B (en) * | 2020-06-17 | 2022-04-22 | 天津科技大学 | Pediococcus acidilactici with cervical cancer resistance effect and application thereof |
CN117377480A (en) * | 2020-10-14 | 2024-01-09 | 音芙医药科技(上海)有限公司 | Application of nicotinamide mononucleotide and lactobacillus fermentum in preparation of preparation for relieving skin photoaging |
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CA3223348A1 (en) * | 2021-07-09 | 2023-01-12 | Claudio De Simone | Species, strains and compositions of lactic acid bacteria capable of modulating body oxygenation by increasing hif-1.alpha. levels |
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