CN108430482A - The control of cell Redox level - Google Patents

The control of cell Redox level Download PDF

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CN108430482A
CN108430482A CN201680075757.4A CN201680075757A CN108430482A CN 108430482 A CN108430482 A CN 108430482A CN 201680075757 A CN201680075757 A CN 201680075757A CN 108430482 A CN108430482 A CN 108430482A
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bifidobacterium
lysate
bacterium
lactobacillus
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伊丽莎白·麦克纳
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Abstract

Disclosed herein is the composition and method of redox state and/or reduction oxidative stress for regulating and controlling subject, the method and composition include TLR agonists, and the TLR agonists include bacterial lysate and/or lysate fraction.There is disclosed herein composition and method comprising bacterial lysate and/or lysate fraction, the bacterial lysate and/or lysate fraction with and one or more other therapeutic agents or medicament combination and prepare or apply.

Description

The control of cell Redox level
Cross reference to related applications
This application claims the priority for the U.S. Provisional Application No. 62/253,542 that on November 10th, 2015 submits.The application Or the part continuation application for the U.S. Application No. 14/640,075 submitted on March 6th, 2015, is that September in 2013 carries on the 23rd The continuation application of the U.S. Application No. 14/034,044 of friendship requires the U.S. Provisional Application No. submitted on the 21st of September in 2012 61/704,090 priority.The part for the U.S. Application No. 13/743,194 that the application or on January 16th, 2013 submit after Continuous application, requires the priority for the U.S. Provisional Application No. 61/586,975 that on January 16th, 2012 submits.All above-mentioned Shens Please it is incorporated herein by reference in their entirety.
Background technology
Innate immune response is one of the approach for regulating and controlling inflammation.Inflammation by the chemokines that are discharged by damaged cell come Stimulation, and the physical barriers for establishing anti-infective diffusion, and promote the healing of any damaged tissues after pathogen removing.It is acute The process of inflammation by being present in a organized way in cell start, mainly resident macrophages, dendritic cells, tissue are thin Born of the same parents, Kupffer cell and mast cell.These cells, which are presented, is included in surface or intracellular receptor, referred to as pattern recognition receptors (PRR), identification shared extensively by pathogen but with the differentiable molecular pattern of the molecular pattern of host.These molecular patterns are united Referred to as pathogen associated molecular pattern (PAMP).When one of PRR identifies PAMP and responds release inflammation mediator, exempt from The experience activation of epidemic disease cell.
Therefore, PAMP is structure associated with the pathogen group identified by innate immune system cells.It is a large amount of different Chemical type can be used as PAMP, including glycan and glycoconjugate.These structures are referred to as guarding in a quasi-microorganism Small molecule block.They by plant and animal Toll-like receptor (TLR) and other PRR identify.
TLR is conservative receptor, can recognize that the structure from bacterium, fungi, protozoan and virus.Although TLR by Body is located at plasma membrane surfaces, but and the combination of receptor be that cross-film is transmitted and intercellular signal is caused to conduct response.TLR signals are final Lead to the gene for inducing or inhibiting to coordinate inflammatory response.For example, the activation of specific TLR causes a series of intracellular events, cause It is characterized in that generating the immune response of proinflammatory cytokine.TLR signal transductions originate from cytoplasm Toll- interleukin 1s (TIR) structural domain is conservative in all TLR.Adapter molecule MyD88 containing both TIR structural domains and death domain It is related to the TIR structural domains of TLR and IRAK albumen.The phosphorylation of IRAK causes and the correlation of TRAF6 and subsequent NF- κ B Activation and proinflammatory cytokine secretion.Previously it is proved the immunological regulation egg from vaccinia virus (vaccinia virus) White A52R is the intracellular inhibitor of TIR dependent signals conduction.When being expressed in HEK293 cells, A52R is shown as responding Inhibit NF- κ B in the stimulation of various TLR (combination for including TLR4, TLRS and TLR2 and TLR6 and TLR2 and TLR1) Activation.In addition, a kind of synthetic ligands Polys (1 of the A52R in response to TLR3：0) inhibit NF- kB activations.TLR3 and antiviral elder generation Nature immune response is related.
One of the main response of activation is to change the redox state of cell.Reactive oxygen species (ROS) can be used for preventing Imperial purpose.Exactly the presence of ROS consumes antioxidant (reducing agent) and leads to more oxidisability redox states.ROS and Oxidizing condition can not only cause the activation of cellular damage and gene, redox state itself that can also control gene table It reaches.For example, when condition becomes more to aoxidize, the sulfydryl on oxidizable chemical group such as certain albumen can be aoxidized.Then The state of oxidation for identifying these albumen leads to the activation of specific gene, such as control redox state and promotion or control The gene of inflammation, or generate the gene of exception or disease promotion albumen.
Inflammation is complex biological response of the bodily tissue to noxious stimulus (such as pathogen, damaged cell or stimulus) A part.Autoimmune disorders may also lead to inflammation (when bodily tissue is mistakenly identified as external).Inflammation It is initially as the protective response for being related to immunocyte, blood vessel and molecule mediator.One purpose of inflammation is to eliminate cell The initial reason of injury removes the non-viable non-apoptotic cell and tissue being damaged in original damage and inflammatory process, and starts tissue repair. Conceptive differentiation inflammation and infection are useful, and there is wherein inflammation is not to be invaded by microorganism or infected many pathology of driving Situation, such as atherosclerosis, type III hypersensitivity, wound and ischemic.There is also wherein microorganism invasion will not cause through The pathologic condition of allusion quotation inflammatory response, such as eosinophilia.However very few inflammation may lead to harmful " invasion Person " (such as cell of bacterium, virus and mutation) progressive disorganization and the survival for damaging organism, excessive inflammation ( In the case of chronic inflammation) host disease may be caused, such as Hay Fever, periodontitis, atherosclerosis, rheumatoid arthritis Even cancer (such as gallbladder cancer).
The startup of redox variation and the resulting inflammatory response to pathogen are the elder generations for infection control The key components of nature immune response.Since the lasting generation of inflammation mediator may lead to chronic inflammation, tissue damage Develop with disease, so inflammation is usually by tight control.The signal cascade and climax gene started by PAMP/TLR interactions Activation is related to many morbid states, including septicemia, autoimmune disease, asthma, heart disease and cancer.For example, it is assumed that When bacterium and its uncontrolled Hosts mediator of product activation (such as may lead to multiple organ failure, cardiovascular failure With dead proinflammatory cytokine) network when septicemia occurs.Abnormal TLR signal transductions response may cause excessive thin Born of the same parents activate response, lead to septicemia.
Inflammation (either chronic or acute) due to and cause to generate and release from impaired and/or inflammatory tissue It puts free radical and other ROS increases, and therefore lead to or cause oxidative stress.Meanwhile when ROS injury tissues, inflammation It may be caused by oxidative stress.Therefore, inflammation and associated various illnesss can also be considered as " oxidative stress relevant disease Or illness ".Other redox levels that stress be also resulted in such as psychological stress change, and lead to oxidative stress or even inflammation. When redox state causes oxidative stress status, positive feedback loop in this way, the state can be continued with self.Oxidation Property redox state and oxidative stress should be happened in determining position and finite time.When oxidisability redox state When position is improper and/or continues the long time, there are pathology or morbid states.It is inappropriate caused by chronic or acute inflammation Redox state or oxidative stress enhance various pathology or morbid state, and vice versa.
Oxidative stress is the pathological forms of oxidisability redox state, is related to ROS (including the freedom of abnormal incrementss Base) damaging action.Free radical is single atom or molecule, with it is at least one by Single Electron (" unpaired ") rather than The external electrical track of two electronics (" pairing ") " occupying ".The presence of unpaired electron so that free radical compounds are extremely living Jump.They may spontaneously react and therefore damage a large amount of crucial cellular elements.A certain number of ROS including free radical It is generated naturally due to cell metabolism.For example, the synthesis of some hormones is related to the generation of free radical, and polymorphonuclear leukocyte It is thin that (polymorphonuclear leukocytes) uses the generation of free radical to be killed as a kind of form of " chemical warfare " Thus bacterium protects the body from infection.Other free radicals such as nitric oxide (NO) is the basis of body stable state, because of their conducts Chemical messenger adjusts critical function, including vascular tone, platelet aggregation, cell adherence etc..
Free radical have it is potential dangerous because they spontaneously tend to fill them with the second electronics it is unfilled External orbital.Two electronics are in the condition that the presence of same track is maximum stability-least energy.Therefore, when free radical with When " target molecules " with one or more " available " electronics such as monounsaturated fatty acid molecule (such as arachidonic acid) collision, It is immediately from target molecules " extraction " electronics.Since this effect-" oxidation "-original free radical loses its potential danger Property, and newly-generated molecule quilt " oxidation ", and transfer to be likely to become new free radical, so if available without antioxidant In inhibiting it, then make reaction permanence.Reaction can continue to other molecules, including carbohydrate, lipid, amino acid, peptide, Albumen, nucleotide, nucleic acid etc. (" chain reaction effect ").This effect of free radical may cause different degrees of tissue to damage Wound, and (or on the contrary due to) inflammatory response may be caused.The initial or major site of ROS releases can be to invading micro-organism Appropriate response, but invader is not destroyed, or if Redox homeostasis does not restore after invader destroys, oxidation is also Original state, which may be spread, and the second lasting oxidisability redox state may cause has chronic, the damage of tissue damage Venereal disease is of science.Another example is traumatic brain injuries to do harm to (TBI), leads to the local inflammation in brain and oxidisability redox shape State.If stable state cannot be rebuild, chronic oxidative redox state may lead to chronic tissue damage and chronic trauma brain Sick (CTE).
Therefore there are the needs to composition and method for controlling cell Redox level in the art.
Invention content
Method disclosed herein and composition are not limited to specific advantage or function.
On the one hand, present disclose provides the toll samples receptors (TLR) of the redox state for regulating and controlling subject to swash Dynamic agent composition, the composition include：(a) at least one lysate comprising bacterium and/or the TLR of lysate fraction excitements Agent, wherein at least one or more of TLR or NLR of TLR agonist activations；(b) it is used to enhance the optional rush of composition absorption Into agent；(c) it is used to increase the optional carrier of composition volume, wherein can measure using a effective amount of composition to subject It is horizontal that ground reduces the oxidative stress in subject.
On the other hand, present disclose provides regulation and control subject redox state method, the method includes to Subject in need applies the cracking compositions according to the disclosure of therapeutically effective amount.In some embodiments, pass through The variation of isoprostane concentration in subject is measured to assess redox state regulation and control.
On the other hand, present disclose provides regulation and control subject redox state method, the method includes with Lower step：(a) dosage for separating on subject in need repeatedly administration time and being made of composition, the composition packet Contain：(i) at least one lysate comprising bacterium and/or toll samples receptor (TLR) agonist of lysate fraction, wherein institute State agonist activation at least one or more of different TLR or NLR；(ii) it is used to enhance the optional accelerating agent of composition absorption； (iii) is used to increase the optional carrier of composition volume, and (b) measures the body fluid of subject to detect oxidative stress water Flat variation.
On the other hand, present disclose provides the method for the amount of isoprostane in the urine for reducing subject or blood, institutes The method of stating includes the following steps：(a) urine of subject or the level of isoprostane in blood are determined；(b) it is applied to subject A effective amount of composition, the composition include：(i) include at least one bacterial lysate and/or lysate from bacterium Toll samples receptor (TLR) agonist of fraction, wherein at least one or more of different TLR of the TLR agonist activations or NLR；(ii) is used to enhance the optional accelerating agent of composition absorption；And (c) continue to apply composition the urine until subject The horizontal of isoprostane is reduced in liquid or blood.
On the other hand, present disclose provides composition, the composition includes：(a) it can activate at least one or more The bacterial lysate and/or lysate fraction of kind toll samples receptor (TLR) or Nod samples receptor (NLR)；(b) it is used to enhance combination The optional accelerating agent that object absorbs；(c) it is used to increase the optional carrier of composition volume.
On the other hand, present disclose provides include the pharmaceutical preparation for cracking compositions according to the disclosure, wherein institute It states pharmaceutical preparation and is prepared for cheek or sublingual administration.In some embodiments, pharmaceutical preparation is formulated into after application not It is dissolved in less than 1 minute.
On the other hand, present disclose provides the method for production bacterial lysate, this approach includes the following steps：(a) will Bacterial fermentation in growth medium is to stablizing growth period to generate zymotic fluid；(b) bacterium is collected from zymotic fluid；(c) it will receive The bacterium obtained carries out pasteurize；And (d) with the bacterium of lysozyme lysis pasteurize to generate bacterial lysate.At some In embodiment, bacterium is harvested in mid-log phase, late log phase, stationary phase early stage, middle stable phase or stationary phase in later stage.
On the other hand, present disclose provides the bacterial lysates generated according to method comprising the following steps：(a) it will give birth to Bacterial fermentation in long culture medium is to stablizing growth period to generate zymotic fluid；(b) bacterium is collected from zymotic fluid；It (c) will harvest Bacterium carry out pasteurize；And (d) with the bacterium of lysozyme lysis pasteurize to generate bacterial lysate.In some realities It applies in mode, bacterium is harvested in mid-log phase, late log phase, stationary phase early stage, middle stable phase or stationary phase in later stage.
On the other hand, present disclose provides for mitigating and applying the relevant one or more oxidative stress phases of medicament The method for closing side effect, the method includes the cracking compositions of therapeutically effective amount, the lysate are applied with pharmaceutical agent combinations Composition includes：(a) lysate of bacterium and/or lysate fraction；(b) it is used to enhance the optional accelerating agent of composition absorption； (c) it is used to increase the optional carrier of composition volume；Wherein, while or in any order and passing through identical or different application Approach applies medicament and cracking compositions.
On the other hand, present disclose provides the sides for treating oxidative stress relevant disease or illness in subject Method, the method includes applying the composition of therapeutically effective amount to the subject, the composition includes：(a) it can activate The bacterial lysate and/or lysate fraction of at least one or more of toll samples receptor (TLR) or Nod samples receptor (NLR)；(b) Optional accelerating agent for enhancing composition absorption；(c) it is used to increase the optional carrier of composition volume.
On the other hand, present disclose provides the method for the oxidative stress for reducing subject, the method includes： (a) level of the oxidative stress in subject is determined by the amount of isoprostane in the urine or blood of measurement subject；(b) A effective amount of composition is applied to subject, the composition includes：(i) include at least one lysate from bacterium and/ Or toll samples receptor (TLR) agonist of lysate fraction, wherein at least one or more of TLR of the TLR agonist activations or NLR；(ii) is used to enhance the optional accelerating agent of composition absorption；And (c) continue to apply composition until oxidative stress Level reduces, and is determined by the decrement of isoprostane in the urine of subject.
On the other hand, present disclose provides Therapeutic combinations, the combination includes：(a) compositions are cracked, it includes (i) bacterial lysate and/or the cracking of at least one or more of toll samples receptor (TLR) or Nod samples receptor (NLR) can be activated Object fraction；(ii) it is used to enhance the optional accelerating agent of composition absorption；(iii) is used to increase the optional load of composition volume Body；(b) one or more medicaments；Wherein, while or application cracking compositions and one or more medicaments in any order, And wherein, via identical or different administration method application cracking compositions and one or more medicaments.
On the other hand, present disclose provides the pharmaceutical preparations for including following combination：(a) compositions are cracked, it includes (i) bacterial lysate and/lysate of at least one or more of toll samples receptor (TLR) or Nod samples receptor (NLR) can be activated Fraction；(ii) it is used to enhance the optional accelerating agent of composition absorption；(iii) is used to increase the optional carrier of composition volume； (b) one or more medicaments.In some embodiments, one or more medicaments are selected from the group being made up of：It is anti- Spasm agent, motion stimulant, bisfentidine, muscarine antagonist；Chelating agent, prostaglandin analogue, aminosalicylate, Corticosteroid, the drug for influencing immune response, irritant purgative, the drug for influencing bile composition and flowing, bile acid chelating Agent, Dopamine D2 receptor, proton pump inhibitor, opioid, opioid receptors antagonist, antalgesic, sleep drug, Cardiac glycoside, phosphodiesterase inhibitors, thiazide, diuretics, Potassium-sparing diuretic, aldosterone antagonists, osmotic diuresis agent, the rhythm of the heart Arrhythmic agents, beta-adrenoceptor blocking drug object, hypertension drug, drug, the nitric acid for influencing renin-angiotensin system Salt, calcium blockers, antianginal drug, peripheral vasodilator agent, parasympathomimetic agent, anti-coagulants, nucleoprotamine, antiplatelet Drug, fibrinolytic drug object, Antifibrinolytic agents, regulation and control Lipid pharmaceutical, omega-fatty acid compound, CNS medicines Object, anti-infectives, or another drug selected from the group being made up of：Benzetropine, the third ring pyridine, Biperiden, adamantane Amine, bromocriptine, pergolide, Entacapone, Tolcapone, selegiline, Pramipexole, budesonide, Formoterol, fumaric acid Quetiapine, Olanzapine, pioglitazone, montelukast, zoledronic acid, Valsartan, Latanoprost, irbesartan, clopidogrel, Atomoxetine, Dexamfetamine, ritalin, modafinil, bleomycin, D actinomycin D, daunorubicin, idarubicin, rice support are mould Element, mitoxantrone, azacitidine, capecitabine, Cladribine, clofarabine, cytarabine, fludarabine, fluorouracil, Ji His shore of west, mercaptopurine, methopterin, nelarabine, pemetrexed, Raltitrexed, thioguanine, apomorphine, betamethasone, can Pine, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, Triamcinolone acetonide, cyclosporin, west Luo Mosi, tacrolimus, interferon-' alpha ' and interferon beta.
On the other hand, present disclose provides preparation, the preparation includes：(a) compositions are cracked, it includes (i) energy Enough activate the bacterial lysate and/or lysate grade of at least one or more of toll samples receptor (TLR) or Nod samples receptor (NLR) Point；(ii) it is used to enhance the optional accelerating agent of composition absorption；(iii) is used to increase the optional carrier of composition volume；With (b) the people's anti-TNF alpha antibodies or its antigen-binding fragment or tnf inhibitor detached.In some embodiments, people's anti-TNF alpha is anti- Body or its antigen-binding fragment are adalimumabs.On the other hand, present disclose provides this preparations to prepare for treating Purposes in the drug of the rheumatoid arthritis (RA) of subject, Delayed onset RA or psoriatic arthritis.On the other hand, originally Open rheumatoid arthritis (RA), the method for Delayed onset RA or psoriatic arthritis provided for treating subject, institute The method of stating includes that this preparation of therapeutically effective amount is applied to subject.
In any method disclosed herein or some embodiments of composition, the bacterium is Gram-positive or leather Gram-negative bacteria.In any method disclosed herein or some embodiments of composition, gram-positive bacterium is selected from By the bacterium of Bacillus acidi lactici (Lactobacillaceae) section, the bacterium of streptococcus (Streptococcaceae) section, bifid bar The group of the bacterium of bacterium (Bifidobacteriaceae) section and the bacterium composition of bacillus (Bacillaceae) section.At some In embodiment, gram-positive bacterium is selected from by bacillus coagulans (Bacillus coagulans), gemma Bacillus acidi lactici (Lactobacillus sporogenes), streptococcus thermophilus (Streptococcus thermophilus), animal bifid bar Bacterium (Bifidobacterium animalis), Bifidobacterium (Bifidobacterium), animal (animalis), subspecies are dynamic Object (subspecies animalis), bifidobacterium infantis (Bifidobacterium infantis), bifidobacterium longum (Bifidobacterium longum), bifidobacterium breve (Bifidobacterium breve), Lactobacillus acidophilus (Lactobacillus acidophilus), lactobacillus plantarum (Lactobacillus plantarum), cheese lactic acid bar Bacterium (Lactobacillus casei), lactobacillus delbrueckii (Lactobacillus delbrueckii), lactobacillus delbrueckii Subspecies bulgaricus (Lactobacillus delbrueckii subspecies bulgaricus), Lactococcus lactis (Lactococcus lactis), Lactococcus lactis subsp. lactis (Lactococcus lactis subspecies Lactis), streptococcus lactis (Streptococcus lactis), streptococcus thermophilus (Streptococcus Thermophilus), bifidobacterium lactis (Bifidobacterium lactis), bifidobacterium breve (Bifidobacterium Breve), Pediococcus acidilactici (Pediococcus aciditactici) and Lactobacillus helveticus (Lactobacillus Hetveticus) the group formed.
In any method disclosed herein or some embodiments of composition, gramnegative bacterium is selected from by false single Born of the same parents bacterium (Pseudomonas) belongs to, klebsiella (Klebsiella) belongs to, Xanthomonas campestris (Xanthomonas) belongs to, Shigella (Shigella) belong to the group of the bacterium composition belonged to enterobacteria (Enterobacter).In some embodiments, gram-negative Property bacterium be selected from by Klebsiella oxytoca (Klebsiella oxytocia), shigella flexneri (Shigella Flexneri), xanthomonas campestris (Xanthomonas campestris) and Pseudomonas fluorescens (Pseudomonas Flourescens) the group formed.
In any method disclosed herein or some embodiments of composition, TLR agonists, lysate, lysate At least one of fraction or the activation of cell wall fraction TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2 Or it is a variety of.In some embodiments, TLR agonists, lysate, lysate fraction or cell wall fraction activation TLR2, TLR3, Two or more in TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2.In some embodiments, TLR excitements Agent, lysate, lysate fraction or cell wall fraction activate TLR2 and TLR4.In some embodiments, TLR agonists, split It solves object, lysate fraction or cell wall fraction and activates TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2 In it is three or more.
In any method disclosed herein or some embodiments of composition, accelerating agent selects free amino acid, amino The group of sugar and sugar composition.In some embodiments, carrier is selected from the group being made of adhesive, matrix and combinations thereof.At some In embodiment, matrix includes at least one hydrophobic polymer and at least one hydrophilic polymer.In some embodiments In, adhesive is selected from the group being made of sugar, sugar alcohol and combinations thereof.In some embodiments, sugar alcohol is selected from by mannitol, mountain The group of pears sugar alcohol, xylitol and combinations thereof composition.
In some embodiments, composition is manufactured into selected from by pastille, chewing gum, chewable tablets, candy and solution tablet The dosage form of the group of composition.In some embodiments, TLR agonists are delivered to oral mucosa by dosage form.In some embodiments In, oral mucosa is selected from the group being made of hypoglossis mucous membrane, cheek mucous membrane and combinations thereof.
In some embodiments of any method and composition disclosed herein, composition is prepared for oral mucosa Delivering；In some embodiments, composition is prepared for the delivering of sublingual or cheek.In some embodiments, composition quilt It is configured to be no less than in 1 minute after application and dissolve.
To those skilled in the art, these and other aspect, advantage and alternative solution will pass through reading It is described in detail below and refer to the attached drawing and become apparent in appropriate circumstances in conjunction with appended claims.
Description of the drawings
Fig. 1 shows the diagram for the toll samples receptor (TLR) for showing various response approach.
Fig. 2 shows exemplary stimulating effect of the present composition to selection TLR/NLR cell lines；Value in figure corresponds to In the average value of screening experiment three times.
Fig. 3 shows compared with Bulgarian Lactobacillus lysate, the knot of the TLR stimulations of Pediococcus acidilactici lysate Fruit.
Fig. 4 shows the result of the TLR stimulations of the bacillus coagulans lysate with different harvest times.
Fig. 5 is shown from Lactobacillus acidophilus (Lactobacillus acidophilus), Lactobacillus helveticus (Lactobacillus helviticus), lactobacillus plantarum (Lactobacillus plantarum) and streptococcus thermophilus The result of the TLR stimulations of the gram-positive bacterium lysate of (Streptococcus thermophilus).
Fig. 6 is shown from Escherichia coli (Escherichia coli), Klebsiella oxytoca (Klebsiella Oxytocia), shigella flexneri (Shigella flexneri), xanthomonas campestris (Xanthomonas ) and the TLR of the gramnegative bacterium lysate of Pseudomonas fluorescens (Pseudomonas flourescens) campestris The result of stimulation.
Fig. 7 shows compared with xanthans, the result of the TLR stimulations of xanthomonas campestris lysate.
Fig. 8, which is shown in the urine of the operation veteran that PTSD is diagnosed after the composition using the disclosure, urinates isoprostane Horizontal reduce.
Fig. 9 shows that the sleep defect for the operation veteran that PTSD is diagnosed after the composition using the disclosure is reduced.
Figure 10 shows that the neurologic condition for the operation veteran that PTSD is diagnosed after the composition using the disclosure is reduced.
Figure 11 shows that the overall mood for the operation veteran that PTSD is diagnosed after the composition using the disclosure improves.
Figure 12 shows that the total energy level for the operation veteran that PTSD is diagnosed after the composition using the disclosure increases Add.
Figure 13 shows the totality of the articulation health for the operation veteran that PTSD is diagnosed after the composition using the disclosure Satisfaction increases.
Figure 14 shows the digestive health satisfaction for the operation veteran that PTSD is diagnosed after the composition using the disclosure Level increases.
Figure 15 shows that the irritability level for the operation veteran that PTSD is diagnosed after the composition using the disclosure is reduced.
Figure 16 shows the sexual function for operation veteran's self-report that PTSD is diagnosed after the composition using the disclosure The aggregate level of satisfaction increases.
Figure 17 shows operation veteran's daytime drowsiness's degree reduction of PTSD diagnosis after the composition using the disclosure.
Figure 18 shows that the life for operation veteran's self-report that PTSD is diagnosed after the composition using the disclosure is full The aggregate level of meaning degree increases.
Figure 19 shows that the level of depression for the operation veteran that PTSD is diagnosed after the composition using the disclosure is reduced.
Figure 20 after showing the lysate using the disclosure there are isoprostane levels in the individual for shaking history to reduce.
Specific implementation mode
For all purposes, herein cited all publications, patents and patent applications are hereby by quoting clearly simultaneously Enter.
Cell Redox (oxidationreduction) state change is very big.Oxidation and reduction reaction are the passes that cell biological can be learned Key.Usually when food molecule oxidation as energy be enriched with molecule such as NADP (nicotinamide-adenine dinucleotide phosphate) and When ATP (atriphos) leads to electron-transport and final capture energy, activated in such a way that downstream oxidation/reduction reaction balances TLR.As used herein, term " balance " refers to the balance of stable state；That is, being not necessarily amount of oxidation equal in given system Also commercial weight the case where, but aoxidize and reduction in immune state and therefore be the metabolic homeostasis of host the case where.However, depositing In many cell situations, wherein redox state changes.In general, cell is equipped with antioxidant molecule, but work as these molecules When exhausting, the redox state of cell changes.One the possible reason is for defence or similar purpose and purposeful real estate Liveliness proof oxygen species (ROS), such as O2-(superoxide radical), OH (hydroxyl radical free radical) and H2O2(hydrogen peroxide).When oxidation is gone back When Yuanping City's weighing apparatus changes, oxidative stress may be following.Oxidative stress is the increased damaging action (body of ROS horizontal abnormalities Body cell and structural) pathological state that is triggered.Oxidative stress be the increase of ROS, immune runaway generation and/or The direct result that antioxidant reduces the physiological activity that excessive ROS is defendd.Inflammation (either chronic or acute) and its It stress may lead to the increase of generation and the release of ROS in impaired and/or inflammatory tissue with infection, thus change cell Therefore redox equilibrium simultaneously leads to oxidative stress.Simultaneously as ROS injury tissues, oxidative stress may cause inflammation. Many diseases and morbid state are related to the variation of redox state and oxidative stress caused by chronic or acute inflammation, or Vice versa by person.Do not have harmful side effect currently used for treating chronic or acute inflammation therapy.This document describes for Change the composition and method of oxidative stress and the redox level in associated disorder treatment.
Before the disclosed method and composition of detailed description, multiple terms will be defined.As used herein, unless up and down Text in addition explicitly point out, otherwise singulative "one", "an" and "the" include plural referents.For example, referring to " nucleic acid " Refer to one or more nucleic acid.
In order to describe and limit the present invention, it is noted that term " substantially " be used herein to mean that be attributable to it is any fixed Amount compares, is worth, measuring or probabilistic intrinsic degree of other expressions.Term " substantially " is also used for indicating fixed herein Amount indicates can be from described with reference to different degree, the variation of the basic function of discussion topic without causing.
As described above, pathogen associated molecular pattern (PAMP) can be by stimulating TLR to activate innate immune response, institute It states TLR usually to be activated by conservative non-self biological chemical structure, to protect host from infection.Bacteria lipopolysaccharide (LPS) It is found on the bacterial cell membrane of certain bacteriums, it is considered to be typical PAMP.The identification receptor of innate immune system TLR4 specific recognitions LPS.Other PAMP include bacterial flagellin (being identified by TLRS), lipoteichoicacid, peptide glycan and usually With the relevant Nucleic acid variant of virus, the double-stranded RNA (dsRNA) such as identified by TLR3 or the non-methylated CpG identified by TLR9 Block.
However, in some cases, PAMP reduces inflammation.EPS (exocellular polysaccharide) is a kind of substance of stimulation immune response, The negative regulatory factor of TLR can be stimulated by having been displayed, and be reduced so as to cause inflammatory response.More specifically, it has been shown that EPS stimulations are exempted from It is epidemic disease globulin IL-1 associated receptors, toll interaction proteins, B cell lymphoma 3- coding albumen, A20, mitogen-activated The expression of protein kinase phosphorylation -1 and interleukins associated kinase M, and have shown that the negative tune for leading to TLR and inflammation Control.
These seem contradictory PAMP effects at least partly can be by the mutual of innate immune system and microorganism group It acts on to explain.Immune system is not present in vacuum.Even if when active inflammation response does not occur for organism, immunocyte Also the impact for the PAMP for coming from environment (especially from microorganism group) can be responded.In view of the various TLR being activated by Body is generating the downstream oxidation reducing condition in immune state and metabolic homeostasis, the system send out " clear all " signal with It avoids that responding unintentionally for base microorganisms group composition may be damaged.Therefore, the cell of PAMP and innate immune system is correct Reach or restore in some cases immune state and generation in conjunction with that can control entire oxidation-reduction system and lower or raise it Thank to stable state.
Fig. 1 shows the diagram of transmembrane TLR.Although the ligand of molecule, which receives (stimulant), is partly located at plasma membrane surfaces On, but the transmembrane domain of albumen can pass through the conformation change that occurs when ligand binding by the cytoplasm table of signal transduction to film Face.In cytoplasmic surface, which is connected from many different signal transduction paths.It shows proliferation/differentiation and answers Swash response approach.It should be noted that a TLR type cannot control two approach in this standard drawing simultaneously.But some TLR controls an approach or one group of approach, other TLR control a different approach or one group of approach.In addition, a type of TLR may control different approach according to the cell type where it；Therefore, the correct balance of delivering TLR agonists is to dimension The state that keeps steady is extremely important.
Downstream signal transduction mechanism can be more or less shared.In Fig. 1, proliferation response mainly uses ERK approach, And response uses MEKK and TAK approach.In each approach, signaling molecule is phosphorylated, and there may be phosphorylations Cascade is with amplified signal.Finally, phosphorylated protein enters nucleus (passing through nucleopore), wherein phosphorylation intermediate changes transcription And translation.In this way, TLR can control integral basis because.In short, thousands of genes is activated by TLR signal transductions, and And in general, TLR constitutes one of the entrance of most pleiotropism but tight control for Gene regulation.
TLR activation primarily responsive to one of be if necessary change cell downstream oxidation reducing condition.Redox becomes The startup of change and the resulting inflammatory response to pathogen are the key that the innate immune responses for infection control Component part.Inflammation (either chronic or acute) be induced by it and cause to generate from impaired and/or inflammatory tissue and The increase of free radical and other ROS is discharged, and therefore leads to or cause oxidative stress.Meanwhile when ROS injury tissues, Inflammation may be caused by oxidative stress.Therefore, inflammation and associated various illnesss can also be considered as " oxidative stress phase Related disorders or illness ".
Oxidative stress as biochemical condition is not shown usually other than the specific pathologies illness of its induction appoints The clinical symptoms or clinical sign of what specificity.It may usually keep undiscovered, along with the damage to patient, Zhi Daolin Bed doctor suspects that it exists and determines detection oxidative stress.
Various common diseases and/or illness are usually related to oxidative stress.Another example is Alzheimer's diseases.It grinds Study carefully and show that chronic oxidative stress increase Protein tau phosphorylation level, this is biological known in one kind of Alzheimer's disease Marker.Research also shows that oxidative stress leads to the neurodegeneration that tau is induced in Alzheimer's disease model.
Other well known " oxidative stress relevant disease or illness " is including but not limited to：It is Aceruloplasminemia, acute With chronic alcoholic liver disease, acute autoimmune myocarditis, sickle cell acute disease chest syndrome, acute pancreatitis, urgency Property Respiratory Distress Syndrome(RDS), alcoholic liver disease, amyotrophic lateral sclerosis, artery/systemic hypertension, asbestosis, asthma, altogether Ji imbalance telangiectasia, atherosclerosis, atopic dermatitis, cerebral ischemia, broncho-pulmonary dysplasia, burn, certain A little cancer, extracorporal circulatory system, angiocardiopathy, cataract, cellulitis, side effects of chemotherapy, chronic fatigue syndrome, chronic third Type hepatitis, chronic kidney disease, chronic obstructive pulmonary disease, chronic renal failure, colitis, coronary artery disease, Creutz Fei Erte- Cortico-striatal spinal degeneration, Crohn's disease, cutaneous Leishmaniasis, cystic fibrosis, type 1 diabetes, diabetes B, dyslipidemia, Tang Shi Syndrome, eclampsia, advanced renal disease, erectile dysfunction, Friedreich ataxia, headache, heart failure, pylorus spiral shell Bacillus infection/inflammation, haemodialysis side effect, hepatic sclerosis, HIV infection, Huntington disease, hyperbarism, high courage Sterol mass formed by blood stasis, hyperhomocysteinemiainjury, hyperlipidemia, idiopathic pulmonary fibrosis, interstitial lung disease, ischemia/reperfusion damage Evil, juvenile chronic arthritis, kidney transplant failure, leukaemia, lung cancer, lung damage, macular degeneration, male sterility, meniere It is syndrome, meningitis, mild cognitive impairment, multiple sclerosis, myelodysplastic syndrome, myocardial infarction, myocarditis, new Raw youngster's broncho-pulmonary dysplasia, obesity, osteoarthritis, osteoporosis, pancreatitis, Parkinson's disease, periodontosis, peritonaeum are saturating Analyse side effect, light aging, posttraumatic stress disorder, pre-eclampsia, primary biliary cirrhosis, broncho-pulmonary disease, early ageing, Psoriasis, psoriatic arthritis, pulmonary hypertension, radiotherapy side effect, adjuvant arthritis, clear-cell carcinoma, respiratory distress are comprehensive Simulator sickness, retinopathy of prematurity, posterior cord fibrosis (retrolenticolar fibroplasy), rheumatic disease, class wind Wet arthritis, sarcoidosis, septicemia, sickle cell disease, sleep apnea, spherocytosis, spinal cord damage Evil, apoplexy, synapse nucleoprotein, systemic amyloidosis, systemic loupus erythematosus, systemic sclerosis (chorionitis), thrombus Formed, Protein tau disease, it is traumatic stress pulmonary tuberculosis, unstable angina pectoris, uremia, venous insufficiency, adult progeria And cerebrohepatorenal syndrome.
Oxidative stress mediates the control for being permitted snagged pathological state and redox level, and redox water Flat control and oxidative stress thus will prevent many tissue damages, to allow to be easier to control potential disease, In, it reduces oxidative stress and is not enough to realize the control to disease.For example, myocardial infarction is the heart flesh caused by angiemphraxis The death or damage of meat.Possibility effect of the oxidative stress in causing angiemphraxis is bypassed, once block, it is impacted Muscle cell becomes anoxic and final death.But it if obstruction is rapid to reverse (such as passing through " blood coagulation destruction " drug), follows Ring restores, and theoretically, impacted muscle cell will be saved.However, in many cases, restoring although cycle is rapid, most First damage can cause inflammatory response, lead to oxidative stress and muscle cell injury.Control this oxidative stress actually The damage to cardiac muscle cells can be eliminated.In all these diseases and obstacle, the regulation and control of oxidative stress can alleviate or Treat disease or the symptom and/or the cause of disease of obstacle.
The variation of redox state may lead to the oxidation of sulfydryl on key protein, but these albumen itself are often difficult to It measures.However, the oxidation by previously mentioned sulfydryl or other Chemical oxidizing mechanism (such as mistakes by leading to electronics transfer Oxidation) chronic or Acute oxidative stress or redox variation increase can with and many other groups of cells will be changed At.
Isoprostane is the essential fatty acid (master being catalyzed by free radical under the direct effect of no cyclo-oxygenase (COX) If arachidonic acid) peroxidating formed internal prostaglandin-like compound, this be prostaglandin formed normal mechanism.This A little compounds have effective bioactivity as the inflammation mediator for increasing pain perception.These molecules are by least two differences Approach control.One approach is mediated by COX enzymes, and COX enzymes convert lipid to isoprostane with responsive genes activation and signal Molecule.In alternative route, lipid is direct oxidation into isoprostane to respond high oxidative redox state.Before different Row alkane is inflammation mediator, they form a part for positive feedback loop, this can maintain impaired oxidisability redox shape State.
Isoprostane (such as F2 isoprostanes) thus be oxidative stress animals and humans model in oxidisability aoxidize The precise marking object of reducing condition, and due to their genetic stability and their easy surveys in body fluid such as urine and blood Property, measure isoprostane have become assessment vivo oxidation stress most one of reliable method.This simplicity and stability So that measure isoprostane becomes important and reliable in exploring effect of the oxidative stress in human diseases pathogenesis Tool.Isoprostane levels are directly related with the oxidative stress of oxidisability redox state and generation.Even if oxidisability oxygen The site for changing reducing condition is somewhat limited, and the isoprostane of generation can also be surveyed in body fluid (such as urine) Amount, stress site and caused inflammation far from oxygenization.
Other biologic artifacts that can be aoxidized include but not limited to albumen, metalloproteinases, lipid, aliphatic acid, carbon water Compound, neurotransmitter, DNA, vitamin, polyphenol, antioxidant and coenzyme.Therefore, such as, but not limited to superoxide dismutase The components such as enzyme (SOD), peroxidase, glutathione and by exposure to reactive materials (such as, but not limited to advanced oxygen Change albumen, malonaldehyde, 8-hydroxyquinoline etc.) the oxidised form of cell composition be other potential oxidative stress biomarkers Object.
In view of importance of the inflammation in immune response and its oxidative stress, oxidative stress relevant disease may be passed through Or detrimental consequences caused by illness and/or other processes, it is important that organism keeps the tight control to redox state. In addition, in view of the interwoven relation between oxidative stress and inflammation, it has been suggested that measure the biomarker of inflammation as oxidation Property stress indirect biomarker.These biomarker (such as, but not limited to C- proteins C reactives, serum amyloid proteins A and cell factor) it is restricted in terms of it obtains the ability of the inferior grade variation of inflammation, and therefore limit it and obtain inferior grade The ability of redox variation.Another method be concern biomarker (such as isoprostane) to measure redox state, And change the mechanism of redox state.
Redox can be changed by increasing reducing substances (antioxidant) or reducing oxidant.By adding antioxygen Agent or antioxidant therapy control harmful redox level almost without success (referring to Ho etc., Biological markers of oxidative stress：Applications to cardiovascular research and practice.2013Redox Biology).Evidence suggests dietary antioxidants-are used for a long time to be used as prophylactic.But It is that, when immune system cannot reach or keep the redox level of stable state, the antioxidant of addition usually can not effectively entangle Positive balance.
The another way for influencing redox state is to be directed to downstream targets；Such strategy includes using aspirin With glucocorticoid to block the targeting of NF- kB activations and specific inflammatory mediator such as TNF-α.It is congenital in mediation in view of them Property immune response and inflammation in effect, congenital and inflammatory response provides another target to TLR in order to control.
As described above, TLR helps to mediate innate immune response by inducing or inhibiting the gene of coordination inflammatory reaction. TLR is identified and is responded various signals.These signals are combined with specificity T LR can induce or inhibit transmitting inflammation to promote or block Gene signal pathway.It, can be with mediated immunity response and inflammation validity by with specific reagent targeting specific TLR.
Inhibit a variety of TLR dependences responses or the response of activation specific may by targeting common signal transduction ingredient Be proved to be to control inflammation the effective ways of response.Therefore, compositions disclosed herein can be used for treating and TLR signal transductions Approach (such as inflammation of TLR inductions) relevant oxidative stress obstacle, the method includes application therapeutically effective amounts such as this Composition described in text, wherein impacted TLR is one or more in TLR2, TLR4, TLR5, TLR7 and TLR9.
As used herein, term " therapeutically effective amount " refers to being enough to cause expectancy effect in subject to subject's application Amount.
As used herein, it is to allow the biology of active constituent that term " pharmaceutical preparation " and " pharmaceutical composition ", which refer to its form, It learns activity effectively and the preparation without containing additional component, the additional component has and can not connect to the subject of preparation to be administered The toxicity received.Term " product ", " supplement " and " composition " is used to refer to comprising the thin of the disclosure interchangeably herein The pharmaceutical composition of bacterium lysate, lysate fraction and/or cell wall fraction.
Composition as described herein can be modified to target individual TLR or TLR groups.By targeting individual TLR or TLR The case where group, composition as described herein can be used for mediated acute or chronic inflammation.In addition, composition as described herein is available In inhibiting the phenomenon that abnormal inflammatory and restore the general level of the health of inflammation.
Therefore, this document describes the compositions and method for regulating and controlling oxidative stress.Such as by measuring various kinds of cell system In NF- κ B expression assessed, composition can activate various TLR.Composition as described herein can also be reduced or be lowered The activity of TLR reduces or is regulated and controled so as to cause level of inflammation.When reaching the appropriate balance of TLR activation, cell Redox shape State is optimized and oxidative stress reduces.This can be by providing containing different types of in combination with two or more The composition of the PAMP of TLR is realized.
In some cases, the lysate of the microorganism of single type can be as the agonist of two or more TLR. As disclosed herein, the exact way of processing microbial lytic object can influence the TLR stimulated by lysate.In some implementations It, can be by the different lysates or fraction of microorganism of the combination from single type or from a plurality of types of micro- lifes in mode The lysate of object or fraction complete the activation of TLR groups.
There are many different but similar PAMP combined with given TLR types, although having different affinity.Also Stimulate the PAMP molecules of entirely different TLR types.How lysate or fraction, which process, may influence present in final product PAMP compositions.Therefore, different PAMP work palettes are presented in different types of microorganism.As disclosed herein, it provides Stimulate and (be used as agonist) composition of specific TLR types to lead to the notable downward of oxidative stress simultaneously.
It is surprising that stimulation TLR not necessarily leads to the increase of oxidative stress.On the contrary, microorganism group is continuous It is normal condition to stimulate TLR, will not lead to inappropriate redox state and oxidative stress.Partial interpretation may with it is given The position of TLR receptors and the type of TLR receptors are related.The activation of TLR receptors on mucous membrane generates and is located in body The TLR receptors of same type in portion's tissue activate different results.It is not only restricted to specifically explain or mechanism, the disclosure carries It has supplied application or has increased the method for microflora group signal, by interrupting to abnormal oxidation reducing condition and oxidative stress The positive feedback loop of energy supply simultaneously " resets " whole system to establish stable state again.
The therapeutic activity composition of the disclosure includes non-synthetic bioactivator, one kind of preferably one or more microorganisms Or various kinds of cell wall fraction, the microorganism include gram-positive bacterium, gramnegative bacterium or combinations thereof, such as to split The form for solving object, together with accelerating agent and optional one or more other additives (including release components), to allow to combine Object is absorbed into the interaction of the mucosal wall in the mucosal wall of subject in need for the treatment of or with subject in need for the treatment of.
As used herein, term " dosage " " should include injecting or loading dose, and further include chronic or maintenance dose.Root According to the present invention, active therapeutic agent is the lysate of bacterium, lysate fraction or cell wall fraction, is filled according to specific treatment use Needed for two kinds of agonist in a variety of TLR, the amount of the bacterium such as gram-positive bacterium or gramnegative bacterium It is about 0.01mg therapeutic agents/kg body weight to about 100mg/ kg body weights.In some embodiments, the active treatment of the disclosure Agent is applied with the dosage of about 0.01mg therapeutic agents/kg body weight to about 10gm therapeutic agents/kg body weight.In some embodiments In, the active therapeutic agent of the disclosure is applied with the dosage of about 0.01mg therapeutic agents/kg body weight to about 1gm therapeutic agents/kg body weight With.In some embodiments, the active therapeutic agent of the disclosure is treated with about 0.01mg therapeutic agents/kg body weight to about 50mg The dosage of agent/kg body weight is applied.In some embodiments, the active therapeutic agent of the disclosure is with about 0.05mg therapeutic agent/thousand The dosage of gram weight to about 30mg therapeutic agents/kg body weight is applied.In some embodiments, the active therapeutic agent of the disclosure with The dosage of about 0.05mg therapeutic agents/kg body weight to about 5mg therapeutic agents/kg body weight is applied.In some embodiments, herein Disclosed active therapeutic agent is with about 0.1mg therapeutic agents/kg body weight or about 0.2mg therapeutic agents/kg body weight or about 0.3mg is controlled Treat agent/kg body weight or about 0.4mg therapeutic agents/kg body weight or about 0.5mg therapeutic agents/kg body weight or about 0.6mg treatments Agent/kg body weight or about 0.7mg therapeutic agents/kg body weight or about 0.8mg therapeutic agents/kg body weight or about 0.9mg treatments Agent/kg body weight or about 1mg therapeutic agents/kg body weight or about 2mg therapeutic agents/kg body weight or about 3mg therapeutic agents/kilogram Weight or about 4mg therapeutic agents/kg body weight or about 5mg therapeutic agents/kg body weight or about 6mg therapeutic agents/kg body weight or About 7mg therapeutic agents/kg body weight or about 8mg therapeutic agents/kg body weight or about 9mg therapeutic agents/kg body weight or about 10mg is controlled Treat the dosage application of agent/kg body weight.In some embodiments, above-mentioned dosage describes the activity applied daily to subject The total amount of ingredient, wherein total amount are segmented into twice daily or more time application, or can be applied with single daily dose Amount.
As used herein, term " therapeutic agent " and " active constituent " refer to and the non-active ingredient phase in composition or preparation To lysate, lysate fraction and/or the cell wall fraction of the disclosure or combinations thereof.
In some embodiments, pharmaceutical composition disclosed herein is applied with dosage form, such as with oral preparation (packet Include tablet formulation) application, it includes about 0.01mg to about 10gm active constituents/dosage or about 0.5mg to about 50mg activity at Point/dosage or about 3mg to about 30mg active constituents/dosage or every dose of about 10mg to about 30mg active constituents/dosage.At some In embodiment, by pharmaceutical preparation with about 0.5mg or about 1mg or about 5mg or about 10mg or about 15mg or about 20mg or About 25mg or about 30mg active constituents/dosage formulation and/or application.In some embodiments, by the pharmaceutical composition of the disclosure Object prepares piece agent, and every includes about 0.5mg to about 30mg active constituents/piece.In some embodiments, each tablet includes About 0.5mg active constituents.In some embodiments, each tablet includes about 1mg active constituents.In some embodiments, Each tablet includes about 5mg active constituents.In some embodiments, each tablet includes about 10mg active constituents.At some In embodiment, each tablet includes about 15mg active ingredients.In some embodiments, each tablet includes about 25mg activity Ingredient.In some embodiments, each tablet includes about 40mg active constituents.In some embodiments, each tablet packet Containing about 50mg active constituents.In some embodiments, each tablet includes about 1gm active constituents.In some embodiments, Each tablet includes about 10gm active constituents.
In some embodiments, the pharmaceutical preparation of the disclosure is administered once a day to daily application three times.In some realities It applies in mode, the pharmaceutical preparation of the disclosure is administered once a day.In some embodiments, the pharmaceutical preparation of the disclosure is applied daily With twice.In some embodiments, the pharmaceutical preparation of the disclosure is applied three times daily.
In some embodiments, pharmaceutical preparation is applied with dosage level and frequency so that subject receives in total about 0.01mg to about 10gm active therapeutic agents/day or in total active therapeutic agent/day of about 1mg to about 1gm or in total about 5mg to about 1gm active therapeutic agents/day or in total about 5mg are to about 500mg active therapeutic agents/day, or about 12mg to about 375mg/ days in total. In some embodiments, the pharmaceutical preparation of the disclosure is applied with dosage level and frequency so that subject receives in total about 1mg or about 2mg or about 3mg or about 4mg or about 5mg or about 6mg or about 7mg or about 8mg or about 9mg or about 10mg, Or about 11mg or about 12mg or about 13mg or about 14mg or about 15mg active constituents (i.e. lysate, lysate fraction and/or Cell wall fraction or combinations thereof)/day or more (if necessary).In some embodiments, the pharmaceutical preparation of the disclosure is with agent Amount is horizontal and frequency application so that subject receives about 12mg or about 24mg or about 36mg or about 48mg in total or about 60mg or about 72mg or about 84mg or about 96mg or about 108mg or about 120mg or about 132mg or about 144mg or about 156mg or about 168mg or about 180mg active constituents (i.e. lysate, lysate fraction and/or cell wall fraction or its group Close)/day or more (if necessary).In some embodiments, the pharmaceutical preparation of the disclosure is applied with dosage level and frequency, So that subject receives about 15mg or about 30mg or about 45mg or about 60mg or about 75mg or about 90mg or about in total 105mg or about 120mg or about 135mg or about 150mg or about 165mg or about 180mg or about 195mg or about 210mg, Or about 225mg active constituents (i.e. lysate, lysate fraction and/or cell wall fraction or combinations thereof)/day or more is (if needed It wants).In some embodiments, the pharmaceutical preparation of the disclosure is applied with dosage level and frequency so that subject receives in total About 25mg or about 50mg or about 75mg or about 100mg or about 125mg or about 150mg or about 175mg or about 200mg or About 225mg or about 250mg or about 275mg or about 300mg or about 325mg or about 350mg or about 375mg or about 400mg Active constituent (i.e. lysate, lysate fraction and/or cell wall fraction or combinations thereof)/day or more (if necessary).
Any and all above-mentioned dosage and amount of application are suitable for the single therapy application of the active constituent of the disclosure, And the embodiment that wherein active constituent of the disclosure is applied with one or more other therapeutic agents or pharmaceutical agent combinations.
Active constituent
The active constituent being ready to use in the composition and method of the disclosure includes bacterial lysate, lysate fraction or cell Wall fraction.Active constituent can be manufactured, generate or be derived by any gram-positive bacterium or gramnegative bacterium organism.
Term " lysate " as used herein refers to the composition prepared by lytic cell (such as bacterial cell).It depends on Exact process conditions for generating lysate, lysate contains whole cellular contents, and contains in some embodiments There is relevant surfaces component such as exocellular polysaccharide.
Non-limiting example technique according to the production active constituent of the disclosure is as shown in Example 1, and is usually directed to Following steps：(1) zymogenous bacteria in growth medium；(2) centrifuged bacterial suspension is therefrom to harvest bacterium；It (3) will harvest Bacterium wash and pasteurize；(4) cell wall of bacterium is destroyed to crack bacterium；(4) mixture of freeze-drying gained To obtain active constituent, such as bacterial lysate, lysate fraction or cell wall fraction.
It is present in lysate, lysate fraction and/or the cell of the disclosure of responsible TLR activation and oxidative stress reduction Structure in wall fraction is structure common and conservative between all bacterial micro-organisms.Therefore, in principle, it is possible to using any Bacterial organisms produce the active constituent (i.e. lysate, lysate fraction and/or cell wall fraction) of the disclosure.
In some embodiments, the bacterial organisms of the active constituent for producing the disclosure are that Gram-positive is thin Bacterium.In some embodiments, gram-positive bacterium is selected from：Lactobacillus acidophilus (Lactobacillus Acidophilus), Bu Shi Bacillus acidi lacticis (Lactobacillus buchneri), Lactobacillus casei (Lactobacillus Casei), chain Bacillus acidi lactici (Lactobacillus catenaforme), cellobiose Bacillus acidi lactici (Lactobacillus Cellobiosus), curling Bacillus acidi lactici (Lactobacillus crispatus), lactobacillus curvatus (Lactobacillus Curvatus), lactobacillus delbrueckii (Lactobacillus delbrueckii), lactobacillus delbrueckii subspecies bulgaricus (Lactobacillus delbrueckii subsp.bulgaricus), lactobacillus delbrueckii breast subspecies (Lactobacillus Delbruecldi subsp.lactis), Lactobacillus helveticus (Lactobacillus helveticus), Zhan Shi Bacillus acidi lacticis (Lactobacillus jensenii), Lay scholar's Mans Bacillus acidi lactici (Lactobacillus leichmannii), small lactic acid Bacillus (Lactobacillus minutus), secondary Lactobacillus casei (Lactobacillus paracasei), plant lactic acid Bacillus (Lactobacillus plantarum), rhamnose lactic acid bacteria (Lactobacillus rhamnosus), Roche breast Acidfast bacilli (Lactobacillus rogosae), saliva Bacillus acidi lactici (Lactobacillus salivarius), gemma lactic acid Bacillus (Lactobacillus sporogenes) (also referred to as bacillus coagulans (Bacillus coagulans)), short lactic acid Bacillus (Lactobacillus brevis), Jia Shi Bacillus acidi lacticis (Lactobacillus gasseri), fermentation lactobacillus (Lactobacillus fermentum), bifidobacterium adolescentis (Bifidobacterium adolescentis), animal bifid Bacillus (Bifidobacterium animalis) (especially B. animals, animal subspecies), bifidobacterium angulatum (Bifidobacterium angulatum), bifidobacterium bifidum (Bifidobacterium bifidum), bifidobacterium breve (Bifidobacterium breve), chain Bifidobacterium (Bifidobacterium catenulatum), bifidobacterium dentium (Bifidobacterium dentium), bifidobacterium eriksonii (Bifidobacterium eriksonii), baby's bifid bar Bacterium (Bifidobacterium infantis), bifidobacterium lactis (Bifidobacterium lactis) (animal breast bifid bar Bacterium subspecies), bifidobacterium longum (Bifidobacterium longum), plant Bifidobacterium (Bifidobacterium Plantarum), false chain Bifidobacterium (Bifidobacterium pseudo-catenulatum), bifidobacterium pseudolongum (Bifidobacterium pseudo-longum), Lactococcus lactis (Leptococcus lactis), streptococcus lactis (Streptococcus lactis) (also referred to as Lactococcus lactis subsp. lactis), gossypose streptococcus (Streptococcus Raffinolactis), acidaminococcus fermentans (Acidaminococcus fermenta), fermentation Cytophaga (Cytophaga fermentans), fermentation red educate bacterium (Rhodoferax fermentans), fermentable fiber monad (Cellulomonas fermentans), zymomonas mobilis (Zymomonas mobilis), Pediococcus acidilactici (Pediococcus acidilactici), streptococcus thermophilus (Streptococcus thermophilus) and its function etc. Same variant.
In some embodiments, the bacterial organisms of the active constituent for producing the disclosure are that Gram-negative is thin Bacterium.In some embodiments, gramnegative bacterium is selected from：Acinetobacter baumannii (Acinetobacter baumannii), Actinobacillus (Actinobacilllus), acetobacter xylinum (Acetobacter xylinus), bacteroides thetaiotaomicron (Bacteroides thetaiotaomicron), bacteroides fragilis (Bacteroides fragalis), pertussis Boulder are special Salmonella (Bordetella pertussis), Bacillus abortus (Brucella abortus), campylobacter jejuni (Campylobacter jejuni), not Lloyd's's citrobacter (Citobacter freundii), enterobacter cloacae (Enterobacter cloacae), Enterobacter sakazakii (Enterobacter sakasakii), cyanobacteria (Cyanobacteria), pears water epidemic disease Erwinia (Erwinia amylovora), Escherichia coli (Escherichia Coli), soil draws hot francis fungus (Franciscella tularensis), helicobacter pylori (Helicobacter Pylori), haemophilus influenzae (Haemophilus influenza), legionella pneumophila (Legionella Pneumophila), Moraxella catarrhalis (Moraxella catarrhalis), Neisseria gonorrhoeae (Neisseria Gonorrhoeae), proteus mirabilis (Proteus mirabilis), pseudomonas aeruginosa (Pseudomonas Aeruginosa), Pseudomonas fluorescens (Pseudomonas flourescens), Bacterium enteritidis (Salmonella Enteritidis), salmonella typhi (Salmonella typhi), serratia marcescens (Serratia Mareescens), shigella flexneri (Shigella flexneri), comma bacillus (Vibrio cholera), vibrio marinopraesens (Vibrio algenily), Ralstonia solanacearum (Ralstonia solanaceaerum), mycobacterium tuberculosis (Mycobacterium tuberculosis), card Na Shi mycobacterias (Mycobacterium kanassi), Cray primary of hastening parturition Bacterium (Klebsiella oxytocia) and Klebsiella Pneumoniae (Klebsiella pneumonia) and xanthomonas campestris (Xanthomonas campestris).In some embodiments, gramnegative bacterium is selected from：Pseudomonad (Pseudomonas) belong to, klebsiella (Klebsiella) belongs to, Xanthomonas campestris (Xanthomonas) belongs to, shigella dysenteriae (Shigella) belong to and enterobacteria (Enterobacter) belongs to.In some embodiments, gramnegative bacterium is large intestine bar Bacterium (Escherichia coli), Klebsiella oxytoca (Klebsiella oxytocia), shigella flexneri (Shigella Flexneri), Pseudomonas fluorescens (Pseudomonas flourescens) and xanthomonas campestris (Xanthomonas Campestris one or more) and in its function equivalent modifications.
All the above bacterium is considered to production immunostimulatory cells ingredient, and such as, but not limited to EPS is (extracellular Polysaccharide), it is different from LPS (lipopolysaccharides) found in many bacteriums.The bacterium of other types can be used for the group of the disclosure It closes in object and method, such as those of disclosed in the prior art and in ECACC (European Cell Culture Collection), ASTM (American Society for Tests and Materials), ATCC (American type culture collection) and DSM (German microorganism and cell culture Collection) in it is typically available those.
About the fermentation step for producing lysate, lysate fraction or cell wall fraction according to the disclosure, for use In fermentation acceptable growth medium by the specific bacteria depending on being growing.Typical growth medium include comprising Below those：Nitrogen source (1-4%) may include following yeast extract, lactoprotein and casein hydrolysate, soybean and soybean It is one or more in hydrolysate, meat extract, peptone or ammonia salt；Hydrolysis carbon aquation containing simple sugars or generation simple sugars Close the simple sugars or ingredient of object, such as, but not limited to glucose or lactose (0.5-3%)；With minerals (0.05-0.3%), May include the salt of sodium, manganese, magnesium, calcium and potassium.Surfactant, cysteine HCL and ribonucleotide (0.001- can be added 0.75%) it is grown with sertoli cell.PH value growth medium being adjusted between 6 to 8.In some embodiments, depend on In the pH value range of the specific bacteria being growing, growth medium be about 6.0 to 6.5.In some embodiments, growth training The pH value range for supporting base is about 6.5 to 7.0.In some embodiments, the pH value range of growth medium is about 7.0 to 7.5.
In some embodiments, the culture medium being inoculated with during fermentation incubates between 30-50 DEG C.In some embodiment party In formula, the culture medium being inoculated with during fermentation incubates between 30-40 DEG C.In some embodiments, the culture medium of inoculation exists About 30 DEG C or about 31 DEG C or about 32 DEG C or about 33 DEG C or about 34 DEG C or about 35 DEG C or about 36 DEG C or About 37 DEG C or about 38 DEG C or about 39 DEG C or about 40 DEG C or about 45 DEG C incubations.In some embodiments, it connects The culture medium of kind is incubated at about 30 DEG C.In some embodiments, the culture medium of inoculation is incubated at about 33 DEG C.In some realities It applies in mode, the culture medium of inoculation is incubated at about 35 DEG C.In some embodiments, the culture medium of inoculation is in about 37 DEG C of temperature It educates.In some embodiments, the culture medium of inoculation is incubated at about 40 DEG C.In some embodiments, the culture medium of inoculation It is incubated at about 45 DEG C.
In some embodiments, before harvesting bacterium, continue fermentation about 6 hours to about 120 hours.In some implementations In mode, before harvesting bacterium, continue fermentation about 12 hours to about 48 hours.In some embodiments, in harvest bacterium Before, continue fermentation about 12 hours to about 24 hours.In some embodiments, continue fermentation about 14 hours or about 15 hours, Or about 16 hours or about 17 hours or about 18 hours or about 19 hours or about 20 hours or about 22 hours or about 24 hours, Or about 48 hours.In some embodiments, continue fermentation until bacterial growth reaches mid-log phase, late log phase, early stage surely Periodically, middle stable phase or stationary phase in later stage.In some embodiments, continue fermentation until bacterium reaches stable growth period. In some embodiments, can be used before Downstream processing well known to a person skilled in the art technology keep ferment, such as But it is not limited to the control of cooling and pH value, if necessary up to 14 days or for more time.
It is usually that zymotic fluid is cooling and bacterium is harvested by centrifugation after fermentation.In some embodiments, after fermentation will Zymotic fluid is cooled to about 1 DEG C to about 25 DEG C.In some embodiments, zymotic fluid is cooled to about 1 DEG C or about 2 DEG C or about 3 DEG C or about 4 DEG C or about 5 DEG C or about 6 DEG C or about 7 DEG C or about 8 DEG C or about 10 DEG C.In some embodiments, by zymotic fluid It is cooled to about 4 DEG C to about 7 DEG C.
After cooling, is centrifuged and detached cell with surrounding growth culture medium.Then pass through repeated centrifugation and settling flux Cell is washed in fresh culture, deionized water, water or other solution, is then resuspended in fresh culture or other solution In to prepare for pasteurization step.
In some embodiments, the bacterium Clostridiuni of washing is sterilized.In some embodiments, bacterium at about 75 DEG C extremely About 85 DEG C of pasteurizes 30 minutes to 60 minutes.In some embodiments, the bacterium of harvest is in about 80 DEG C of pasteurizes.One In a little embodiments, pasteurize carries out about 30 minutes or about 45 minutes or about 60 minutes.
After pasteurize, processing cell concentration object is to destroy cell wall and thus expose TLR agonists.The destruction of cell wall It can be completed by using chelating agent, detergent, surfactant and hydrolase.The example for the hydrolase that can be used includes But it is not limited to lysozyme, such as chicken (hen) egg white lysozyme (such as Or), lysin, endolysin and hydrolase.In some implementations In mode, lysozyme is added in the bacterial cell suspension of pasteurize to the ultimate density of 0.01-4 volumes %.One In a little embodiments, lysozyme is added to the bacterial cell suspension of pasteurize to final concentration of about 0.5 volume % or about 1 volume % or about 2 volume % or about 3 volume % or about 4 volume %.In some embodiments, it is continued with lyases The bacterial suspension of pasteurize about 1 to about 10 hour or about 6 to about 8 hours or about 5 hours or about 6 hours is about 7 small When or about 8 hours or about 9 hours or about 10 hours.In some embodiments, at about 25 DEG C to about 50 DEG C or about 30 DEG C To about 45 DEG C or about 35 DEG C or about 37 DEG C, or at about 40 DEG C, or at about 42 DEG C, or carried out with cracking at a temperature of about 45 DEG C The bacterial suspension of enzymatic treatment pasteurize.After cracking, usually lysate is freezed and is lyophilized.
In some embodiments, and as described in more detail below, then by freeze dried substance and accelerating agent such as N- Acetyl D aminoglucoses HCl (NAG) is mixed.Optionally, it depends on the circumstances, other formulation excipients can be added to generate solid shape The pill or powder of formula.
In some embodiments, it can be split by specific by changing raw material, process materials or process conditions to change Solve one or more specific TLR of object activation or stimulation.As used herein, term " TLR specificity " refers to by being split comprising bacterium Solve one or more specific TLR of the given combination object activation of the disclosure of object, lysate fraction and/or cell wall fraction. In some embodiments, TLR specificity is changed according to the density that bacterial cell is grown during fermentation.In some embodiments In, producing the certain detail strain of active constituent or subspecies also leads to the difference of TLR specificity.In some embodiments, Pasteur Lead to the difference of TLR specificity for cracking the certain enzyme of bacterial cell after sterilization.
As used herein, when with receptor or other biomolecular targets used in connection with, term " activation ", " stimulation ", " target To " and " agonism " be interchangeable and refer to and the combination and activation of receptor (such as toll samples receptor) so that change, Adjust or influence in other ways the signal transduction cascade of receptor downstream.
It should be understood that can before cracking to cell carry out classification or can be by well known biochemistry side Method (including such as differential centrifugation or column chromatography, such as gel permeation chromatography, ion-exchange chromatography, hydrophobic medium chromatography or precipitation Deng) lysate of above-mentioned production is classified.In some embodiments, lysate classification production has different TLR special The fraction of property；The fraction more lesser amount of TLR than complete lysate is targeted for example, can produce.
In some embodiments, including the ingredient of exocellular polysaccharide can with the lysate of the disclosure, lysate fraction and/ Or cell wall grade subassembly.Exocellular polysaccharide can activate TLR.Thus, for example, being originated from xanthomonas campestris (Xanthomonas Campestris xanthans) can be applied in combination with lysate, lysate fraction and/or the cell wall fraction of the disclosure to increase The TLR of composition is added to activate and/or change the TLR specificity of composition.In some embodiments, xanthans itself is cracking Object fraction, for example, being split derived from xanthomonas campestris (Xanthomonas campestris) fermenting and producing in xanthans In the embodiment for solving object, such as by dividing xanthomonas campestris (Xanthomonas campestris) lysate Grade.Other ingredients and delivery form
The therapeutic composition of the disclosure can include further and optionally one or more accelerating agents with auxiliary activity The therapeutic delivery that agent passes through biomembrane.Can be amino acid, N- alkylations peptide, sugar, ammonia according to the useful accelerating agent of the disclosure Base sugar or amino sugar chelate.Amino sugar chelate includes one or more amino carbohydrate ligands, one or more saturated hydroxies Acceptable metal on Carboxylic acid ligand and nutrition, wherein at least one of described one or more amino carbohydrate ligands are Portugals Osamine, and wherein, the metal is selected from the group being made of manganese, magnesium, sodium, potassium and zinc, and wherein, it is described one or more full It is gluconic acid with hydroxy carboxylic acid's ligand, and wherein, the ratio of acceptable metal on the glucose amine ligand and nutrition It is 2：1, wherein metal is non-ferric in nutrition.
According to one aspect of the disclosure, therapeutic preparation may include one or more acetylations or deacetylated ammonia Base sugar, the amino sugar are selected from the list by NAG, galactosamine, N- acetylgalactosamines, mannosamine and ManNAc The group of body, oligomer and/or its polymer form (including chitin) and people's glucosaminoglycan and its derivative composition.It closes herein Refer to having identical or essentially identical ability to form cell in sterilization period in the term " its derivative " that amino sugar uses The amino sugar derivative of toxic decomposition products.According to the other aspects that the disclosure selects, the accelerating agent is to be selected to be relied by poly- L- Propylhomoserin, aminoglucose, poly-L-arginine, galactosamine, ManNAc (NAM；N-Ac-Man), N-15 acetylglucosamines (NAG；N-Ac-Glc), N, N'- diacetyl aminoglucose (NAG-NAG；Two thioglucose of N, N'- diacetyl), N, N', N ", N " '-tetra-acetylated aminoglucose (NAG-NAG-NAG-NAG；N, N', N ", N " '-tetra-acetylated ox sulphur tetrose) and its mixture The member of the group of composition.
Optionally and it is equally acceptable that, the accelerating agent can be that acylated glycosyloxy sugar or 2-12 are optionally acylated low Glycan oxygroup saccharide part, a-1,2 and/or a-1, the sugar of 6 connections, wherein the sugar is selected from by D-MANNOSE, D- galactolipins, D- What gulose (ghicose), D- gulosamines (ghicosamine), N-acetyl-glucosamine and 6-deoxy-L-mannose formed Group, wherein oligomeric glycosyloxy saccharide part can include identical or different sugar.
In another embodiment, composition of the invention is selected from by pastille, chewing gum, chewable tablets and solution tablet The dosage form of the group of (such as molten slow, fast dissolving tablet or Dospan or other suitable controlled release preparations) composition.
In one embodiment, by the activating agent of the disclosure by the oral transmucosal delivery of subject, the oral cavity is viscous Film is selected from the group being made of hypoglossis mucous membrane, buccal mucosa and combinations thereof.It can be with sublingual administration the composition so that active constituent passes through Hypoglossis mucous membrane delivers.
In another embodiment, carrier is normally solid, semisolid or liquid, such as adhesive, matrix or its group It closes.Suitable adhesive for the present composition includes but not limited to sugar alcohol such as mannitol, D-sorbite and xylitol； Sugar such as lactose, dextrose, sucrose, glucose and Icing Sugar；Other materials for example inositol, molasses, maltodextrin, starch, cellulose, Microcrystalline cellulose, polyvinylpyrrolidone, Arabic gum, guar gum, bassora gum, alginate, extract of Irish moss, Pan Wa Er glue, ghatti gum, isapgol husk mucus (psyllium),Larch arabinogalactan, gelatin, Methylcellulose, ethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyacrylic acid (such as carbopol), silicon Sour calcium, calcium phosphate, Dicalcium Phosphate, calcium sulfate, kaolin, sodium chloride, polyethylene glycol and combinations thereof.For the present composition Suitable matrix includes the material for example in gum base materials well known in the art many not soluble in water and insoluble in saliva. In some cases, matrix includes at least one hydrophobic polymer and at least one hydrophilic polymer.Conjunction for matrix The non-limiting example of suitable hydrophobicity and hydrophilic polymer includes natural and synthetic polymer such as elastomer, rubber and its group It closes.The example of suitable natural polymer includes but not limited to the substance of plant origin, such as tunny gum, gelutong, Du Secondary glue, hat glue and combinations thereof.The example of suitable synthetic polymer includes elastomer, such as butadiene-styrene copolymer, different Butylene and isoprene copolymer (such as " butyl rubber "), polyethylene, polyisobutene, polyvinylesters (such as poly- acetic acid second Enester and Opaseal) and combinations thereof.In other cases, matrix includes butyl rubber (i.e. isobutene And isoprene copolymer), the mixing of polyisobutene and optional polyethylene lactate (such as with molecular weight about 12000) Object.
In another embodiment, the present composition can further include sweetener, flavoring agent, protective agent, increasing Mould agent, wax, elastomer solvent, packing material, preservative or combinations thereof.In another embodiment, the present composition can To further include lubricant, wetting agent, emulsifier, solubilizer, suspending agent, colorant, disintegrant or combinations thereof.In a kind of reality It applies in mode, compared with about 75 to about 100 microns of typical mean drug particle size, the average grain of combination of traditional Chinese medicine object described herein Degree is about 20 microns.In another embodiment, the average particle size of combination of traditional Chinese medicine object described herein is less than or equal to carrier The average particle size of ingredient (such as matrix, adhesive etc.).
In the one side of the disclosure, therapeutic composition can optionally include buffer system to increase the pH value of saliva To the pH value of about 8.0 to about 11, but regardless of the starting pH of saliva in the oral cavity of subject to be treated.The foregoing describe for this The suitable therapeutic agent of invention.The suitable carbonate and bicarbonate for buffer system of the present invention are also described above. In some cases, composition also includes abiotic therapeutic agent, such as NSAID.
Suitable citrate, phosphate and borate include but not limited to citric acid, phosphoric acid or boron well known in the art Any salt of acid.For example, in some embodiments, citrate is selected from by sodium citrate, potassium citrate, calcium citrate, lemon The group of lemon acid magnesium and ammonium citrate composition.
In other embodiments, phosphate is selected from by sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, phosphoric acid hydrogen What dipotassium, calcium dihydrogen phosphate, dicalcium phosphate, magnesium dihydrogen phosphate, two magnesium of phosphoric acid hydrogen, ammonium dihydrogen phosphate and diammonium hydrogen phosphate formed Group.In other embodiments, borate is selected from the group being made of Boratex, potassium borate, line borate, antifungin and ammonium borate. In some cases, buffer system includes carbonate, bicarbonate and/or citrate.In some other cases, buffer body System includes carbonate, bicarbonate and/or phosphate.In other cases, buffer system include carbonate, bicarbonate and/ Or borate.
Other than the buffer system comprising carbonate, bicarbonate and/or metal oxide, other buffer systems are applicable in In the composition of the present invention.For example, in alternate embodiments, ternary buffer system include carbonate, bicarbonate and Citrate, phosphate or borate.In another alternate embodiments, buffer system include carbonate or bicarbonate with And two or more are selected from the buffer for the group being made of metal oxide, citrate, phosphate and borate.Another In kind alternate embodiments, buffer system is the binary buffer system comprising carbonate or bicarbonate and metal oxide. In another alternate embodiments, buffer system is comprising carbonate or bicarbonate and citrate, phosphate or boric acid The binary buffer system of salt.In another alternate embodiments, buffer system is comprising metal oxide and citrate, phosphorus The binary buffer system of hydrochlorate or borate.In another alternate embodiments, buffer system is comprising carbonate and carbonic acid The binary buffer system of hydrogen salt.
Delivery form
The therapeutic composition of the present invention can take the form of solid, semisolid, freeze-dried powder or liquid dosage form, such as Tablet (such as chewable tablets, slow mechanism dissolved piece, fast dissolving tablet), pill, capsule, pastille, candy, glue, powder, solution, suspension Agent, emulsion, aerosol etc..Dosage form can be chewing gum, fast dissolving tablet, candy or pastille.
As used herein, term " dosage form " refers to being suitable as people experimenter, mammal and other nonmammalians to move The physical discrete unit of the unit dose of object, each unit contain the therapeutic agent of predetermined amount and one or more suitable drugs Excipient such as carrier, the therapeutic agent, which is computed, can generate required breaking-out, tolerance and therapeutic effect.Prepare this dosage form Method be known to the skilled person or will be apparent.For example, in some embodiments, this hair Bright chewing gum can be prepared according to the program standard in industry.In other embodiments, tablet of the invention, pastille Or candy dosage form (such as sucker or lollipop) can be according to " the The Science and Practice of such as Remington Of Pharmacy, 20th Ed ", [Lippincott, Williams＆Wilkins (2003) and " Pharmaceutical Dosage Forms, Volume 1：Tablets ", 2nd Ed., Marcel Dekker, Inc., New York, N.Y. (1989)] prepared by the program described in.Under any circumstance, dosage form to be administered contains the activity of a certain amount of therapeutically effective amount Therapeutic agent, illness being treated when for alleviating introduction application according to the present invention.
As used herein, term " carrier " refers to that the typical case of diluent or medium as drug (such as therapeutic agent) is lazy Property substance.The term further includes the typical inert substance for assigning composition adherence.Suitable carrier for the present composition Including but not limited to solid, semisolid or liquid (such as adhesive or matrix).Those of ordinary skill in the art's known adhesive Example.Adhesive can be pre-processed by means commonly known in the art to improve its mobility and taste, such as is freeze-dried [see, for example, " Fundamentals of Freeze-Drying, " Pharm.Biotechnol., Vol.14, pp.281-360 (2002)；"Lyophilization of Unit Dose Pharmaceutical Dosage Forms," Drug.Dev.Ind.Pharm.,Vol.29,pp.595-602(2003)]；It is prepared by solid solution；And with suitable lubricant into The dusting of row lubricant and wet granulation are (see, for example, Remington：The Science and Practice of Pharmacy, ibid).When preparation includes adhesive, composition of the invention can include about 15 weight % to about 90 weights Measure the adhesive of % and the adhesive of about 35 weight % to about 80 weight %.However, it will be recognized by those skilled in the art, The composition of the present invention can be prepared in the case of no any adhesive, such as with the frangible dosage form of production height.
Tablet
When dosage form is tablet such as solution tablet (i.e. disintegrated tablet) or chewable tablets, the present composition includes as described herein Therapeutic agent, derived from one or more bacteriums or its pharmaceutically acceptable salt, accelerating agent, carrier (such as adhesive) and buffering System (including binary buffer system or ternary buffer system).Tablet composition can further include lubricant, wetting agent, emulsification Agent, suspending agent, preservative, sweetener, flavoring agent, colorant and disintegrant.Typically, tablet composition of the invention includes about The active therapeutic agent (in the form of any selection, being measured by its free alkali form) of 0.001 weight % to about 10.0 weight %, and And more typically about 1.0% to about 5.0%.It will be understood by those skilled in the art that above-mentioned percentage is according to activity used The specific release speed of the amount of active therapeutic agent and required active therapeutic agent needed for the specific source of therapeutic agent, final preparation Rate will be different.Tablet composition buffer system offer be more than at least about 8.0, at least about 9.5 and/or about pH value 9.9 to The about final salivary pH of pH value 11.
In some embodiments, tablet is solution tablet, is such as dissolved without the slow of chewing by the saliva of subject Slow dissolving or fast dissolving tablet agent.For example, the solution tablet being placed on subject's tongue can be used for the cheek delivering of therapeutic agent.Alternatively, The solution tablet being placed in below subject's tongue can be used for the sublingual of therapeutic agent.Such dosage form is for paediatrics and old age Patient is especially desirable, because child and the elderly are often difficult to chew certain articles.Typically, solution tablet is configured to applying Afterwards in about 1 to about 15 minute, in about 2 to about 10 minutes, dissolved in for example, about 2,3,4,5,6,7,8,9 or 10 minutes.This field Technical staff should be understood that fast dissolving tablet faster than the dissolving of slow mechanism dissolved piece, usually gradual by the saliva of subject It dissolves rather than quickly dissolves.In one embodiment, slow mechanism dissolved or fast dissolving tablet are within the time more than about 1 minute Therapeutic agent is delivered by hypoglossis mucous membrane.
In certain other embodiments, tablet is chewable tablets, is chewed and is configured to quick or gradually molten by subject Solution.For example, the chewable tablets being placed on subject's tongue can be used for the cheek delivering of therapeutic agent.During chewing, chewable tablets can be Moved in oral cavity, can rest on sometimes between gum and cheek or tongue below.Therefore, therapeutic agent contained in chewable tablets At least part can also be delivered sublingual (passing through hypoglossis mucous membrane).Typically, by chewable tablets be configured to after application about 1 to It is molten in for example, about 2,3,4,5,6,7,8,9 or 10 minutes in about 2 to about 10 minutes and in no less than 1 minute in about 15 minutes Solution.
As described above, the solution tablet and chewable tablets of the present invention are typically formulated as about 1 to 15 minute after application, and applying It is no less than dissolved in about 1 minute with rear.However, although these time ranges are suitable for that therapeutic agent is made to be exposed to mouth to the maximum extent Transmucosal (such as sublingual and/or buccal mucosa), but they not always obey user's compliance (for example, user may gulp down It swallows too frequent, therefore, hinders maximum across mucosa absorption).Therefore, in certain circumstances, it may be necessary in patient compliance and Therapeutic agent obtains balance between the maximum exposure time of oral mucosa.This can for example, by reduce tablet size (for example, from About 700-800mg to about 200-300mg) come in fact without reducing the buffer system of per unit dose or the concentration of therapeutic agent or amount It is existing.In addition, the slight change of tablet formulation for example replaces with a kind of flavoring agent another (such as chocolate of spearmint) Or a kind of adhesive or sweetener are replaced with into another (such as with mannitol or the lactose of D-sorbite) and can be used for reducing stream Saliva.
With other pharmaceutical agent combinations
Many pharmaceutically active agents generate harmful side effect, these side effects pass through biochemistry and other generations by activating agent Thank to the ROS drivings of generation when reaction carries out.Therefore, composition as described herein is answered for treating oxidative stress and oxidisability Swash relevant disease and illness attractive candidate, and can with one or more pharmaceutical agent combinations well known in the art, Such as any medicament listed in Physician's Desk Reference (can be in http://www.pdr.net is obtained).
In some embodiments, the active constituent Yu targeted oxidative of the disclosure stress, inflammation, immune response and/or Oxidative stress relevant disease or the agents known of illness combine or they can be with generation oxidative stress as side effect Pharmaceutical agent combinations.In the case where medicament targets certain Other diseases states but generates oxidative stress as side effect, with this The combination of inventive composition reduces to be damaged caused by oxidative stress, and by allowing higher doses without by aoxidizing Property stress caused by prohibitive damage and enhance the effect of medicament.It should be understood that may with the optimum of specific combination Need to adjust lysate most preferably to target correct TLR in the presence of adding medicament.
Therefore, on the one hand, present disclose provides for reducing or mitigating and apply the relevant one or more oxygen of medicament Change property stress related side effects method, the method includes application the disclosure lysate, lysate fraction and/or cell wall The combination of fraction and drug.In some embodiments, while or in any order and passing through identical or different administration method Using medicament and cracking compositions.In some embodiments, medicament is that have one or more oxidative stress related secondary Any medicament of effect, such as what is listed in Physician's Desk Reference have one or more oxidative stress Any medicament of related side effects (can be in http://www.pdr.net is obtained).In some embodiments, medicament be selected from by Antirheumatic drug, anti-inflammatory agent, chemotherapeutics, radiotherapeutic agents, immunosuppressor, interferon, the chemotherapeutics based on interferon and cytotoxicity The group of medicine composition.In some embodiments, oxidative stress related side effects are selected from Aceruloplasminemia, artery/system Property hypertension, arthritis, asthma, atherosclerosis, atopic dermatitis, cancer, carcinoma of urinary bladder, leukaemia, uterine cancer, uterine neck Cancer dizziness, Nausea and vomiting, constipation, diarrhea, insomnia, drowsiness, dizziness, sexual hypoesthesia, temporarily goes into a coma, trembles, the mistake of jaundice, the rhythm of the heart Often, heart rate increase, decreased heart rate, measles, depression, clinical depression, cerebral ischemia, broncho-pulmonary dysplasia, cardiovascular disease Disease, cataract, cellulitis, side effects of chemotherapy, chronic fatigue syndrome, colitis, coronary artery disease, dyslipidemia, Eclampsia, erectile dysfunction, incoordination, headache, heart failure, haemodialysis side effect, hepatic sclerosis, hypercholesterolemia, Hyperhomocysteinemiainjury, hyperlipidemia, interstitial lung disease, lung damage, macular degeneration, male sterility, mild cognitive barrier Hinder, myocardial infarction, myocarditis, myopathy, neuropathy, obesity, osteoarthritis, osteoporosis, pancreatitis, periodontosis, peritonaeum Dialysis side effect, posttraumatic stress disorder, pre-eclampsia, psoriasis, psoriatic arthritis, pulmonary hypertension, radiotherapy pair are made With, adjuvant arthritis, Respiratory Distress Syndrome(RDS), rhabdomyolysis, rheumatic disease, septicemia, sleep apnea, in Wind, suicidal thought, amyloidosis, thrombosis, Protein tau disease, unstable angina pectoris, uremia or vein function are not Entirely.
In some embodiments, the medicament with one or more oxidative stress related side effects is selected from by with the following group At group：Selected from by atropine sulfate, dicyclomine hydrochloride, scopolamine butylbromide, propantheline bromide, alverine citrate and The Anticonvulsants of the group of hydrochloric acid mebeverine composition；Motility excitant selected from the group being made of metoclopramide and domperidone； Bisfentidine selected from the group being made of for fourth and ranitidine cimetidine, famotidine Buddhist nun；Muscarine antagonist；It is selected from By the chelating agent for the group that two citric acid trisodium citrate and ulcerlmin form；Prostaglandin analogue；Selected from by Balsalazide sodium, U.S. sand Draw the aminosalicylate of the group of piperazine, Olsalazine and salicylazosulfapyridine composition；Selected from by beclomethasone dipropionate, cloth how The corticosteroid of moral, the group of hydrocortisone and prednisolone composition；Selected from by cyclosporin, mercaptopurine, methotrexate (MTX), Ah The drug of the influence immune response of the group formed up to the wooden monoclonal antibody and infliximab；Selected from by Bisacody, dihydroxy anthraquinone, The irritant laxative of the group of more library esters and guttalax composition；Influence the drug of bile composition and flowing；Selected from by cholestyramine Fat, Oxyphencyclimine, camylofin, mebeverine, Trimebutine, rociverine, dicyclomine, dihexyverine, difemerine, two Benzene piperazine ester, benzene oxazolone, Mepenzolate, Pipenzolate, glycopyrronium bromide, Ao Fen Australia amine, monodral, methantheline, proparacaine, Otilonium Bromide, Tridihexethyl, isopropylamine, hexocyclium, Poldine, Bei Funing, diphemanil, tiemonium iodide, prifinium bromide, thiophene Piperazine bromine ammonium, benzene piperazine dimension woods, papaverine, Drotaverine, moxaverine, 5-HT3 antagonists, 5-HT4 agonists, fenpiprane, Diisopromine, Chlorbenzoxamine, Pinaverium Bromide, fenoverine, idanpramine, proxazole, alverine, Trepibutone, different U.S. Spit of fland, caroverine, 1,3,5-trihydroxybenzene, silicone, recipavrin, atropine, hyoscyamine, hyoscine, butylscopolamine, methyl The bile acid chelating of the group of hyoscine, methyl atropine, fentonium bromide, Cimetropium Bromide and main Dopamine D2 receptor composition Agent；Matter selected from the group being made of Omeprazole Sodium, Lansoprazole sodium, Pantoprazole Sodium, esomeprazole sodium and RABEPRAZOLE SODIUM Sub- pump inhibitor；Opioid and opioid receptors antagonist；Selected from by paracetamol, Diclofenac, fluorobenzene Salicylic acid, Etodolac, fenoprofen, Flurbiprofen, brufen, Indomethacin, Ketoprofen, ketorolac, Meclofenamic Acid, first That fragrant acid, Meloxicam, Nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin sodium, plug come Former times cloth, buprenorphine, butorphanol, codeine, hydrocodone, Hydromorphone, levorphanol, pethidine, methadone, morphine, Naboo The antalgesic for the group that coffee, Oxycodone, Oxymorphone, pentazocine, propoxyhene and C16H25NO2 form；Selected from by nitrazepam, fluorine west Dissolve, Lip river antrypol, Lormetazepam, Temazepam, Zaleplon, zolpidem, zopiclone, chloraldurate, trichloroethyl phosphate, Clormethiazole, Oxazepam, triazolam, estazolam, Clonazepam, alprazolam, eszopiclone, ramelteon, song The group that oxazolone, amitriptyline, doxepin, benzodiazepine, melatonin, diphenhydramine and herbal remedies form is slept Dormancy drug；Cardiac glycoside selected from the group being made of digoxin and foxalin；Selected from what is be made of Enoximone and milrinone The phosphodiesterase inhibitors of group；Selected from by bendroflumethiazide, chlorthalidone, Cyclopenthiazide, her that amide, metolazone and Xi Pa amine The thiazide of the group of composition and related diuretics；Diuretics selected from the group being made of frusemide, bumetanide and Torasemide； Potassium-sparing diuretic selected from the group being made of Amiloride, triamterene, eplerenone and spirolactone and aldosterone antagonist Agent；Osmotic diuresis agent；Selected from by adenosine, Amiodarone Hydrochloride, disopyramide, flecainide acetate, propafenone hydrochloride and hydrochloric acid benefit The antiarrhythmic medicament of the group of cacaine composition；Selected from by Propranolol, atenolol, acebutolol, finish bisoprolol fumarate salt, Carvedilol, celiprolol, esmolol, Eibar Luo Er, metoprolol tartrate, Nadolol, Nebivolol, oxygen alkene Lip river The beta-adrenoceptor blocking drug object of the group of that, pindolol, Sotalol and timolol composition；Selected from by pacifying for health, wave Raw smooth, diazoxiide, hydralazine, iloprost, minoxidil, silaenafil, sitaxentan, sodium nitroprussiate, clonidine, methyl DOPA, moxonidine, guanethidine monosulfate, Doxazosin, indoramin, prazosin, Terazosin, benzene oxygen aniline and methylsulphur The hypertension drug of the group of sour phentolamine composition；Selected from by captopril, Cilazapril, enalapril maleate, Fu Xin Puli, Imidapril, lisinopril, Moexipril, perindopril tert-butylamine salt, quinapril, Ramipril, Trandolapril, Candesartan Cilexetil, Eprosartan, irbesartan, Losartan, olmesartan medoxomil, Telmisartan, Valsartan and aliskiren The drug of the influence renin-angiotensin system of the group of composition；Selected from by glyceryl trinitrate, isosorbide dinitrate, list Isosorbidi dinitras, Amlodipine Besylate Tablet, diltiazem, felodipine, isradipine, lacidipine, Lercanidipine, nitre The nitrate of the group of pyrrole amine methyl esters, nifedipine, Nimodipine, verapamil, Ivabradine, nicorandil and ranolazine composition, Calcium channel blocker, antianginal drug；Selected from by Cilostazol, inositol niacin alcohol ester, moxisylyte, naftidrofuryl oxalate and oneself The peripheral blood vessel expansion of the group of ketone theobromine composition and related drugs；Selected from by dopamine, Dopexamine, ephedrine, aramine, The parasympathomimetic agent of the group of noradrenaline acid tartrate, tartaric acid norephedrine and benzene ephedrine composition；Selected from by Heparin, bemiparin, dalteparinSodium, Enoxaparin, tinzaparin, danaparoid, bivalirudin, lepirudin, Epoprostenol, sulphur What dalteparinSodium, neodicoumarin, acenocoumarin, phenindione, dabigatran etcxilate, razaxaban and protamine sulfate formed The anti-coagulants and nucleoprotamine of group；Selected from by Abciximab, aspirin, clopidogrel, persantine, eptifibatide, pula lattice The antiplatelet drug of the group of thunder and tirofiban composition；Selected from by Alteplase, Reteplase, streptokinase, Tenecteplase, urine The fibrinolytic drug object and Antifibrinolytic agents of the group of kinases, etamsylate and Trenaxmine composition；Selected from by Ah Atorvastatin, Fluvastatin, Pravastatin, rosuvastatin, Simvastatin, colesevelam, cholestyramine resin, Colestipol, according to Pool for rice shellfish, Bezafibrate, ciprofibrate, fenofibrate, Gemfibrozil, acipimox, niacin, omega-fatty acid compound, The regulation and control Lipid pharmaceutical of ethanolamine oleate and the group of sodium tetradecyl sulfate composition；Selected from by benperidol, chlorpromazine, fluorine piperazine Thioxanthene, haloperidol, levomepromazine, pericyazine, perphenazine, pimozide, chloropyrazine, promazine, Sulpiride, triperazine, pearl Diuril alcohol, Amisulpride, Aripiprazole, Clozapine, Olanzapine, Paliperidone, kui gentle ziprasidone, Risperidone, Sertindole, benzene thiophene second in heptan Amine, Flupentixol, fluphenazinum, Olanzapine embonate, pipotiazine palmitate, risperidone, Zuclopenthixol, Karma west Flat, sodium vedproate, valproic acid, lithium carbonate, lithium citrate, amitriptyline, clomipramine, dosulepin, imipramine, lofepramine, Nortriptyline, trimipramine, Mianserin, Trazodone, nardil, Isocarboxazid, parnitene, Moclobemide, western phthalein are general Orchid, escitalopram, Prozac, Fluvoxamine, Paxil, Sertraline, agomelatine, Duloxetine, Flupentixol, rice nitrogen Flat, Reboxetine, tryptophan, Venlafaxine, atomoxetine, Sai meter Ming, methylphenidate, modafinil, Ai Si licarbazepines, Oxcarbazepine, ethymal, Gabapentin, pregabalin, scheme for lacosamide, Lamotrigine, Levetiracetam, phenobarbital, Puli Rice ketone, phenytoinum naticum, rufinamide, Tiagabine, Topiramate, sabril, Zonisamide, Ropinirole, rotigotine, compound benzene Amine dopamine, levodopa, compound karr DOPA, Rasagiline, selegiline, Entacapone, Tolcapone, amantadine, adjacent first Benzene hamming, procyclidine, benzhexol, haloperidol, Piracetam, Riluzole, tetrabenazine, Acamprosate, disulfiram, An Feita The group of ketone, varenicline, buprenorphine, lofexidine, donepezil, galanthamine, Memantine hydrochloride and rivastigmine composition CNS drugs；Selected from by penicillin, ospen, flucloxacillin, temocillin, Amoxicillin, ampicillin, compound Ah Moses Woods, compound flucloxacillin, Piperacillin, Ticarcillin, Pivmecillinam, cephalosporins, Cefaclor, cefadroxil, head Cefalexin, Cefixime, cefotaxime, Cefradine, cefotaxime, cefuroxime, ertapenem, Imipenem, Metro training South, aztreonam, tetracycline, demethylchlortetra cylinum, Doxycycline, lymecycline, minocycline, terramycin, tigecycline, celebrating are big mould Element, amikacin, neomycin, tobramycin, erythromycin, azithromycin, clarithromycin, Ketek, clindamycin, chlorine Mycin, Fusidic Acid, vancomycin, teicoplanin, Daptomycin, Linezolid, Quinupristin, polymyxin E, compound sulfonamide Methylisoxazole, sulphadiazine, trimethoprim, capreomycin, seromycin, ethambutol, isoniazid, pyrazinamide, Li Fu Bu Ting, rifampin, streptomysin, dapsone, Clofazimine, metronidazole, Tinidazole, Ciprofloxacin, lavo-ofloxacin, Mo Xisha Star, acidum nalidixicum, promise fluorine draw star, Norfloxacin, furantoin, methenamine hippurate, anphotericin, anidulafungin, Ka Bo Fragrant net, Fluconazole, Flucytosine, griseofulvin, Itraconazole, ketoconazole, mikafen, nystatin, posaconazole, special ratio Naphthalene sweet smell, voriconazole, Abacavir, Didanosine, emtricitabine, Lamivudine, stavudine, tenofovir disoproxil, Qi Duofu Determine, atazanavir, darunavir, fosamprenavir, indinavir, Luoping Nai Er, Nai Feinawei, Ritonavir, inverase, replace La Nawei, efavirenz, etravirine, nevirapine, enfuirtide, Maraviroc, Merck, acyclovir, general former times Lip river Wei, isoprinosine, valaciclovir, cidofovir, Ganciclovir, phosphonic acid, valganciclovir, Aldoforwe ester, Entecavir, Sebivo, amantadine, Oseltamivir, zanamivir, palivizumab, Ribavirin, Artemether, chloroquine, Mefloquine, primary Ammonia quinoline, chloroguanide, pyrimethamine, quinine, fortimicin, diloxanide chaff, flagyl, Tinidazole, mepacrine, Pentostam The anti-infectives for the group that sodium, Atovaquone, penta amidine of edetic acid(EDTA), mebendazole and piperazine form；Selected from by benzetropine, the third ring Pyridine, Biperiden, amantadine, bromocriptine, pergolide, Entacapone, Tolcapone, selegiline, Pramipexole, cloth how Moral, Formoterol, quetiapine fumarate, Olanzapine, pioglitazone, montelukast, zoledronic acid, Valsartan, Latanoprost, It is irbesartan, clopidogrel, atomoxetine, Dexamfetamine, ritalin, modafinil, bleomycin, D actinomycin D, soft red mould Element, idarubicin, rice Tobramycin, mitoxantrone, azacitidine, capecitabine, Cladribine, clofarabine, cytarabine, fluorine Up to draw shore, fluorouracil, gemcitabine, mercaptopurine, methopterin, nelarabine, pemetrexed, Raltitrexed, thioguanine, Ah Flutter morphine, betamethasone, cortisone, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, song The other medicines of the group of An Naide, cyclosporine, sirolimus, tacrolimus, interferon-' alpha ' and interferon beta composition.
Therefore, the therapeutic preparation of the disclosure can further include one or more additional therapeutic agents, such as below Any therapeutic agent of description.In some embodiments, composition is as the Sterile pharmaceutical for including pharmaceutically acceptable carrier The part supply of composition.Including this composition of additional therapeutic agent can be in that (depending on will for any suitable form It is administered to the expectation method of patient).In some embodiments, be co-administered the active constituent of the disclosure with it is one or more Additional therapeutic agent, although not necessarily being combined with one or more additional therapeutic agents with single formulation.In some embodiments In, the active constituent of the disclosure is applied by a kind of administration method, and the additional therapeutic agent being co-administered passes through the second application way Diameter is applied.For example, the active constituent of the disclosure can be administered orally, mucosal administration, sublingual administration, cheek are applied etc., and apply jointly One or more additional therapeutic agents pass through the applications such as parenteral, intravenous.
The example for the compound that can be combined with the present composition includes antirheumatic, anti-inflammatory agent, chemotherapeutics, radiotherapy Agent, immunosuppressor, interferon, chemotherapeutics or cytotoxic drug based on interferon.
Antirheumatic includes but not limited to Anranofin, imuran, chloroquine, Beracilline, disodium aurothiomalate hydroxyl Base chloroquine, myocrisin and salicylazosulfapyridine methotrexate (MTX).
Anti-inflammatory agent includes but not limited to dexamethasone, Pentasa, mesalazine, Ah intestines gram ingot, codeine phosphate, benzene first Hydrochlorate, fenbufen, naproxen, Diclofenac, Etodolac and Indomethacin, aspirin and brufen and other non-steroidals With anti-inflammatory agent (NSAIDS).
Chemotherapeutant includes but not limited to radioactive molecule, toxin, and also referred to as (it is wrapped for cytotoxin or cytotoxic agent It is i.e. harmful to cell survival to include any reagent), reagent and the liposome containing chemotherapy compound or other vesicas.Suitableization The example for treating agent includes but not limited to 1- boldenones, 5 FU 5 fluorouracil Dacarbazine, Ismipur, 6- thioguanines, puts Line rhzomorph D, adriamycin, Aldesleukin, alkylating agent, allopurinol sodium, hemel, Amifostine, arimidex, Anthramycin (AMC)), antimitotic agent, Cisplatin (II) (DDP) cis-platinum), diamino dichloro platinum, anthracycline, antibiotic, Antimetabolite, asparaginase, BCG viable bacterias (in bladder), betamethasone sodium phosphate and betamethasone acetate, are won Bicalutamide Bleomycin sulfate, busulfan, calcium leucovorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), card are not Take charge of spit of fland (BSNU), Chlorambucil, cis-platinum, Cladribine, colchicin, conjugated estrogen, cyclophosphamide, cyclophosphamide, Cytarabine, cytarabine, cytochalasin B, cyclophosphamide, Dacarbazine, dactinomycin D, dactinomycin D (are formerly referred to as putting Line rhzomorph), daunorubicin hydrochloride, daunomycin citrate, denileukin, dexrazoxane, dibromannitol, dihydroxy-anthracene Diketone, docetaxel, dolasetron mesilate, doxorubicin hydrochloride, Dronabinol, bacillus coli L-asparaginase, emetine, Epoetin-α, Erwinia l-Asparaginase, esterified estriol, estradiol, estramustine phosphate sodium, ethidium bromide, acetylene Estradiol, Etidronic Acid, the Etoposide citrate factor, etoposide phosphate, Filgrastim, floxuridine, Fluconazole, phosphoric acid Fludarabine, fluorouracil, Flutamide, folinic acid, gemcitabine hydrochloride, glucocorticoid, goserelin acetate, gramicidins D, Granisetron Hydrochloride, hydroxycarbamide, idarubicin hydrochloride, ifosfamide, Interferon Alpha-2b, irinotecan hydrochloride, Letrozole, Calciumlevofolinate, leuprorelin acetate, levamisole hydrochloride, lidocaine, lomustine, maytenin, mustine hydrochlcride, tumer Hydroxyprogesterone, megestrol acetate, hydrochloric acid melphalan, purinethol, mesna, methotrexate (MTX), methyltestosterone, mithramycin, silk Rimocidin C, mitotane, mitoxantrone, Nilutamide, octreotide acetate, muriatic ondansetron, taxol, Pamidronate Disodium, Spray department statin, hydrochloric acid pilocarpine, Primycin, the Polifeprosan with card chlorine mustard implantation material, Porfimer Sodium, procaine, Procarbazine hydrochloride, Propranolol, Rituximab, sargramostim, streptozotocin, tamoxifen, taxol, Teniposide, Ghost thiophene, testosterone lactone, totokaine, thiotepa, Chlorambucil, thioguanine, phosphinothioylidynetrisaziridine, hydrochloric acid Hycamtin, Chinese holly Rafter acid Toremifene, Herceptin, vitamin A acid, valrubicin, vinblastine sulfate, vincristine sulphate and tartaric acid Changchun are auspicious Shore.
In the other aspects of the disclosure, the active constituent of the disclosure is combined with TNF-α antagonist or anti-TNF-α antibody to be applied With.The example of this TNF-α antagonist includes but not limited to Soluble TNF-ot receptors；Etanercept ( ) or its segment, derivative or the like Immunex；Infliximab (Centacor) or it derives Object, analog or antigen-binding fragment；The known macrophage TNFR-IgG activated by interferon-γ blocks TNF-α to generate Adalimumab (Humira and Exemptia), IL-10；Mouse product TBP-1；Vaccine CytoTAb (Protherics)；Antisense Molecule 104838 (ISIS)；Peptide RDP-58 (SangStat)；Thalidomide (Celgene)；CDC-801(Celgene)；DPC- 333(Dupont)；VX-745(Vertex)；AGIX-4207(AtheroGenics)；ITF-2357(Italfarmaco)；NPI- 13021-31(Nereus)；SCIO-469(Scios)；TACE targeting agents (Immunix/AHP)；CLX-120500(Calyx)；Thiophene Azoles bacterium (Dynavax)；Anranofin (Ridaura) (SmithKline Beecham Pharmaceuticals)；Quinacrine (mepacrine dichlorohydrate)；Tenidap (Enablex)；Melanin (Large Scale Biological) With the anti-p38MAPK agent of Uriach.
It combines and applies with rapamycin or similar macrocyclic antibiotic in the active constituent of another aspect of the present disclosure, the disclosure With.As used herein, rapamycin includes rapamycin and its all analogs, derivative and conjugate, and with Other immunophilins of the identical pharmacological property of rapamycin include inhibition (the mammal rapamycin of TOR or mTOR Target) (for example, serving as TOR kinase inhibitors).It may be used as other immunosuppressor of one or more drugs or therapeutic agent Including but not limited to cyclosporin, tacrolimus (FK-506), imuran and mycophenolate mofetil.
Can include angiogenic agent, such as vascular endothelial growth factor with other therapeutic agents of the active ingredient combinations of the disclosure Sub (VEGF) and fibroblast growth factor (FGF)；Angiotensin receptor blocker；Nitric oxide donors；Antisense widow's core Thuja acid and combinations thereof；Cell cycle inhibitor, mTOR inhibitors and growth factor receptors signal transduction kinase inhibitor；Class regards Huang Alcohol；Periodical CDK inhibitor；HMG CoA reductases inhibitor (such as statins) and protease inhibitors.
Tnf inhibitor
For tumor necrosis factor (TNF) inhibitor in the method and composition of the present invention, especially TNF α inhibitor Including interfering the active any reagent of TNF α.In a preferred embodiment, TNF α inhibitor can neutralize TNF α activity, special Be not with the relevant harmful TNF α activity of oxidative stress disease and obstacle, such as [referring to definition] and relevant complication and Symptom.
As used herein, term " human TNF alpha " (being abbreviated herein as hTNF α, or referred to as hTNF) be intended to indicate that with Human cell factor existing for 17kD secreted forms and 26kD film combining forms, biologically active form by Non-covalent binding 17kD The tripolymer of molecule forms.For example, in Pennica, D. waits (1984) Nature 312:724-729；Davis, J.M., etc. (1987)Biochemistry 26:1322-1326 and Jones, E.Y. wait (1989) Nature 338:Into one in 225-228 Step describes the structure of hTNF α.Term human TNF alpha is intended to include recombination human TNF alpha (rhTNF α), can be recombinantly expressed by standard Method preparation or commercially available (such as purchased from R＆D Systems, Minneapolis, Minn.).The TNF α of this paper is also equally known as TNF。
Term " TNF α inhibitor " refers to the interference active reagent of TNF α.The term further includes that as described herein each is anti- TNF α human antibody and antibody moiety and U.S. Patent number 6,090,382；6,258,562；6,509,015 and U.S. Patent number 7, Those of described in 223,394.In one embodiment, in the present invention TNF α inhibitor that uses be anti-TNF alpha antibodies or its Segment, including infliximab (Johnson and Johnson；It is described in U.S. Patent number 5,656,272, It is incorporated herein by reference), CDPS71 (Humanized monoclonal anti-tnf-alpha IgG4 antibody), (Humanized monoclonal is anti-by CDP870 TNF-α antibody fragment), (Peptech), the CNTO148 (goli mumabs of anti-TNF dAb；Medarex and Centocor, referring to WO02/12502) and adalimumab (The laboratories Abbott, the anti-TNFmAb of people are described in the U.S. as " D2E7 " The patent No. 6,090,382).Additional TNF antibody for use in the present invention is described in U.S. Patent number 6,593,458；6,498, 237；6,451,983 and 6,448,380, each is incorporated herein by reference.In another embodiment, TNF Inhibitor is TNF fusion proteins, for example, Yi Naxi sauce (Amgen；It is described in WO91/03553 and WO09/406, 476, be incorporated herein by reference).In another embodiment, TNF α inhibitor is recombination TNF binding proteins (r-TBP- 1)(Serono)。
As used herein, term " antibody " is intended to indicate that two weights by four polypeptide chains, being connected with each other by disulfide bond The immunoglobulin molecules of chain (H) and two light chains (L) composition.Each heavy chain by heavy chain variable region (be abbreviated as herein HCVR or VH it) is formed with heavy chain constant region.Heavy chain constant region is made of three domain Cs H1, CH2 and CH3.Every light chain is by light chain variable Area's (being abbreviated as LCVR or VL herein) and constant region of light chain composition.Constant region of light chain is made of a domain C L.The areas VH and VL It can be further subdivided into the hypervariable region of referred to as complementary determining region (CDR), wherein being scattered with more conservative region, referred to as framework region (FR).Each VH and VL is made of three CDR and four FR, is aligned to carboxyl terminal from amino terminal in the following order： FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4.The antibody of the present invention is described in further detail in U.S. Patent number 6,090, 382；6,258,562 and 6,509,015, each is incorporated herein by reference in their entirety.
As used herein, term " human antibody " be intended to include with from human germline immunoglobulin's sequence variable region and The antibody of constant region.The human antibody of the present invention may include not by the amino acid residue of human germline immunoglobulin's sequential coding (such as passing through external random or site-specific mutagenesis or the mutation introduced by internal somatic mutagenesis), such as in CDR And especially CDR3.However, as used herein, term " human antibody " is not intended to include wherein being originated from another mammalian species As the CDR sequence of the germline of mouse has been transplanted to the antibody on people's Frame sequence.
As used herein, term " recombinant human antibody " is intended to include preparing by recombinant means, expression, generating or detach All human antibodies, such as use the antibody (as described below) for the recombinant expression carrier expression being transfected into host cell, separation Antibody (as described below) from recombination combination human antibody library, is isolated from the animal to human immunoglobulin gene's transgenosis The antibody of (such as mouse) is (see, for example, Taylor etc. (1992) Nucl.Acids Res.20:6287), or by being related to people Any other means of Ig gene sequences montage to other DNA sequence dnas are prepared, expressed, generating or the antibody of separation. Such recombinant human antibody has variable region and constant region from human germline immunoglobulin's sequence.However, in certain implementations In mode, make such recombinant human antibody carry out mutagenesis in vitro (or when user Ig sequence transgenic animals, internal body cell Mutagenesis), and therefore the amino acid sequence in the areas VH and VL of recombinant antibodies be derived from ethnic group system VH and VL sequences and with its phase The sequence of pass may not be the sequence being naturally occurring in internal human antibody germline library.
In one embodiment, term " TNF α inhibitor " does not include infliximab.In another embodiment In, term " TNF α inhibitor " does not include adalimumab and infliximab.
In one embodiment, term " TNF α inhibitor " do not include Etanercept and optional adalimumab, Infliximab and adalimumab and infliximab.
In one embodiment, term " TNF α antibody " does not include infliximab.In one embodiment, art Language " TNF α antibody " does not include adalimumab.In another embodiment, term " TNF α antibody " does not include that Ah 's wood is single Anti- and infliximab.
In one embodiment, the invention is characterised in that for treating or determining that the TNF α for the treatment of Crohn disease inhibits The application of the effect of agent and composition, wherein TNF α antibody are that have with high-affinity and low dissociation yield combination human TNF alpha and also The human antibody of the separation of high neutralising capacity or its antigen-binding portion thereof.Preferably, the human antibody for the present invention is that recombination neutralizes The anti-hTNF Alpha antibodies of people.The present invention most preferably recombinates neutralizing antibody and is referred to herein as D2E7, also referred to asOr (amino acid sequence in the areas D2E7VL is shown in SEQ ID NO to adalimumab：In 1；The amino in the areas D2E7VH Acid sequence is shown in SEQ ID NO：In 2).D2E7 (adalimumab/) property be described herein, And it is respectively incorporated herein by reference.The method of the present invention can also be used and be experienced for treating rheumatoid arthritis The chimeric and humanized murine-hTNF Alpha antibodies of clinical trial (see, for example, Elliott, M.J., wait (1994) Lancet 344:1125-1127；Elliot, M.J. wait (1994) Lancet 344:1105-1110；Rankin, E.C. are waited (1995) Br.J.Rheumatol.34:334-342)。
Therefore, on the one hand, present disclose provides the toll sample receptors of the redox state for regulating and controlling subject (TLR) agonist compositions, the composition include：(a) include at least one or more of lysate and/or lysate of bacterium The TLR agonists of fraction, wherein TLR agonist activations at least one or more of TLR or NLR；(b) it is used to enhance composition suction The optional accelerating agent received；(c) it is used to increase the optional carrier of composition volume, wherein apply a effective amount of group to subject Closing object measurably reduces the level of the oxidative stress in subject.In some embodiments, agonist activation at least two Different TLR and/or NLR.In some embodiments, bacterium is gram-positive bacterium or gramnegative bacterium.
In some embodiments, composition is applied with pharmaceutical agent combinations to enhance the activity of medicament.In some embodiments In, composition is applied with pharmaceutical agent combinations to reduce the side effect of medicament.In some embodiments, the side effect of medicament is oxidation Property stress.
On the other hand, present disclose provides the method for the redox state for regulating and controlling subject, this method includes Any lysate or lysate the fraction composition disclosed herein of therapeutically effective amount is applied to subject in need.At some In embodiment, desirably through the variation for measuring isoprostane concentration or by including but not limited to the gene table in subject The other methods assessment redox state regulation and control reached.In some embodiments, subject is mammal.In some implementations In mode, mammal is people.In some embodiments, subject is the animal of nonmammalian, such as fish, poultry, Shellfish and insect such as drosophila.In some embodiments, redox state is oxidisability and leads to oxidisability It stress.In some embodiments, the oxidative stress of people is related to posttraumatic stress disorder.
On the other hand, present disclose provides regulation and control subject redox state method, the method includes with Lower step：(a) dosage for separating on subject in need repeatedly administration time and being made of composition, the composition packet Contain：(i) include at least one lysate and/or toll samples receptor (TLR) agonist of lysate fraction, wherein the excitement Agent activates at least one or more of different TLR；(ii) it is used to enhance the optional accelerating agent of composition absorption；(iii) is used for Increase the optional carrier of composition volume, and (b) measures the body fluid of subject to detect the variation of oxidative stress level. In some embodiments, TLR agonist activations at least three kinds of different TLR.In some embodiments, TLR agonists include Lysate and/or lysate fraction from single bacterial species and/or cell wall fraction.In some embodiments, TLR swashs Dynamic agent includes lysate and/or lysate fraction from least two bacterial species or strain.
In some embodiments, body fluid is measured to assess the variation of isoprostane concentration in subject.One In a little embodiments, by including but not limited to change that the method for gene expression in subject measures isoprostane concentration indirectly Change.In some embodiments, subject is mammal.In some embodiments, mammal is people.In some implementations In mode, subject is the animal in addition to mammal, such as, but not limited to fish, poultry, shellfish and insect example Such as drosophila.In some embodiments, the oxidative stress of people is related to posttraumatic stress disorder.
On the other hand, present disclose provides the method for the amount of isoprostane in the urine for reducing subject or blood, institutes The method of stating includes the following steps：(a) urine of subject or the level of isoprostane in blood are determined；(b) it is applied to subject A effective amount of composition, the composition include：(i) include at least one bacterial lysate and/or lysate from bacterium Toll samples receptor (TLR) agonist of fraction, wherein at least one or more of TLR or NLR of TLR agonist activations；With (ii) it is used to enhance the optional accelerating agent of composition absorption；And (c) continue to apply composition urine or blood until subject The horizontal of isoprostane in liquid is reduced.
On the other hand, present disclose provides composition, the composition includes：(a) it can activate at least one or more The bacterial lysate and/or lysate fraction of kind toll samples receptor (TLR) or Nod samples receptor (NLR)；(b) it is used to enhance combination The optional accelerating agent that object absorbs；(c) it is used to increase the optional carrier of composition volume.
On the other hand, present disclose provides the pharmaceutical preparations for including any composition disclosed herein.In some implementations In mode, the pharmaceutical preparation is prepared for cheek or sublingual administration.In some embodiments, pharmaceutical preparation is formulated into It is no less than in 1 minute and dissolves after.
On the other hand, present disclose provides the method for production bacterial lysate, this approach includes the following steps：(a) will Gram-positive bacterium or gramnegative bacterium in growth medium are fermented to stablizing growth period to generate zymotic fluid；(b) Bacterium is collected from zymotic fluid；(c) bacterium of harvest is subjected to pasteurize；And (d) use lysozyme lysis pasteurize Bacterium is to generate bacterial lysate.In some embodiments, after starting any specifically fermentation, in the difference of growth cycle Time harvests lysate.In some embodiments, the zymogenous bacteria in the culture medium that feature determines.
On the other hand, present disclose provides the bacterial lysate generated according to method, this approach includes the following steps： (a) by growth medium gram-positive bacterium or gramnegative bacterium ferment to stablize growth period with generate fermentation Liquid；(b) bacterium is collected from zymotic fluid；(c) bacterium of harvest is subjected to pasteurize；And (d) use lysozyme lysis Pasteur The bacterium of sterilization is to generate bacterial lysate.In some embodiments, after starting any specifically fermentation, in growth cycle Different time harvest lysate.In some embodiments, the zymogenous bacteria in the culture medium that feature determines.
On the other hand, present disclose provides for mitigating and applying the relevant one or more oxidative stress phases of medicament The method for closing side effect, the method includes applying the composition of therapeutically effective amount with pharmaceutical agent combinations, the composition includes： (a) lysate of bacterium and/or lysate fraction；(b) it is used to enhance the optional accelerating agent of composition absorption；(c) it is used to increase Add the optional carrier of composition volume；Wherein, while or medicine is applied in any order and by identical or different administration method Agent and cracking compositions.In some embodiments, lysate and/or lysate fraction activate at least one or more of TLR Or NLR.In some embodiments, lysate and/or lysate fraction activate at least two TLR and/or NLR.In some realities It applies in mode, lysate and/or lysate fraction activate at least three kinds of TLR and/or NLR.
In some embodiments, the relevant side effect of one or more oxidative stress is selected from the group being made up of： Artery/systemic hypertension, arthritis, asthma, atherosclerosis, atopic dermatitis, cancer, carcinoma of urinary bladder, leukaemia, uterus Cancer cervical carcinoma, dizziness, Nausea and vomiting, constipation, diarrhea, insomnia, drowsiness, dizziness, sexual hypoesthesia, temporarily goes into a coma, trembles, is yellow Subcutaneous ulcer, arrhythmia cordis, heart rate increase, decreased heart rate, measles, depression, clinical depression, cerebral ischemia, broncho-pulmonary dysplasia, Angiocardiopathy, cataract, cellulitis, side effects of chemotherapy, chronic fatigue syndrome, colitis, coronary artery disease, blood Fat exception, eclampsia, erectile dysfunction, incoordination, headache, heart failure, haemodialysis side effect, hepatic sclerosis, high courage are solid It is alcoholemia, hyperhomocysteinemiainjury, hyperlipidemia, interstitial lung disease, lung damage, macular degeneration, male sterility, slight Cognitive disorder, myocardial infarction, myocarditis, myopathy, neuropathy, obesity, osteoarthritis, osteoporosis, pancreatitis, periodontal Disease, peritoneal dialysis side effect, posttraumatic stress disorder, pre-eclampsia, psoriasis, psoriatic arthritis, pulmonary hypertension, radiotherapy Method side effect, adjuvant arthritis, Respiratory Distress Syndrome(RDS), rhabdomyolysis, rheumatic disease, septicemia, sleep-respiratory Pause, apoplexy, suicidal thought, amyloidosis, thrombosis, Protein tau disease, unstable angina pectoris, uremia or vein Insufficiency.
On the other hand, present disclose provides the sides for treating oxidative stress relevant disease or illness in subject Method, the method includes applying the composition of therapeutically effective amount to the subject, the composition includes：(a) it can activate The bacterial lysate and/or lysate fraction of at least one or more of toll samples receptor (TLR) or Nod samples receptor (NLR)；(b) Optional accelerating agent for enhancing composition absorption；(c) it is used to increase the optional carrier of composition volume.
In some embodiments, the relevant illness of oxidative stress is Aceruloplasminemia, acute and chronic alcohol Property hepatopathy, acute autoimmune myocarditis, drepanocytosis acute chest syndrome, acute pancreatitis, acute respiratory distress Syndrome, alcoholic liver disease, amyotrophic lateral sclerosis, artery/systemic hypertension, asbestosis, asthma, incoordination capillary It is blood vessel dilatation disease, atherosclerosis, atopic dermatitis, cerebral ischemia, broncho-pulmonary dysplasia, burn, certain cancers, external It is cycle, angiocardiopathy, cataract, cellulitis, side effects of chemotherapy, chronic fatigue syndrome, chronic hepatitis C, chronic Nephrosis, chronic obstructive pulmonary disease, chronic renal failure, colitis, coronary artery disease, Creutzfeldt-Jakob disease, gram Engler sieve disease, cutaneous Leishmaniasis, cystic fibrosis, type 1 diabetes, diabetes B, dyslipidemia, Down syndrome, son Epilepsy, advanced renal disease, erectile dysfunction, Friedreich ataxia, headache, heart failure, helicobacter pylori infections/ Inflammation, haemodialysis side effect, hepatic sclerosis, HIV infection, Huntington disease, hyperbarism, hypercholesterolemia, Hyperhomocysteinemiainjury, hyperlipidemia, idiopathic pulmonary fibrosis, interstitial lung disease, ischemia/reperfusion damage, teenager are slow Property arthritis, kidney transplant failure, leukaemia, lung cancer, lung damage, macular degeneration, male sterility, meniere syndrome, brain Film inflammation, mild cognitive impairment, multiple sclerosis, myelodysplastic syndrome, myocardial infarction, myocarditis, newborn's branch gas Pipe pulmonary hypoplasia, obesity, osteoarthritis, osteoporosis, pancreatitis, Parkinson's disease, periodontosis, peritoneal dialysis pair are made With, light aging, posttraumatic stress disorder, pre-eclampsia, primary biliary cirrhosis, broncho-pulmonary disease, early ageing, ox-hide Tinea, psoriatic arthritis, pulmonary hypertension, radiotherapy side effect, adjuvant arthritis, clear-cell carcinoma, Respiratory Distress Syndrome(RDS), Retinopathy of prematurity, posterior cord fibrosis, rheumatic disease, rheumatoid arthritis, sarcoidosis, septicemia, sickle cell Anemia, sleep apnea, spherocytosis, spinal cord lesion, apoplexy, synucleinopathies, systemic amyloidosis sample Denaturation, systemic loupus erythematosus, systemic sclerosis (chorionitis), thrombosis, Protein tau disease, it is traumatic stress pulmonary tuberculosis, Unstable angina pectoris, uremia, venous insufficiency, adult progeria and cerebrohepatorenal syndrome.
On the other hand, present disclose provides the method for the oxidative stress for reducing subject, the method includes： (a) level of the oxidative stress in subject is determined by the amount of isoprostane in the urine or blood of measurement subject；(b) A effective amount of composition is applied to subject, the composition includes：(i) include from gramnegative bacterium or gram sun Property at least one lysate of bacterium and/or toll samples receptor (TLR) agonist of lysate fraction, wherein the TLR excitements Agent activates at least one or more of different TLR or NLR；(ii) is used to enhance the optional accelerating agent of composition absorption；And (c) continue to apply composition until the reduction of oxidative stress level, the decrement for passing through isoprostane in subject's urine determine.
In some embodiments, continue to apply bacterial lysate in any of above aspect until in the urine of subject The amount of isoprostane is less than about 3ng/mg kreatinins, is less than about 2ng/mg kreatinins, less than about 1ng/mg kreatinins or is less than about 0.5ng/mg kreatinins.
On the other hand, present disclose provides the pharmaceutical preparations for including following combination：(a) compositions are cracked, it includes (i) bacterial lysate and/lysate of at least one or more of toll samples receptor (TLR) or Nod samples receptor (NLR) can be activated Fraction；(ii) it is used to enhance the optional accelerating agent of composition absorption；(iii) is used to increase the optional carrier of composition volume； (b) one or more medicaments.In some embodiments, one or more medicaments are selected from the group being made up of：It is anti- Spasm agent, motion stimulant, bisfentidine, muscarine antagonist；Chelating agent, prostaglandin analogue, aminosalicylate, Corticosteroid, the drug for influencing immune response, irritant purgative, the drug for influencing bile composition and flowing, bile acid chelating Agent, Dopamine D2 receptor, proton pump inhibitor, opioid, opioid receptors antagonist, antalgesic, sleep drug, Cardiac glycoside, phosphodiesterase inhibitors, thiazide, diuretics, Potassium-sparing diuretic, aldosterone antagonists, osmotic diuresis agent, the rhythm of the heart Arrhythmic agents, beta-adrenoceptor blocking drug object, hypertension drug, drug, the nitric acid for influencing renin-angiotensin system Salt, calcium blockers, antianginal drug, peripheral vasodilator agent, parasympathomimetic agent, anti-coagulants, nucleoprotamine, antiplatelet Drug, fibrinolytic drug object, Antifibrinolytic agents, regulation and control Lipid pharmaceutical, omega-fatty acid compound, CNS medicines Object, anti-infectives, or another drug selected from the group being made up of：Benzetropine, the third ring pyridine, Biperiden, adamantane Amine, bromocriptine, pergolide, Entacapone, Tolcapone, selegiline, Pramipexole, budesonide, Formoterol, fumaric acid Quetiapine, Olanzapine, pioglitazone, montelukast, zoledronic acid, Valsartan, Latanoprost, irbesartan, clopidogrel, Atomoxetine, Dexamfetamine, ritalin, modafinil, bleomycin, D actinomycin D, daunorubicin, idarubicin, rice support are mould Element, mitoxantrone, azacitidine, capecitabine, Cladribine, clofarabine, cytarabine, fludarabine, fluorouracil, Ji His shore of west, mercaptopurine, methopterin, nelarabine, pemetrexed, Raltitrexed, thioguanine, apomorphine, betamethasone, can Pine, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, Triamcinolone acetonide, cyclosporin, west Luo Mosi, tacrolimus, interferon-' alpha ' and interferon beta.
On the other hand, present disclose provides preparation, such as pharmaceutical preparation, it includes：(a) compositions are cracked, it is described Cracking compositions, which include (i), can activate the thin of at least one or more of toll samples receptor (TLR) or Nod samples receptor (NLR) Bacterium lysate and/or lysate fraction；(ii) it is used to enhance the optional accelerating agent of composition absorption；(iii) is for increasing group Close the optional carrier of object product；(b) the people's anti-TNF alpha antibodies or its antigen-binding fragment or tnf inhibitor detached.At some In embodiment, people's anti-TNF alpha antibodies or its antigen-binding fragment are adalimumabs.In some embodiments, the disclosure carries The combination preparation of this aspect has been supplied to prepare for treating the rheumatoid arthritis (RA) of subject or the drug of Delayed onset RA In purposes.In some embodiments, as disclosed herein, present disclose provides the rheumatoid passes for treating subject The method of section scorching (RA) or Delayed onset RA, the method includes the combination system of this aspect of therapeutically effective amount is applied to subject Agent.In some embodiments, subject alreadys exceed 50 years old.In some embodiments, by people's anti-TNF alpha antibodies or its resist Former binding fragment is applied to subject with double all dosage regimens.In some embodiments, by people's anti-TNF alpha antibodies or its antigen Binding fragment is applied to subject with 30mg or higher dosage.In some embodiments, TNF α inhibitor is TNF α fusion Albumen.In some embodiments, TNF α fusion protein is Etanercept.In some embodiments, anti-TNF alpha antibodies or its Antigen-binding fragment is infliximab or goli mumab.In some embodiments, anti-TNF alpha antibodies or its antigen knot It is adalimumab to close segment.
On the other hand, present disclose provides inhibit the relevant disease of oxidative stress or obstacle progress in people experimenter Method, the subject have with to the relevant disease of the harmful relevant oxidative stress of obstacle of TNF α activity or obstacle. This method includes：The lysate of the disclosure, lysate fraction and/or thin are applied to the subject with oxidisability disease or obstacle Cell wall fraction and the people's anti-TNF alpha antibodies or its antigen-binding portion thereof of separation so that in subject oxidative stress progress by To inhibition, wherein people's anti-TNF alpha antibodies or its antigen-binding portion thereof are during L929 is measured outside standard body with 1 × 10-7M or lower IC50Neutralize human TNF alpha cytotoxicity.In some embodiments, the lysate of the disclosure and people's anti-TNF alpha or its antigen-binding portion Divide the different time application under different administration scheme.In some embodiments, people's anti-TNF alpha antibodies be goli mumab or Its antigen-binding portion thereof.In some embodiments, people's anti-TNF alpha antibodies are adalimumab or its antigen-binding portion thereof.One In a little embodiments, people's anti-TNF alpha antibodies or its antigen-binding portion thereof are applied to subject with double all dosage regimens.At some In embodiment, the method further includes applying additional therapeutic agent to the subject.In some embodiments, by this public affairs The time for the lysate application at least 24 weeks opened.In some embodiments, anti-TNF alpha antibodies or its antigen-binding portion are given With at least 24 weeks time.In some embodiments, the lysate, anti-TNF alpha antibodies of the disclosure or its antigen-binding portion thereof, Or both repair or prevent the oxidative damage to subject by the combination of one or more different mechanisms.
In any method disclosed herein or some embodiments of composition, the bacterium is Gram-positive or leather Gram-negative bacteria.In any method disclosed herein or some embodiments of composition, gram-positive bacterium is selected from By the bacterium of Bacillus acidi lactici (Lactobacillaceae) section, the bacterium of streptococcus (Streptococcaceae) section, bifid bar The group of the bacterium of bacterium (Bifidobacteriaceae) section and the bacterium composition of bacillus (Bacillaceae) section.At some In embodiment, gram-positive bacterium is selected from by bacillus coagulans (Bacillus coagulans), gemma Bacillus acidi lactici (Lactobacillus sporogenes), streptococcus thermophilus (Streptococcus thermophilus), animal bifid bar Bacterium (Bifidobacterium animalis), Bifidobacterium (Bifidobacterium), animal (animalis), subspecies are dynamic Object (subspecies animalis), bifidobacterium infantis (Bifidobacterium infantis), bifidobacterium longum (Bifidobacterium longum), bifidobacterium breve (Bifidobacterium breve), Lactobacillus acidophilus (Lactobacillus acidophilus), lactobacillus plantarum (Lactobacillus plantarum), cheese lactic acid bar Bacterium (Lactobacillus casei), lactobacillus delbrueckii (Lactobacillus delbrueckii), lactobacillus delbrueckii Subspecies bulgaricus (Lactobacillus delbrueckii subspecies bulgaricus), Lactococcus lactis (Lactococcus lactis), Lactococcus lactis subsp. lactis (Lactococcus lactis subspecies Lactis), streptococcus lactis (Streptococcus lactis), streptococcus thermophilus (Streptococcus Thermophilus), bifidobacterium lactis (Bifidobacterium lactis), bifidobacterium breve (Bifidobacterium Breve), Pediococcus acidilactici (Pediococcus aciditactici) and Lactobacillus helveticus (Lactobacillus Hetveticus) the group formed.
In any method disclosed herein or some embodiments of composition, gramnegative bacterium is selected from by false single Born of the same parents bacterium (Pseudomonas) belongs to, klebsiella (Klebsiella) belongs to, Xanthomonas campestris (Xanthomonas) belongs to, Shigella (Shigella) belong to the group of the bacterium composition belonged to enterobacteria (Enterobacter).In some embodiments, gram-negative Property bacterium be selected from by Klebsiella oxytoca (Klebsiella oxytocia), shigella flexneri (Shigella Flexneri), xanthomonas campestris (Xanthomonas campestris) and Pseudomonas fluorescens (Pseudomonas Flourescens) the group formed.
In any method disclosed herein or some embodiments of composition (including preparation), TLR agonists, cracking In object, lysate fraction or the activation of cell wall fraction TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2 It is at least one or more of.In some embodiments, TLR agonists, lysate, lysate fraction or the activation of cell wall fraction Two or more in TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2.In some embodiments In, TLR agonists, lysate, lysate fraction or cell wall fraction activate TLR2 and TLR4.In some embodiments, TLR Agonist, lysate, lysate fraction or cell wall fraction activation TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, It is three or more in NOD1 and NOD2.
In any method disclosed herein or some embodiments of composition (including preparation), accelerating agent is selected from by ammonia The group of base acid, amino sugar and sugar composition.In some embodiments, carrier is selected from and is made of adhesive, matrix and combinations thereof Group.In some embodiments, matrix includes at least one hydrophobic polymer and at least one hydrophilic polymer.At some In embodiment, adhesive is selected from the group being made of sugar, sugar alcohol and combinations thereof.In some embodiments, sugar alcohol is selected from by sweet Reveal the group of sugar alcohol, D-sorbite, xylitol and combinations thereof composition.
In some embodiments, composition is manufactured into selected from by pastille, chewing gum, chewable tablets, candy and solution tablet The dosage form of the group of composition.In some embodiments, TLR agonists are delivered to oral mucosa by dosage form.In some embodiments In, oral mucosa is selected from the group being made of hypoglossis mucous membrane, cheek mucous membrane and combinations thereof.
In some embodiments of any method and composition disclosed herein, composition is prepared for oral mucosa Delivering；In some embodiments, composition is prepared for the delivering of sublingual or cheek.In some embodiments, composition quilt It is configured to be no less than in 1 minute after application and dissolve.
Embodiment
The following examples illustrate the specific implementation mode and its various uses of the present invention.They are just for the sake of explanation Purpose and propose, be not viewed as limitation the present invention.
Embodiment 1：The preparation of active constituent for TLR agonist compositions
How the example of compositions formulated includes following procedure.
Active constituent.As described below, active constituent is originated from bacterial fermentation and cell separation process.Lactobacillus delbrueckii, which is protected, to be added Leah subspecies (Lactobacillus delbrueckii, ssp.bulgaricus) (referred to herein as L.bulgaricus) are The organism used in the embodiment, but the bacterial organisms can be any Gram-positive or gramnegative bacterium or The two.
Lactobacillus delbrueckii subspecies bulgaricus (Lactobacillus delbrueckii ssp bulgaricus) exists Including 1.5% caseic hydrolysate, 1% yeast extract, 3% lactose, 0.2% sodium acetate, 0.02% sodium formate, 0.01% 5- inosine acid disodiums, 0.01% manganese sulfate, 0.05% magnesium sulfate and 0.05% polysorbate80, the grown cultures of pH value 6.4 It ferments in base.The culture medium of inoculation is incubated at 37 DEG C until fermentation reaches stable growth, by being metabolized stopping determination.It will hair Zymotic fluid is cooled to 4 DEG C and by being harvested by centrifugation at about 4000-4500 × g.
Cell flowing is set continuously to wash twice the cell of concentration using chilled water and again by centrifugation.By what is washed Cell concentration object was in 80 DEG C of pasteurizes 45 minutes.
After pasteurize, processing cell concentration object is to destroy cell wall, to crack bacterium and exposure TLR agonists.Make Kept at 40 DEG C with the egg white lysozyme of a concentration of 3 weight % 7 hours to complete the destruction of bacteria cell wall.It is split what is obtained Solution object is freezed and is lyophilized.
Freeze dried substance is mixed with accelerating agent (such as hydrochloric acid N-acetyl-glucosamine (NAG)) to form the De Shi lactic acid of cracking The mixture of bacillus subspecies bulgaricus (Lactobacillus delbrueckii subsp.Bulgaricus) and NAG.Appoint Selection of land adds other formulation excipients to generate the pill or powder of solid form as one sees fit.Then the product is used for following sieve Choosing test.
Embodiment 2：TLR screening test
It is tested by assessing the NF- kB activations in the HEK293 cells for expressing given TLR or Nod samples receptor (NLR) Toll-like receptor (TLR) stimulates.7 kinds of different people TLR (TLR2,3,4,5,7,8 and 9 (Invivogen, San Diego, CA)) and at two different people NLR (protein 1 containing nucleotide combination oligomerization domain and 2 (NOD1 and NOD2)) The activity of upper test sample.As described below, each is tested on TLR or NLR cells with the ultimate density of 1/100 stock solution to match Body, and be compared with reference ligands.The step repeats three times.
Reference ligands, control cell lines and the sample used in embodiment is as shown in table 1.
Table 1：Reference ligands and control cell lines information for ligand screening test
Usual program.By assessing the NF- kB activations in the HEK293 cells for expressing given TLR come in test screen TLR is stimulated.The alkaline phosphatase reporter gene of secretion is controlled by the promoter that transcription factor NF-KB induces.It is expressed by assessing NF- kB activations in the HEK293 cells of given TLR or NLR carry out the stimulations of the TLR in test screen.It, should based on the activation of NF- κ B Reporter gene allows to conduct by TLR/NLR monitoring signals.In 96 containing suitable cell (50000-75000 cells/well) It, will be in 20 μ L samples (pyrolysis product) or positive control ligand adding hole in orifice plate (200 μ L total volumes).The training being added in hole Foster base is designed to SEAP (alkaline phosphatase of the secretion) expression of detection NF κ B inductions.After incubating 16-20 hours, The OD (optical density) at 650nm is read on Molecular Devices Spectra Max 340PC absorption photometric detectors and is remembered Record.
The selection result of these experiments is as shown in Figure 2.These the results show that the typical lysate generated as described above for At least TLR2 (and TLR4 of lesser degree) and NOD2 is strong agonist.
Embodiment 3：Influence of the process variable to the variation of TLR signal transductions
By observing influence of certain change in process to TLR signal transductions, it is noted that TLR signal modes may be changed.
Fig. 3 shows that cellular morphology has the difference on the TLR signals of gram-positive organism.It is protected with bacillus organism Leah Bacillus acidi lactici (L.bulgaricus) is added to compare, from Pediococcus acidilactici (Pediococcus acidilactici, one kind Coccus organism) lysate generate higher TLR4 and lower NOD2 signals, and Pediococcus acidilactici (P.acidilactici) the TLR2 signals generated are only slightly higher than Bulgarian Lactobacillus (L.bulgaricus) generation TLR2 signals.NOD2 activation significantly reduces in Pediococcus acidilactici (P.acidilactici), and which reflects found in coccus Relatively low muramyl peptide.
As shown in figure 4, TLR signal modes are also by the training of bacillus coagulans (Bacillus coagulans) lysate Support the influence of harvest time.Using the shaking flask for the test yeast extract/dextrose culture-medium for being 6.5 containing pH value, at 45 DEG C and Culture bacillus coagulans (Bacillus coagulans) are incubated under 250rpm.The harvest of culture follows splitting for embodiment 1 Object production process is solved, but changes the bacterium harvest time after fermentation according to growth phase：Mid-log phase, late log phase, early stage Stationary phase, middle stable phase and stationary phase in later stage are generated by OD, exhausted substrate, metabolin and EPS is determined.In general, these Statistics indicate that TLR activation specifics can be changed by changing the bacterium harvest time after fermenting.For example, being received from mid-log phase The lysate that the culture obtained generates activates all test targets other than TLR4, and for the and of TLR2,3,5,8,9 NOD1 has higher signal.As culture leaves logarithmic phase and enters stationary phase, TLR signal strengths reduce, and stablize in the later stage Phase stops TLR signals completely.In all stage inoculating cell cultures of harvest, and notice cell count at all time points More than 5 × 108CFU/ml.Endospore is not found when visually inspecting culture.TLR effects from lysate come from nutrition Cell.A large amount of EPS is noticed on the side wall of stationary phase in later stage culture.
Fig. 5 shows the TLR signal modes that the lysate from selected gram-positive organism obtains.By thermophilus Bacterium (Streptococcus thermophilus), Lactobacillus helveticus (Lactobacillus helveticus), acidophilus breast Acidfast bacilli (Lactobacillus acidophilus), lactobacillus plantarum (Lactobacillus plantarum), animal Bifidobacterium lactis spp (Bifidobacterium animalis subsp lactis) and bacillus subtilis (Bacillus Subtilis) in the shaking flask that the test yeast for being 6.5 containing pH value extracts lactose/casein hydrolysate culture medium at 37 DEG C and It is cultivated under 110rpm.By lactobacillus plantarum (Lactobacillus plantarum), bifidobacterium animalis subspecies (B.lactis) and bacillus subtilis (Bacillus subtilis) is in the yeast extract medium/Portugal for being 6.5 containing pH value Cultivated at 37 DEG C and 110rpm in the shaking flask of grape sugar culture-medium, and bacillus subtilis (B.subtilis) at 37 DEG C and It is incubated under 250rpm.0.05% cysteine hydrochloride is also added in culture medium by lactic acid Bifidobacterium (B.lactis).Training The harvest for supporting object follows the lysate production process of embodiment 1.As pointed out in embodiment 4, streptococcus thermophilus (S Thermophilus, a kind of coccus organism) it generates similar to other coccus culture Pediococcus acidilacticis (P.acidilactici) TLR signal modes (higher TLR2 and TLR4 and relatively low NOD2).Although however, newborn bifid bar Bacterium (B.lactis) is different from lactobacillus bulgaricus (L.bulgaricus) form, but has similar TLR patterns.In Switzerland Bacillus acidi lactici (L.helviticus), Lactobacillus acidophilus (L.acidophilus), lactobacillus plantarum (L.plantarum) In the Gram-positive bacillus culture of bacillus subtilis (B.subtilis), TLR patterns are almost without similitude.Switzerland Bacillus acidi lactici (L.helviticus) generates the TLR moulds of the TLR patterns similar to lactobacillus bulgaricus (L.bulgaricus) Formula.Although Lactobacillus acidophilus (L.acidophilus) signal strength is relatively low, the result phase that is generated with coccus of result that generates Seemingly.When harvesting and concentrating culture, Lactobacillus acidophilus (L.acidophilus) do not generate apparent EPS, and Bulgarian Lactobacillus (L.bulgaricus), Lactobacillus helveticus (L.helviticus) and bifidobacterium lactis (B.lactis) all generate bright Aobvious EPS, and all generate similar TLR signal modes.Lactobacillus plantarum (L.plantarum) lysate have with it is other The very different TLR signal modes of gram-positive organism, wherein all TLR signals are all silenced.Signal mode it is this Silence is not obvious from the point of view of the feature of fermentation, but known plants Bacillus acidi lactici (L.plantarum) generation can represent TLR signals Many metabolins of reduction.Other than generating higher TLR4 activation, bacillus subtilis (B.subtilis) has and logarithm The similar TLR patterns of bacillus coagulans (B.coagulans) culture of phase harvest.In general, gram-positive organism The TLR signal modes of body change according to the morphology of organism, EPS generations and metabolin.
Fig. 6 shows the TLR signal modes that the lysate from selected gram negative organism obtains.Use tryptose Enzyme soybean broth cultivates Escherichia coli (Escherichia coli), Klebsiella oxytoca (Klebsiella in shaking flask Oxytocia), shigella flexneri (Shigella flexneri), Pseudomonas fluorescens (Pseudomonas ) and xanthomonas campestris (Xanthomonas campestris) flourescens.It cultivates and hastens parturition under 37 DEG C and 250rpm Klebsiella (K.oxytocia), Escherichia coli (E.coli) and shigella flexneri (S.flexneri), at the same at 30 DEG C and By Pseudomonas fluorescens (P.flourescens) and xanthomonas campestris (Xanthomonas campestris) under 250rpm It incubates.Use the yeast extract/dextrose culture-medium culture xanthomonas campestris for being supplemented with 1% calcium carbonate (Xanthomonas campestris).Before harvest, CaCO is removed by centrifuging 3 minutes with 500 × g3.From zymotic fluid Middle harvest culture follows the lysate production process of embodiment 1.It is wondrous and it is surprising that surveyed when with similar concentration When examination, other than TLR5 and 9, the TLR signal modes of the lysate from gram negative organism (including Escherichia coli) exist It is less than the lysate of gram-positive organism in signal strength.In general, Gram-negative mycoderm/cell wall compares gram Positive bacteria is easier to rupture, this may explain higher TLR9 signals.Observe Klebsiella oxytoca (K.oxytocia) EPS is generated during the fermentation with xanthomonas campestris (X.campestris), and also generates relatively high TLR3,4 and 9 Activation, Klebsiella oxytoca (K.oxytocia) generate highest TLR2 and the NOD1 activation of test strain.Bacterial strain is produced with non-EPS (S.flexneri) it compares, EPS has appeared to change TLR signal modes.It is interesting that all gramnegative bacteriums are surveyed in TLR All there is the NF- kB activations of significant ghost in fixed.This NF- kB activities are subtracted from TLR signals, and explain fluorescence The slight cathode active of the TLR7 and NOD2 of pseudomonad (P.flourescens).
Finally, Fig. 7 shows the TLR signal transductions of the cracking compositions comprising xanthans.These statistics indicate that, by open country The lysate and xanthans itself that campestris (Xanthomonas campestris) bacterial strain generates are (by sarson Huang The EPS that monad generates) all generate TLR activation.Both bacterial strain and EPS xanthans have strong impulse to TLR5, to TLR4 and 9 There is medium activity.These statistics indicate that the lysate from given bacterium bacterial strain and the corresponding EPS from the bacterial strain (such as Xanthans in the embodiment) it may be used to or be mixed into for targeting in the active preparations of TLR.
It is wondrous and it is surprising that these statistics indicate that by give lysate generate TLR signal modes and The intensity of TLR signals depends on the selection of manufacturing process and raw material, including but not limited to culture medium and microorganism.These numbers According to showing that TLR activation specifics can change and customized by change process, bacterial organisms, raw material and reagent parameter.
Embodiment 4：Posttraumatic stress disorder (PTSD) diagnoses oxidative stress, cognition and the life in operation veteran Quality index
PTSD is oxidative stress relevant disease or illness.There are four the purposes of the research：(1) present composition is assessed Quantitatively reduce the horizontal validity of operation veteran's oxidative stress marker isoprostane of PTSD diagnosis；(2) it assesses The validity of the qualitative operation veteran's nitric oxide level for reducing PTSD diagnosis of the present composition；(3) the assessment present invention Composition finds the validity with word recall in the word for the operation veteran for improving PTSD diagnosis；And (4) assessment is originally Validity of the inventive composition in terms of the operation veteran's quality of life parameter for improving PTSD diagnosis.
Emerging evidence-based literature supports the contact between oxidative stress and posttraumatic stress disorder (PTSD).Due to cycle Imbalance between oxidant and antioxidant, oxidative stress occur in vivo and cellular level.Many studies have shown that this Cellular oxidation stress be caused by free radical is to the influence of human nerve physiology.Nitric oxide is considered preventing oxidisability Stress aspect play a significant role.
In the individual and operation veteran that traumatic brain injury occurs, searches word and suffer from influence.It is closed Property head injury/traumatic brain injury (CHI/TBI) and the frequent complications of PTSD.
Subject's selection criteria.
The anticipated number for studying participant is at least 10 people, up to 15 people.
Expected Sex distribution is as close possible to 50% male and 50% women.Male due to being diagnosed as PTSD leaves the army Soldier's number is more, therefore masculinity proportion may be more slightly higher in group of participants.
Pregnant woman is not allowed to participate in research.
Unique age limit be since conscription minimum age is 18 years old, expection the range of age of research from 18 years old to About 80 years old, the upper limit was determined by the general level of the health.
Without the limitation of race or mational origin.Expection percentage based on race reflects the participation in big Houston area The ratio that person is recruited.These percentages are substantially：It is 44% Hispanic (Hispanic), 26% white man (white), 23% non- It is continent descendants American (African America), 6% Asian (Asian), 1% other.
It is included in and is listed in the table below 2 with exclusion criteria.
2. embodiment 3 of table be included in and exclusion criteria.
Methods and procedures
Under informed consent, participant be estimated with assess cellular oxidation stress level, nitric oxide level, language/ Word ability of discovery, anxiety and level of depression and current quality of life parameter.
Participant is provided 15 days compositions, and the composition can reduce oxidative stress by inference, specifically by different in urinating Indicated by the reduction of forefront alkane level.Sublingual two (2) of taking are secondary daily for a 12mg products tablet in two (2), in total daily 48mg.
In order to minimize measurement fluctuation, placebo is not used, subject compares as the measurement of oneself.All subject's quilts It is assigned to identical seminar and receives identical program.
Oxygen is measured by the urinalysis of isoprostane using commercially available measuring method (Oxford Biomedical Research) The property changed stress.Creatine is carried out to the sample of collection using kreatinin assay kit (Oxford Biomedical Research) Acid anhydride is standardized to control the difference of urine concentration level.
Every participant detected the isoprostane levels minimum value in his/her urine with the 15th day on day 1.At 15 days In every day of research, it is desirable that consistent individual subset submits urine sample over time may hair as inspection to establish data point The method of raw isoprostane variation.Retain third party's progress isoprostane measurement (ignorant to goal in research).
All participants have carried out the secondary language testing in three (3) with the 15th day in private chamber on day 1.The language used is surveyed Examination is the 4th edition acceptance word picture vocabulary test the 4th edition (ROWPVT-4), expressivity word picture vocabulary test (EOWPVT- And nonverbal intelligence test the 4th edition (TONI-4) 4).
In addition, it is desirable that every participant completed anxiety and depressed self-assessment scale (Zung with the 15th day on day 1 Self-Rating Scale for Anxiety and Depression), life is satisfied with scale (SWLS) and Eppworth is thermophilic Sleep scale (the Eppworth Sleepiness Scale).These tables are filled in private chamber, and are compiled using standard method Code is to cover the identification information of participant.
Every participant fills in is sent to his/her daily quality of life 4 points of every morning by Email (QOL) it investigates.In order to allow every participant to be familiar with QOL investigation forms and establish stronger data baseline, everyone start he/ She starts to record his/her score in QOL is investigated using minimum four (4) day before product.
Data analysis and data monitoring
After collecting above-mentioned parameter in 15 days, analysis and research data with determine oxidative stress and nitric oxide level, The trend of word ability of discovery, the presence of anxiety/depression and overall life quality scores.Used statistical analysis technique is Directly, because only having evaluated a quantitative parameter, i.e. isoprostane.Use multivariate statistics testing and analysis data appropriate.
Risk gain is assessed.
Risk：The risk of this experiment is " minimum ".Therefore, agree to that injury language is must not in letter of consent It wants, therefore clinical trial protocol (CTA) is not necessarily to.Minimum risk classification is since tested product is considered as The fact that the food-grade GRAS compounds found in Yoghourt.Further, since urine and saliva are the body fluid of unique collection, therefore do not have Have and carries out invasive program.
When collecting data, about 35 people (male and female) are taking the product.In research, longest use Person began to use the product before 17 months, and reported the adverse side effect without being generated using the product.About totally 35 In a individual using the product, adverse side effect is not reported.
Subject's determination and recruitment method
The research has used convenient sample, and the method for recruiting participant is based primarily upon individual and the profession connection of investigator System.
Subject's ability
If this people is considered lacking enough agreement abilities, them is not allowed to participate in this research.Not not at Year, people participated in this research, and also nobody requires to submit letter of consent or legal representative on the scene.
Subject's comprehension
Enough comprehensions are had occurred that in order to assess, and participant is required to grind to personal explain for carrying out consenting process Study carefully, then them is just allowed to participate in the research.Subject confirms that their all problems are all adequately answered.
As a result
In this study, the effect of replenishers is assessed by measurement/analysis：1) isoprostane levels；2) quality of life tune Come to an end fruit；3) psychology/psychological research result；With 4) oratorical speech result.
As shown in figure 8, causing the horizontal of isoprostane in urine to reduce with replenishers treatment.Isoprostane is not relate to usually And the cyclo-oxygenase (COX) of prostaglandin generation is (main by the peroxidating essential fatty acid of free radical catalysis when directly acting on It is arachidonic acid) prostaglandin-like compound that is formed in vivo.These compounds are in animal and people's oxidative stress model The precise marking object of lipid peroxidation.At the 15th day, most of subjects showed the isoprostane levels of reduction.To the 70th It, all subjects show that isoprostane levels are lower than the 1st day.
As seen in table 3A and table 3B, the amount of isoprostane after treating 15 days is caused to substantially reduce with the composition treatment, Table 2A shows the initial data from the research, and table 3B shows that the percentage for calculating oxidative stress marker reduces and hundred Divide than the result after improving.In table 3A and 3B, " PTSD+ " is the participant for being diagnosed as having PTSD." PTSD- " be not by It is diagnosed as the participant with PTSD." TX+ " is the participant that composition is used before research." XX- " is that this was not used The participant of composition.
As shown in table 3B, subject shows that isoprostane levels reduce by 60% after treating 15 days, then in treatment 70 Isoprostane levels additionally reduce by 3.18% after it.In addition, subject shows oxidative stress biology mark after treating 15 days Remember that object level improves 469%, then oxidative stress biomarker (isoprostane) is horizontal after treating 70 days additionally improves 53.19%.
Table 3A：PTSD oxidative stress studies initial data
Table 3B：PTSD oxidative stress datas
It is required that subject is with the grade self-assessment of 1-10 and evaluates their sleep, wherein value 1 corresponds to sleep and lacks It falls into, and value 10 corresponds to without sleep defect.As shown in figure 9, compared with the sleep of self-assessment in the 1st day evaluation quality, the 70 days all subjects show that sleep defect is reduced.
It is required that subject is with the grade self-assessment of 1-10 and evaluates their neurologic condition, wherein value 1, which corresponds to, to be come Pain is not accommodated greatly from neurologic condition, and value 10 corresponds to the minimum from neurologic condition and does not accommodate pain.Such as figure Shown in 10, compared with the 1st day, at the 15th day, all subjects (other than 2) (P03 and P04) showed from neuropathy The minimum of symptom does not accommodate pain.Compared with the 1st day, at the 70th day, all patients showed certainly (other than 1 (P03)) The minimum of neurologic condition does not accommodate pain or-in the case of P04-(notices that P04 is being studied without difference in terms of discomfort It is showed when beginning from the minimum of neurologic condition and does not accommodate pain).
It is required that subject is with the grade self-assessment of 1-10 and evaluates their overall mood, wherein value 1 corresponds to usual Unhappy or uneasy mood, and value 10 corresponds to usual happy or easily mood.As shown in figure 11, at the 15th day it is all by Examination person shows the improvement of overall mood (other than 2).Compared with the 1st day, in the 70th day all patients (in addition to 1 (P04) other than) all show the improvement of overall mood.
It is required that subject is with the grade self-assessment of 1-10 and the total energy level for evaluating them, wherein value 1 corresponds to Low-level energy, and value 10 corresponds to high-caliber energy.As shown in figure 12, compared with the 1st day, the 15th day and the 70th day All subjects (other than P03) all show the increase of energy level.
It is required that subject is with the grade self-assessment of 1-10 and evaluation, they (pass through the total satisfaction of its articulation health Estimate that many factors including flexibility, stiff and pain determine), wherein value 1 corresponds to low-level satisfaction, and Value 10 corresponds to high-caliber satisfaction.As shown in figure 13, compared with the 1st day, at the 15th day all subjects (in addition to P03 and Other than P04) show improvement to the level of satisfaction in its joint.The trend continued at the 70th day.
It is required that subject is with the grade self-assessment of 1-10 and evaluates their total satisfactions to its digestive health, In, value 1 corresponds to low-level satisfaction, and value 10 corresponds to high-caliber satisfaction.As shown in figure 14, compared with the 1st day, At the 15th day, all subjects showed the improvement to its digestive health level of satisfaction (in addition to P01 and P04).The trend exists Continue within 70th day.
It is required that subject is with the grade self-assessment of 1-10 and the overall irritability level for evaluating them, wherein value 1 corresponds to High-caliber choler, and value 10 corresponds to the choler of floor level.As shown in figure 15, compared with the 1st day, in the 70th day institute There is subject to show the reduction of choler level.
It is required that subject is with the grade self-assessment of 1-10 and evaluates their the satisfaction aggregate levels to its sexual function, In, value 1 corresponds to low-level satisfaction, and value 10 corresponds to high-caliber satisfaction.As shown in figure 16, compared with the 1st day, At the 70th day, all subjects showed the increase to the level of satisfaction of its sex expression (other than P04 and P05).
According to the guideline of Epworth Sleepiness Scales (ESS), it is desirable that subject's self-assessment and its daytime drowsiness of evaluation Aggregate level.ESS is the questionnaire of a self-management, there is 8 problems.It provides the general water of the daytime drowsiness of a people Flat or their average sleep tendencies in daily life measurement.It has become the world standard method for carrying out this assessment.ESS It is required that people would generally be in 8 kinds of different situations or most people as daily life to them according to 4 graduation (0-3 points) Drowsiness or the chance fallen asleep are evaluated in the activity that a part participates in, although not necessarily daily.It is not required for people every The frequency dozed off in the case of kind.This is heavily dependent on the frequency that they occur in these cases.On the contrary, it can be wanted Ask they when the chance that can all doze off in each case.This needs spirit to judge, it appears that most people can be with Significant mode is made decision.Total ESS scorings are the summations of 8 item ratings, can be between 0-24.Score higher, the people Daytime drowsiness's degree it is higher.Total ESS scorings provide the estimation-of everyone general features their in daily life flat Drowsiness level.
As shown in figure 17, the reduction of daytime drowsiness is shown in the 15th day all subjects.Compared with the 1st day, the 70th Its all subject for completing research all shows the reduction of daytime drowsiness (other than P03).
It is required that subject is with the grade self-assessment of 1-40 and evaluates their life satisfaction degree aggregate level, wherein value 1 Corresponding to low-level satisfaction, and value 40 corresponds to high-caliber satisfaction.As shown in figure 18, compared with the 1st day, the 15th The life satisfaction degree level of its all subject all increases.The trend continued at the 70th day.
It is required that guideline self-assessment and evaluation their anxiety of the subject according to Zung depression self-assessment scales Aggregate level.Zung depression self-assessment scales by Duke University psychiatrist William W.K.Zung MD design with Assessment is diagnosed as the level of the depression of patients with depression.
Zung depression self-assessment scales are that a brief self-management is investigated to quantify the depressive state of patient.The amount Table has 20 evaluations emotion related with depression, the grade of psychology and somatization.There are ten positive wording and ten disappear Pole wording problem.The scoring ranging from 1 to 4 of each problem is (according to these answers：It is " some time ", " some times ", " more Time ", " plenty of time ").The test scope that scores is from 20 to 80.It is divided into four ranges, wherein：20-44 and normal range (NR) Correlation, 45-59 is related to mild depression state, and 60-69 is related to moderate depressive patients state, 70+ and severe depression state It is related.As shown in figure 19, compared with the 1st day, at the 15th day, all subjects showed depression (other than P01 and P05) Horizontal reduction.Compared with the 1st day, the drop of anxiety level is all shown in the 70th day subject P02, P03, P04, P06 and P07 It is low.
Embodiment 5：With the reduction of the relevant side effect of oxidative stress.
Reduce headache.17 years old male that cerebral concussion three times is undergone in 1.5 years before treatment is daily with the dosage of 45mg The lysate of the administered twice disclosure.At the 14th day for the treatment of, incremental dose to twice daily 75mg active constituents.Before treatment, Patient's report frequently headache.F2- isoprostanes (F2IsoP) are measured as 2.4ng/mg kreatinins in urine before treatment.Figure 20 is aobvious Show that the isoprostane measured in Urinary reduces in 85 days, from 72-85 days average out to 0.82ng isoprostanes/mg creatines Acid anhydride.Alphabetical A-H in Figure 20 indicates following event：(A) the 1st to 3 day, baseline F2IsoP was horizontal；(B) the 3rd day, in 9.99ng/ There is severe headache at peak in mgF2IsoP；(C) the 1st to 13 day, using twice daily 45mg lysates, with daily headache；(D) 13rd day, patient begin to use twice daily 75mg lysates to solve headache；(E) the 18th day to 89 days, headache was It solves and continues to be resolved；(F) the 30th day, new impact event was played soccer, and was had a headache 18 hours, disorderly with vision and nerve Disorderly；(G) the 81st day, scene pressure events showed that raised F2IsoP is horizontal, but without result in headache；(H) the 1st to 89 day, different Forefront alkane Trendline shows reduction 98% in 89 days.In general, these are statistics indicate that the oxidisability that response lysate is applied Stress adjoint reduction.In addition, subjects reported is significantly reduced using having a headache after lysate.
Other reductions with the relevant side effect of oxidative stress.It will be with the relevant one or more pairs of experience of pharmacy application The bacterial lysate of the disclosure is co-administered with the dosage of twice daily 45-100mg by the patient of effect.It is split starting to be co-administered Before solving object, F2- isoprostane levels are measured in blood or urine.The co-administration of lysate cause F2IsoP levels with Time continues to decline, the horizontal overall reductions of F2IsoP about 50% in about 45 days, and F2IsoP levels reduce in about 90 days About 95%, along with the reduction with the relevant oxidative stress related side effects of drug.
Embodiment 6：Lysate/adalimumab combination is effective for the skin disease in treatment psoriatic arthritis
It is studied to assess therapeutic group of the bacterial lysate combination of compositions comprising adalimumab and the disclosure The effect of closing object is applied the combinatorial association or respectively and (is aoxidized for the skin disease of psoriatic arthritis (PsA) patient Property stress disorders).
NSAID treatment failures active PsA patient (>3 swelling and>3 tenderness joints) in have studied A Damu mono- The anti-random III phases are studied.By methotrexate (MTX) (MTX) using and psoriasis degree (<3% or>3% body surface area [BSA]) Center segment randomization is carried out in baseline.The patient completed the 24th week will be eligible to continue open label patulous research.
If patient has psoriasis history；More than 18 years old；>3 swelling and>3 tenderness joints；Reaction to NSAID treatments Deficiency is then included in patient.Exclusion criteria includes previously carrying out anti-TNF treatments；Receive A Laisaipu into studying in first 12 weeks；Into Enter the first 6 weeks interior other biological agents of receiving of research；Receive DMARD into studying in first 4 weeks (other than MTX)；Into research Psoriasis systemic therapy is carried out in first 4 weeks；And enter research interior progress phototherapy in first 2 weeks and local treatment.
According to methotrexate (MTX) use (Yes/No) and psoriasis degree (<3% He>3%BSA is participated in) patient is layered, And the oral lysate for receiving 20-50mg is as daily basis, in conjunction with 40mg adalimumabs week about or placebo to 24 Week.
Effect ready for use measures：ACR response criterias (common Primary Endpoint：ACR20 responses in 12nd week)；Into Have when research great psoriasic patient psorasis area and severity index (PASI) (>3%BSA)；With psoriasic doctor Total evaluation (PGA).The research is according to psoriasic severity in baseline：PASI ＜ 10 and PASI >=10 checks patient.
Therefore, it is influenced at baseline>The effect of psoriatic of 3%BSA, measurement included PASI, psoriasis PGA and DLQI. ACR response criterias are measured used also as effect.To baseline PASI<10 and PASI>10 patient carries out ex-post analysis.PASI is analyzed It is carried out by NRI, and PGA and DLQI scores are calculated as LOCF.
The treatment group for receiving the lysate being co-administered experienced injection site reaction (such as pain, rubescent or stimulation) Improve and less total oxidation stress related side effects, this, which will allow to increase, adheres to and to the compliance for the treatment of, this turn And to improve the chance that primary disease provides bigger.
Embodiment 7：Lysate/statin/Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe combination is effective to treatment hypertension
Carry out hypertension therapeutic and receive once a day 20mg Pravastatins and once a day 20mg lisinoprils combine People experimenter is undergoing skin erythema and the oxidative stress related side effects of insomnia.
When to patient additionally using twice daily 45mg by the lysate covered is disclosed herein, solves skin in 60 days The side effect of erythema and insomnia.
Embodiment 8：Lysate/SSRI combinations are effective to treatment clinical depression
It carries out treating depression and receives 60mg Duloxetines once a dayPeople experimenter just In the experience relevant side effect of oxidative stress (orgasm disorder, dizziness, numbness and choler).
When to patient additionally using twice daily 45mg by the lysate covered is disclosed herein, orgasm is solved in 10 days Obstacle, solved in 7 days it is dizzy, solve in 10 days it is numb and 5 days in solve choler.
Embodiment 9：Lysate/hormone combinations are effective to treatment hypothyroidism
It carries out hypothyroidism treatment and receives 150mg levothyrocines once a dayPeople experimenter be undergoing and the relevant alopecia side effect of oxidative stress.
When to patient additionally using twice daily 75mg by the lysate covered is disclosed herein, solved in 180 days de- The side effect of hair.
Embodiment 10：Lysate/reverse transcriptase inhibitor combination is effective to treatment HIV infection
HIV (non-AIDS) is carried out to treat and receive a piece of efavirenz/emtricitabine/Nuo Fuwei ester group richnesses once a day Fumaric esterPeople experimenter be undergoing oxidative stress related side effects (erectile dysfunction, nerve Disease, insomnia and brain atomization).
When to patient additionally using twice daily 45mg by the lysate covered is disclosed herein, erection work(is solved in 10 days It can obstacle, solution neuropathy, solution insomnia, solution brain mist in 3 days in 3 days in 10 days.
Embodiment 11：Lysate/directly effect antiviral drugs combination is effective to treatment hepatitis C
It carries out treating hepatitis c and receives a piece of Lei Dipawei/Suo Feibuwei once a day's People experimenter is undergoing oxidative stress related side effects (brain mist, headache and arthritis).
When to patient additionally using twice daily 75mg by the lysate covered is disclosed herein, brain mist, 10 are solved in 3 days Headache is solved in it, solves arthritis in 14 days.
Embodiment 12：Lysate/anticancer drug combination is effective to treating cancer
Topoisomerase I inhibitor/vincaleukoblastinum alkaloid/the alkanisation for carrying out treatment of cancer and the double weekly doses of receiving is antitumor MedicinePeople experimenter be undergoing oxidation Property stress related side effects (brain mist, discomfort, insomnia and erythema).
When to patient additionally using twice daily 75mg by the lysate covered is disclosed herein, brain mist, 5 are solved in 3 days Discomfort is solved in it, is solved insomnia in 5 days, is solved erythema in 14 days.
Embodiment 13：Lysate/insulin analog combination is effective to treatment diabetes B
It carries out diabetes B treatment and receives the insulin analog insulin glargine of daily dosage People experimenter be undergoing oxidative stress related side effects (erythema (injection site), choler and headache).
When to patient additionally application twice daily 45mg is by being disclosed herein the lysate covered when, solve in 5 days choler, Headache is solved in 7 days, erythema (injection site) is solved in 10 days.
Embodiment 14：Lysate/antibiotic combinations are effective to treatment rheumatoid arthritis
Before 10 months, it is diagnosed with rheumatoid arthritis and the people experimenter treated with tnf inhibitor is also being used The antibiosis extract for treating for leading to 3 grades of diarrhea, as determined by National Cancer Institute (NCI) standard.Meanwhile subject receives additionally Antibiotic to fight the clostridium difficile infection caused by severe diarrhea.In the case where not changing current pharmacological treatments, 45mg lysates are additionally applied 2 times a day to subject.Diarrhea starts to solve within 2 weeks, and it is NCI 2 to improve in one month Grade standard.
Embodiment 15：Lysate/radiation combination is effective to treating cancer
Prostate cancer therapy is carried out to people experimenter and receives following intensity during 40 days of predetermined treatment and/or holds Continuous time increased radiotherapy：It is quick-fried on 9 points in 8 sessions of 180cGy (lcGy=1rad) in one day weekly It sends out twice, one time 8 seconds, one time 5 seconds；In 8 sessions of 180cGy, break out 12 seconds and 9 seconds；In 9 sessions of 180cGy In, it breaks out in the quadrant of 2, right side 14 seconds and 10 seconds, is then broken out 12 seconds and 9 seconds in left side；And in 16 meetings of 200cGy In words, two continuous circles pass through 80 seconds and every a session be all two complete continuous circles in the opposite direction On across.Always on Monday, next each Tuesday doctor can see patient to assess pair for the variation of dose of radiation Effect.Increasing every time leads to nausea 3 hours, occurs after treatment about 2 hours, and 6 hours are no more than after any treatment session completely It solves.In conjunction with radiotherapy in the treatment, the lysate of the disclosure of 75mg dosage is applied to patient, three times a day.Do not applied to patient Any treatment for being used for Nausea and vomiting or bleeding.(" 1 " is worst, and " 10 " are best in 1 to 10 quality of life scale ), patient reports 8 as the beginning of exposure finally upgraded.Patient reports that nausea will not be less than in maximum exposure 7, and continue to fulfil its responsibilities during the entire course for the treatment of daily.
In view of a variety of mechanism of action for the said medicine that the cracking compositions with the disclosure are co-administered, and in view of splitting The mechanism of action for solving object itself, can rationally infer that cracking compositions disclosed herein have most of any drugs to provide The result of the detrimental effect reduction of benefit.For example,It is a kind of α-TNF of injectable, is co-administered with lysate It will produce the improvement of injection site stimulation.According to package insert, which is confirmed as causing arthritis, is such as directly acting on AntiviroticSeen in.When patient by the lysate of the disclosure and defined HCV drugs such asWhen being used together, during treatment side effect reduce and will not continue after treating.
It should be understood that setting as described herein and function are presented just for the sake of example purpose, and it is a variety of Variant is possible.For example, element can be added, be omitted, combined, distributed, resequenced or modified in other ways.Therefore, Following following claims is understood to include the above content for specifically illustrating and describing, conceptive equivalent content, can obviously replace The content in generation and the content for substantially combining basic thought of the invention.Those skilled in the art will recognize that not In the case of departing from the scope of the present invention, various modifications and the modification of the embodiment just described can be configured.Exemplary reality It applies mode to illustrate merely for example purpose, and is not construed as the limitation present invention.It is therefore to be understood that In scope of the appended claims, the present invention can be implemented in a manner of otherwise than as specifically described herein.

Claims (112)

1. a kind of toll samples receptor (TLR) agonist compositions for regulating and controlling the redox state of subject, the combination Object includes：
(a) at least one lysate comprising bacterium and/or the TLR agonists of lysate fraction, wherein the TLR agonists Activate at least one or more of TLR or NLR；
(b) it is used to enhance the optional accelerating agent that the composition absorbs；With
(c) it is used to increase the optional carrier of the composition volume,
Wherein, the oxidisability in the subject is measurably reduced using a effective amount of composition to the subject to answer Swash level.
2. composition according to claim 1, wherein the agonist activation at least two different TLR and/or NLR.
3. composition according to claim 1, wherein the agonist activation at least three kinds different TLR and/or NLR.
4. composition according to claim 1, wherein the bacterium is that gram-positive bacterium or Gram-negative are thin Bacterium.
5. composition according to claim 4,
Wherein, at least one gram-positive bacterium be selected from by Bacillus acidi lactici (Lactobacillaceae) section bacterium, The bacterium of streptococcus (Streptococcaceae) section, the bacterium of Bifidobacterium (Bifidobacteriaceae) section and gemma bar The group of the bacterium composition of bacterium (Bacillaceae) section；And
Wherein, at least one gramnegative bacterium is selected from by pseudomonad (Pseudomonas) category, klebsiella (Klebsiella) belong to, Xanthomonas campestris (Xanthomonas) belongs to, Shigella (Shigella) belongs to and enterobacteria (Enterobacter) group of the bacterium composition belonged to.
6. composition according to claim 4,
Wherein, at least one gram-positive bacterium is selected from by bacillus coagulans (Bacillus coagulans), bud Spore Bacillus acidi lactici (Lactobacillus sporogenes), streptococcus thermophilus (Streptococcus thermophilus), Animal bifidobacteria (Bifidobacterium animalis), Bifidobacterium (Bifidobacterium), animal (animalis), subspecies animal (subspecies animalis), bifidobacterium infantis (Bifidobacterium Infantis), bifidobacterium longum (Bifidobacterium longum), bifidobacterium breve (Bifidobacterium Breve), Lactobacillus acidophilus (Lactobacillus acidophilus), lactobacillus plantarum (Lactobacillus Plantarum), Lactobacillus casei (Lactobacillus casei), lactobacillus delbrueckii (Lactobacillus Delbrueckii), lactobacillus delbrueckii subspecies bulgaricus (Lactobacillus delbrueckii subspecies Bulgaricus), Lactococcus lactis (Lactococcus lactis), Lactococcus lactis subsp. lactis (Lactococcus Lactis subspecies lactis), streptococcus lactis (Streptococcus lactis), streptococcus thermophilus (Streptococcus thermophilus), bifidobacterium lactis (Bifidobacterium lactis), bifidobacterium breve (Bifidobacterium breve), Pediococcus acidilactici (Pediococcus aciditactici) and Lactobacillus helveticus The group of (Lactobacillus hetveticus) composition；And
Wherein, at least one gramnegative bacterium is selected from by Klebsiella oxytoca (Klebsiella oxytocia), good fortune Family name Shigella (Shigella flexneri), xanthomonas campestris (Xanthomonas campestris) and fluorescence are false The group of monad (Pseudomonas flourescens) composition.
7. composition according to claim 1, wherein the TLR agonist activations TLR2, TLR3, TLR4, TLR5, At least one of TLR7, TLR8, TLR9, NOD1 and NOD2 or a variety of.
8. composition according to claim 2, wherein TLR the agonist activations TLR2 and TLR4.
9. composition according to claim 1, wherein the TLR agonist activations TLR2, TLR3, TLR4, TLR5, Two or more in TLR7, TLR8, TLR9, NOD1 and NOD2.
10. composition according to claim 1, wherein the TLR agonist activations TLR2, TLR3, TLR4, TLR5, It is three or more in TLR7, TLR8, TLR9, NOD1 and NOD2.
11. composition according to claim 1, wherein the accelerating agent selects free amino acid, amino sugar and sugar composition Group.
12. composition according to claim 1, wherein the carrier is selected from and is made of adhesive, matrix and combinations thereof Group.
13. composition according to claim 12, wherein the matrix is comprising at least one hydrophobic polymer and at least A kind of hydrophilic polymer.
14. composition according to claim 12, wherein described adhesive, which is selected from, to be made of sugar, sugar alcohol and combinations thereof Group.
15. composition according to claim 14, wherein the sugar alcohol is selected from by mannitol, D-sorbite, xylitol And combinations thereof composition group.
16. composition according to claim 1, wherein the composition is manufactured into selected from by pastille, chewing gum, nozzle Chew the dosage form of the group of piece, candy and solution tablet composition.
17. composition according to claim 16, wherein the agonist is delivered to oral mucosa by the dosage form.
18. composition according to claim 17, wherein the oral mucosa be selected from by hypoglossis mucous membrane, cheek mucous membrane and its The group that group is combined into.
19. composition according to claim 1, wherein applying the composition and pharmaceutical agent combinations to enhance the medicine The activity of agent.
20. composition according to claim 1, wherein applying the composition and pharmaceutical agent combinations to reduce the medicine The side effect of agent.
21. composition according to claim 20, wherein the side effect of the medicament is oxidative stress.
22. a kind of method of the redox state of regulation and control subject, the method includes being controlled to subject in need application Treat a effective amount of composition according to claim 1.
23. according to the method for claim 22, wherein by measure the variation of isoprostane concentration in the subject come Assess redox state regulation and control.
24. according to the method for claim 23, wherein the subject is mammal.
25. according to the method for claim 24, wherein the mammal is people.
26. according to the method for claim 23, wherein the subject is nonmammalian.
27. according to the method for claim 26, wherein the subject is fish, poultry, shellfish and insect.
28. according to the method for claim 27, wherein the insect is drosophila.
29. according to the method for claim 25, wherein the redox state is oxidisability and leads to oxidisability It stress.
30. according to the method for claim 29, wherein the oxidative stress of people is related to posttraumatic stress disorder.
31. a kind of method of the redox state of regulation and control subject, this approach includes the following steps：
(a) dosage for separating on subject in need repeatedly administration time and being made of composition, the composition include：
(i) at least one lysate comprising bacterium and/or toll samples receptor (TLR) agonist of lysate fraction, wherein institute State agonist activation at least one or more of different TLR or NLR；
(ii) it is used to enhance the optional accelerating agent that the composition absorbs；With
(iii) it is used to increase the optional carrier of the composition volume, and
(b) body fluid of the subject is measured to detect the variation of oxidative stress level.
32. the method for the redox state of regulation and control subject according to claim 31, wherein the agonist activation At least two different TLR and/or NLR.
33. the method for the redox state of regulation and control subject according to claim 32, wherein the agonist activation At least three kinds different TLR and/or NLR.
34. the method for the redox state of regulation and control subject according to claim 31, wherein the bacterium is that leather is blue Family name's positive bacteria or gramnegative bacterium.
35. the method for the redox state of regulation and control subject according to claim 34,
Wherein, at least one gram-positive bacterium be selected from by Bacillus acidi lactici (Lactobacillaceae) section bacterium, The bacterium of streptococcus (Streptococcaceae) section, the bacterium of Bifidobacterium (Bifidobacteriaceae) section and gemma bar The group of the bacterium composition of bacterium (Bacillaceae) section；And
Wherein, at least one gramnegative bacterium is selected from by pseudomonad (Pseudomonas) category, klebsiella (Klebsiella) belong to, Xanthomonas campestris (Xanthomonas) belongs to, Shigella (Shigella) belongs to and enterobacteria (Enterobacter) group of the bacterium composition belonged to.
36. the method for the redox state of regulation and control subject according to claim 34,
Wherein, at least one gram-positive bacterium is selected from by bacillus coagulans (Bacillus coagulans), bud Spore Bacillus acidi lactici (Lactobacillus sporogenes), streptococcus thermophilus (Streptococcus thermophilus), Animal bifidobacteria (Bifidobacterium animalis), Bifidobacterium (Bifidobacterium), animal (animalis), subspecies animal (subspecies animalis), bifidobacterium infantis (Bifidobacterium Infantis), bifidobacterium longum (Bifidobacterium longum), bifidobacterium breve (Bifidobacterium Breve), Lactobacillus acidophilus (Lactobacillus acidophilus), lactobacillus plantarum (Lactobacillus Plantarum), Lactobacillus casei (Lactobacillus casei), lactobacillus delbrueckii (Lactobacillus Delbrueckii), lactobacillus delbrueckii subspecies bulgaricus (Lactobacillus delbrueckii subspecies Bulgaricus), Lactococcus lactis (Lactococcus lactis), Lactococcus lactis subsp. lactis (Lactococcus Lactis subspecies lactis), streptococcus lactis (Streptococcus lactis), streptococcus thermophilus (Streptococcus thermophilus), bifidobacterium lactis (Bifidobacterium lactis), bifidobacterium breve (Bifidobacterium breve), Pediococcus acidilactici (Pediococcus aciditactici) and Lactobacillus helveticus The group of (Lactobacillus hetveticus) composition；And
Wherein, at least one gramnegative bacterium is selected from by Klebsiella oxytoca (Klebsiella oxytocia), good fortune Family name Shigella (Shigella flexneri), xanthomonas campestris (Xanthomonas campestris) and fluorescence are false The group of monad (Pseudomonas flourescens) composition.
37. the method for the redox state of regulation and control subject according to claim 31, wherein the TLR agonists Activate at least one of TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2 or a variety of.
38. the method for the redox state of regulation and control subject according to claim 31, wherein the TLR agonists Activate two or more in TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2.
39. the method for the redox state of regulation and control subject according to claim 31, wherein the TLR agonists It activates three or more in TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2.
40. according to the method for the redox state of the regulation and control subject described in claim 38, wherein the TLR agonists Activate TLR2 and TLR4.
41. the method for the redox state of regulation and control subject according to claim 31, wherein the accelerating agent is selected from The group being made of amino acid, amino sugar and sugar.
42. it is according to claim 31 regulation and control subject redox state method, wherein the carrier be selected from by The group of adhesive, matrix and combinations thereof composition.
43. the method for the redox state of regulation and control subject according to claim 42, wherein the matrix includes extremely A kind of few hydrophobic polymer and at least one hydrophilic polymer.
44. the method for the redox state of regulation and control subject according to claim 42, wherein described adhesive is selected from The group being made of sugar, sugar alcohol and combinations thereof.
45. it is according to claim 44 regulation and control subject redox state method, wherein the sugar alcohol be selected from by The group of mannitol, D-sorbite, xylitol and combinations thereof composition.
46. the method for the redox state of regulation and control subject according to claim 31, wherein the composition is made Cause the dosage form selected from the group being made of pastille, chewing gum, chewable tablets, candy and solution tablet.
47. the method for the redox state of regulation and control subject according to claim 46, wherein the dosage form will be described Agonist is delivered to oral mucosa.
48. the method for the redox state of regulation and control subject according to claim 31, wherein the oral mucosa choosing The group of free hypoglossis mucous membrane, cheek mucous membrane and combinations thereof composition.
49. the method for the redox state of regulation and control subject according to claim 31, wherein measured to body fluid To assess the variation of isoprostane concentration in the subject.
50. the method for the redox state of regulation and control subject according to claim 31, wherein the subject is to feed Newborn animal.
51. the method for the redox state of regulation and control subject according to claim 50, wherein the mammal is People.
52. according to the method for claim 31, wherein the subject is nonmammalian.
53. method according to claim 52, wherein the subject is fish, poultry, shellfish and insect.
54. method according to claim 53, wherein the insect is drosophila.
55. the method for the redox state of regulation and control subject according to claim 54, wherein the oxidative stress of people It is related to posttraumatic stress disorder.
56. the method for the amount of isoprostane, the described method comprises the following steps in a kind of urine reducing subject or blood：
(a) urine of the subject or the level of isoprostane in blood are determined；
(b) a effective amount of composition is applied to the subject, the composition includes：
(i) include toll samples receptor (TLR) agonist of at least one lysate and/or lysate fraction from bacterium, In, TLR the agonist activations at least one or more of different TLR or NLR；With
(ii) it is used to enhance the optional accelerating agent that the composition absorbs；And
(c) continue applying said compositions until the horizontal of isoprostane is reduced in the urine or blood of the subject.
57. method according to claim 56, wherein the bacterium is that gram-positive bacterium or Gram-negative are thin Bacterium.
58. method according to claim 57, wherein the bacterium is：
(a) gram-positive bacterium, selected from the group being made up of：Bacillus coagulans (Bacillus coagulans), Gemma Bacillus acidi lactici (Lactobacillus sporogenes), streptococcus thermophilus (Streptococcus Thermophilus), animal bifidobacteria (Bifidobacterium animalis), Bifidobacterium (Bifidobacterium), animal (animalis), subspecies animal (subspecies animalis), bifidobacterium infantis (Bifidobacterium infantis), bifidobacterium longum (Bifidobacterium longum), bifidobacterium breve (Bifidobacterium breve), Lactobacillus acidophilus (Lactobacillus acidophilus), lactobacillus plantarum (Lactobacillus plantarum), Lactobacillus casei (Lactobacillus casei), lactobacillus delbrueckii (Lactobacillus delbrueckii), lactobacillus delbrueckii subspecies bulgaricus (Lactobacillus Delbrueckii subspecies bulgaricus), Lactococcus lactis (Lactococcus lactis), Lactococcus lactis Lactic acid subspecies (Lactococcus lactis subspecies lactis), streptococcus lactis (Streptococcus Lactis), streptococcus thermophilus (Streptococcus thermophilus), bifidobacterium lactis (Bifidobacterium Lactis), bifidobacterium breve (Bifidobacterium breve), Pediococcus acidilactici (Pediococcus ) and Lactobacillus helveticus (Lactobacillus hetveticus) aciditactici；Or
(b) gramnegative bacterium, selected from the group being made up of：Klebsiella oxytoca (Klebsiella oxytocia), Shigella flexneri (Shigella flexneri), xanthomonas campestris (Xanthomonas campestris) and fluorescence Pseudomonad (Pseudomonas flourescens).
59. a kind of composition, it includes：
(a) can activate at least one or more of toll samples receptor (TLR) or Nod samples receptor (NLR) bacterial lysate and/or Lysate fraction；
(b) it is used to enhance the optional accelerating agent that the composition absorbs；With
(c) it is used to increase the optional carrier of the composition volume.
60. a kind of pharmaceutical preparation, it includes the compositions described in claim 59, wherein the pharmaceutical preparation is prepared for Cheek or sublingual administration.
61. pharmaceutical preparation according to claim 60, wherein the pharmaceutical preparation is formulated into is no less than 1 after application Dissolving in minute.
62. composition according to claim 59, wherein the bacterial lysate and/or lysate fraction are grams Negative bacteria or gram-positive bacterium lysate and/or lysate fraction.
63. composition according to claim 62, wherein the bacterial lysate and/or lysate fraction are：
Gram-positive bacterium lysate and/or lysate fraction, selected from the group being made up of：Bacillus acidi lactici (Lactobacillaceae) bacterial lysate and/or lysate fraction, streptococcus (Streptococcaceae) bacteria lysis Object and/or lysate fraction, Bifidobacterium (Bifidobacteriaceae) bacterial lysate and/or lysate fraction or bud Spore bacillus (Bacillaceae) bacterial lysate and/or lysate fraction；Or
Gramnegative bacterium lysate and/or lysate fraction, selected from the group being made up of：Pseudomonad (Pseudomonas) it bacterial lysate and/or lysate fraction, klebsiella (Klebsiella) bacterial lysate and/or splits It is thin to solve object fraction, Xanthomonas campestris (Xanthomonas) bacterial lysate and/or lysate fraction, Shigella (Shigella) Bacterium lysate and/or lysate fraction or enterobacteria (Enterobacter) bacterial lysate and/or lysate fraction.
64. composition according to claim 62, wherein the bacterial lysate and/or lysate fraction are：
(a) gram-positive bacterium lysate and/or lysate fraction, selected from the group being made up of：Bacillus coagulans (Bacillus coagulans), gemma Bacillus acidi lactici (Lactobacillus sporogenes), streptococcus thermophilus (Streptococcus thermophilus), animal bifidobacteria (Bifidobacterium animalis), Bifidobacterium (Bifidobacterium), animal (animalis), subspecies animal (subspecies animalis), bifidobacterium infantis (Bifidobacterium infantis), bifidobacterium longum (Bifidobacterium longum), bifidobacterium breve (Bifidobacterium breve), Lactobacillus acidophilus (Lactobacillus acidophilus), lactobacillus plantarum (Lactobacillus plantarum), Lactobacillus casei (Lactobacillus casei), lactobacillus delbrueckii (Lactobacillus delbrueckii), lactobacillus delbrueckii subspecies bulgaricus (Lactobacillus Delbrueckii subspecies bulgaricus), Lactococcus lactis (Lactococcus lactis), Lactococcus lactis Lactic acid subspecies (Lactococcus lactis subspecies lactis), streptococcus lactis (Streptococcus Lactis), streptococcus thermophilus (Streptococcus thermophilus), bifidobacterium lactis (Bifidobacterium Lactis), bifidobacterium breve (Bifidobacterium breve), Pediococcus acidilactici (Pediococcus ) or Lactobacillus helveticus (Lactobacillus hetveticus) lysate and/or lysate fraction aciditactici； Or
(b) gramnegative bacterium lysate and/or lysate fraction, selected from the group being made up of：Klebsiella oxytoca (Klebsiella oxytocia), shigella flexneri (Shigella flexneri), xanthomonas campestris It (Xanthomonas campestris) or Pseudomonas fluorescens (Pseudomonas flourescens) lysate and/or splits Solve object fraction.
65. a kind of method producing bacterial lysate, this approach includes the following steps：
(a) by the bacterial fermentation in growth medium to stablizing growth period to generate zymotic fluid；
(b) bacterium is collected from the zymotic fluid；
(c) bacterium of harvest is subjected to pasteurize；And
(d) with the bacterium of lysozyme lysis pasteurize to generate bacterial lysate.
66. method according to claim 65, wherein in mid-log phase, late log phase, stationary phase early stage, middle stable Phase or stationary phase in later stage harvest the bacterium.
67. method according to claim 65, wherein the bacterium is that gram-positive bacterium or Gram-negative are thin Bacterium.
68. method according to claim 67,
Wherein, the gram-positive bacterium is selected from bacterium, streptococcus by Bacillus acidi lactici (Lactobacillaceae) section (Streptococcaceae) bacterium and bacillus of bacterium, Bifidobacterium (Bifidobacteriaceae) section of section (Bacillaceae) group of the bacterium composition of section；And
Wherein, the gramnegative bacterium is selected from by pseudomonad (Pseudomonas) category, klebsiella (Klebsiella) Belong to, the bacterium that Xanthomonas campestris (Xanthomonas) belongs to, Shigella (Shigella) belongs to and enterobacteria (Enterobacter) belongs to The group of composition.
69. method according to claim 67,
Wherein, the gram-positive bacterium is selected from by bacillus coagulans (Bacillus coagulans), gemma lactic acid bar Bacterium (Lactobacillus sporogenes), streptococcus thermophilus (Streptococcus thermophilus), animal bifid Bacillus (Bifidobacterium animalis), Bifidobacterium (Bifidobacterium), animal (animalis), subspecies Animal (subspecies animalis), bifidobacterium infantis (Bifidobacterium infantis), bifidobacterium longum (Bifidobacterium longum), bifidobacterium breve (Bifidobacterium breve), Lactobacillus acidophilus (Lactobacillus acidophilus), lactobacillus plantarum (Lactobacillus plantarum), cheese lactic acid bar Bacterium (Lactobacillus casei), lactobacillus delbrueckii (Lactobacillus delbrueckii), lactobacillus delbrueckii Subspecies bulgaricus (Lactobacillus delbrueckii subspecies bulgaricus), Lactococcus lactis (Lactococcus lactis), Lactococcus lactis subsp. lactis (Lactococcus lactis subspecies Lactis), streptococcus lactis (Streptococcus lactis), streptococcus thermophilus (Streptococcus Thermophilus), bifidobacterium lactis (Bifidobacterium lactis), bifidobacterium breve (Bifidobacterium Breve), Pediococcus acidilactici (Pediococcus aciditactici) and Lactobacillus helveticus (Lactobacillus Hetveticus) the group formed；And
Wherein, the gramnegative bacterium is selected from by Klebsiella oxytoca (Klebsiella oxytocia), Fu Shi shigas Bacterium (Shigella flexneri), xanthomonas campestris (Xanthomonas campestris) and Pseudomonas fluorescens The group of (Pseudomonas flourescens) composition.
70. a kind of bacterial lysate, the method according to any one of claim 65-69 generates.
71. a kind of method for mitigating with applying the relevant one or more oxidative stress related side effects of medicament, described Method includes that the cracking compositions of therapeutically effective amount are applied with pharmaceutical agent combinations, and the cracking compositions include：
(a) lysate of bacterium and/or lysate fraction；
(b) it is used to enhance the optional accelerating agent that the composition absorbs；With
(c) it is used to increase the optional carrier of the composition volume；
Wherein, while or the medicament and lysate combination being applied in any order and by identical or different administration method Object.
72. method according to claim 71, wherein the lysate and/or the activation of lysate fraction it is at least one or A variety of TLR or NLR.
73. method according to claim 71, wherein the lysate and/or lysate fraction activate at least two TLR And/or NLR.
74. method according to claim 71, wherein the lysate and/or lysate fraction activate at least three kinds of TLR And/or NLR.
75. method according to claim 71, wherein the lysate and/or lysate fraction activation TLR2, TLR3, At least one of TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2 or a variety of.
76. method according to claim 71, wherein the lysate and/or lysate fraction activate TLR2 and TLR4.
77. method according to claim 71, wherein the lysate and/or lysate fraction activation TLR2, TLR3, Two or more in TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2.
78. method according to claim 71, wherein the lysate and/or lysate fraction activation TLR2, TLR3, It is three or more in TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2.
79. method according to claim 71, wherein the bacterium is that gram-positive bacterium or Gram-negative are thin Bacterium.
80. according to the method described in claim 79,
Wherein, the gram-positive bacterium is selected from bacterium, streptococcus by Bacillus acidi lactici (Lactobacillaceae) section (Streptococcaceae) bacterium and bacillus of bacterium, Bifidobacterium (Bifidobacteriaceae) section of section (Bacillaceae) group of the bacterium composition of section；And
Wherein, gramnegative bacterium be selected from by pseudomonad (Pseudomonas) belong to, klebsiella (Klebsiella) belong to, The bacterium group that Xanthomonas campestris (Xanthomonas) belongs to, Shigella (Shigella) belongs to and enterobacteria (Enterobacter) belongs to At group.
81. according to the method described in claim 79,
Wherein, the gram-positive bacterium is selected from by bacillus coagulans (Bacillus coagulans), gemma lactic acid bar Bacterium (Lactobacillus sporogenes), streptococcus thermophilus (Streptococcus thermophilus), animal bifid Bacillus (Bifidobacterium animalis), Bifidobacterium (Bifidobacterium), animal (animalis), subspecies Animal (subspecies animalis), bifidobacterium infantis (Bifidobacterium infantis), bifidobacterium longum (Bifidobacterium longum), bifidobacterium breve (Bifidobacterium breve), Lactobacillus acidophilus (Lactobacillus acidophilus), lactobacillus plantarum (Lactobacillus plantarum), cheese lactic acid bar Bacterium (Lactobacillus casei), lactobacillus delbrueckii (Lactobacillus delbrueckii), lactobacillus delbrueckii Subspecies bulgaricus (Lactobacillus delbrueckii subspecies bulgaricus), Lactococcus lactis (Lactococcus lactis), Lactococcus lactis subsp. lactis (Lactococcus lactis subspecies Lactis), streptococcus lactis (Streptococcus lactis), streptococcus thermophilus (Streptococcus Thermophilus), bifidobacterium lactis (Bifidobacterium lactis), bifidobacterium breve (Bifidobacterium Breve), Pediococcus acidilactici (Pediococcus aciditactici) and Lactobacillus helveticus (Lactobacillus Hetveticus) the group formed；And
Wherein, the gramnegative bacterium is selected from by Klebsiella oxytoca (Klebsiella oxytocia), Fu Shi shigas Bacterium (Shigella flexneri), xanthomonas campestris (Xanthomonas campestris) and Pseudomonas fluorescens The group of (Pseudomonas flourescens) composition.
82. according to the method described in claim 72, wherein one or more oxidative stress related side effects be selected from by Group consisting of：Aceruloplasminemia, artery/systemic hypertension, arthritis, asthma, atherosclerosis, idiocrasy It is dermatitis, cancer, carcinoma of urinary bladder, leukaemia, uterine cancer, cervical carcinoma, dizziness, Nausea and vomiting, constipation, diarrhea, insomnia, drowsiness, dizzy It is dizzy, sexual hypoesthesia, temporarily go into a coma, tremble, increases of jaundice, arrhythmia cordis, heart rate, decreased heart rate, measles, depression, clinic press down Strongly fragrant disease, cerebral ischemia, broncho-pulmonary dysplasia, angiocardiopathy, cataract, cellulitis, side effects of chemotherapy, confirmed fatigue Syndrome, colitis, coronary artery disease, dyslipidemia, eclampsia, erectile dysfunction, incoordination, headache, heart failure, Haemodialysis side effect, hepatic sclerosis, hypercholesterolemia, hyperhomocysteinemiainjury, hyperlipidemia, interstitial lung disease, lung Damage, macular degeneration, male sterility, mild cognitive impairment, myocardial infarction, myocarditis, myopathy, neuropathy, obesity, bone close Save inflammation, osteoporosis, pancreatitis, periodontosis, peritoneal dialysis side effect, posttraumatic stress disorder, pre-eclampsia, psoriasis, Psoriatic arthritis, pulmonary hypertension, radiotherapy side effect, adjuvant arthritis, Respiratory Distress Syndrome(RDS), rhabdomyolysis Disease, rheumatic disease, septicemia, sleep apnea, apoplexy, suicidal thought, amyloidosis, thrombosis, Protein tau Disease, unstable angina pectoris, uremia or venous insufficiency.
83. a kind of method for treating oxidative stress relevant disease or illness in subject, the method includes to institute The composition that subject applies therapeutically effective amount is stated, the composition includes：
(a) can activate at least one or more of toll samples receptor (TLR) or Nod samples receptor (NLR) bacterial lysate and/or Lysate fraction；
(b) it is used to enhance the optional accelerating agent that the composition absorbs；With
(c) it is used to increase the optional carrier of the composition volume.
84. according to the method described in claim 83, wherein the oxidative stress associated disease be Aceruloplasminemia, Acute and chronic alcoholic liver disease, acute autoimmune myocarditis, drepanocytosis acute chest syndrome, acute pancreas Inflammation, acute respiratory distress syndrome, alcoholic liver disease, amyotrophic lateral sclerosis, artery/systemic hypertension, asbestosis, heavy breathing Asthma, ataxia telangiectasia, atherosclerosis, atopic dermatitis, cerebral ischemia, broncho-pulmonary dysplasia, burning Wound, certain cancers, extracorporal circulatory system, angiocardiopathy, cataract, cellulitis, side effects of chemotherapy, chronic fatigue syndrome, Chronic hepatitis C, chronic kidney disease, chronic obstructive pulmonary disease, chronic renal failure, colitis, coronary artery disease, Creutz Fei Erte-cortico-striatal spinal degeneration, Crohn's disease, cutaneous Leishmaniasis, cystic fibrosis, type 1 diabetes, diabetes B, blood fat are different Often, Down syndrome, eclampsia, advanced renal disease, erectile dysfunction, Friedreich ataxia, headache, heart failure Exhaust, helicobacter pylori infections/inflammation, haemodialysis side effect, hepatic sclerosis, HIV infection, Huntington disease, height Pressure disease, hypercholesterolemia, hyperhomocysteinemiainjury, hyperlipidemia, idiopathic pulmonary fibrosis, interstitial lung disease, ischemic/ Reperfu- sion damage, juvenile chronic arthritis, kidney transplant failure, leukaemia, lung cancer, lung damage, macular degeneration, male sterility, Meniere syndrome, meningitis, mild cognitive impairment, multiple sclerosis, myelodysplastic syndrome, myocardial infarction, Myocarditis, bronchopulmonary dysplasia of newborn, obesity, osteoarthritis, osteoporosis, pancreatitis, Parkinson's disease, periodontal Disease, peritoneal dialysis side effect, light aging, posttraumatic stress disorder, pre-eclampsia, primary biliary cirrhosis, broncho-pulmonary Disease, early ageing, psoriasis, psoriatic arthritis, pulmonary hypertension, radiotherapy side effect, adjuvant arthritis, clear-cell carcinoma, Respiratory Distress Syndrome(RDS), retinopathy of prematurity, posterior cord fibrosis, rheumatic disease, rheumatoid arthritis, sarcoidosis, Septicemia, sickle cell disease, sleep apnea, spherocytosis, spinal cord lesion, apoplexy, synapse nucleoprotein Disease, systemic amyloidosis, systemic loupus erythematosus, systemic sclerosis (chorionitis), thrombosis, Protein tau disease, wound Wound property stress pulmonary tuberculosis, unstable angina pectoris, uremia, venous insufficiency, adult progeria and cerebrohepatorenal syndrome.
85. according to the method described in claim 83, wherein the bacterium is：
(a) gram-positive bacterium, selected from the group being made up of：Bacillus coagulans (Bacillus coagulans), Gemma Bacillus acidi lactici (Lactobacillus sporogenes), streptococcus thermophilus (Streptococcus Thermophilus), animal bifidobacteria (Bifidobacterium animalis), Bifidobacterium (Bifidobacterium), animal (animalis), subspecies animal (subspecies animalis), bifidobacterium infantis (Bifidobacterium infantis), bifidobacterium longum (Bifidobacterium longum), bifidobacterium breve (Bifidobacterium breve), Lactobacillus acidophilus (Lactobacillus acidophilus), lactobacillus plantarum (Lactobacillus plantarum), Lactobacillus casei (Lactobacillus casei), lactobacillus delbrueckii (Lactobacillus delbrueckii), lactobacillus delbrueckii subspecies bulgaricus (Lactobacillus Delbrueckii subspecies bulgaricus), Lactococcus lactis (Lactococcus lactis), Lactococcus lactis Lactic acid subspecies (Lactococcus lactis subspecies lactis), streptococcus lactis (Streptococcus Lactis), streptococcus thermophilus (Streptococcus thermophilus), bifidobacterium lactis (Bifidobacterium Lactis), bifidobacterium breve (Bifidobacterium breve), Pediococcus acidilactici (Pediococcus ) and Lactobacillus helveticus (Lactobacillus hetveticus) aciditactici；Alternatively,
(b) gramnegative bacterium, selected from the group being made up of：Klebsiella oxytoca (Klebsiella oxytocia), Shigella flexneri (Shigella flexneri), xanthomonas campestris (Xanthomonas campestris) and fluorescence Pseudomonad (Pseudomonas flourescens).
86. a kind of method of oxidative stress for reducing subject, the method includes：
(a) oxidisability in the subject is determined by the amount of isoprostane in the urine or blood of the measurement subject Stress level；
(b) a effective amount of composition is applied to the subject, the composition includes：
(i) include toll samples receptor (TLR) agonist of at least one lysate and/or lysate fraction from bacterium, In, at least one or more of TLR or NLR of TLR agonist activations；With
(ii) it is used to enhance the optional accelerating agent that the composition absorbs；And
(c) continue applying said compositions up to different forefront in oxidative stress level reduction, the urine by the subject The decrement of alkane determines.
87. according to the method described in claim 86, wherein continue to apply bacterial lysate until before different in the urine of subject The amount of row alkane is less than about 3ng/mg kreatinins, is less than about 2ng/mg kreatinins, less than about 1ng/mg kreatinins or is less than about 0.5ng/mg kreatinins.
88. according to the method described in claim 86, wherein the bacterium is that gram-positive bacterium or Gram-negative are thin Bacterium.
89. according to the method described in claim 86, wherein the bacterium is：
(a) gram-positive bacterium, selected from the group being made up of：Bacillus coagulans (Bacillus coagulans), Gemma Bacillus acidi lactici (Lactobacillus sporogenes), streptococcus thermophilus (Streptococcus Thermophilus), animal bifidobacteria (Bifidobacterium animalis), Bifidobacterium (Bifidobacterium), animal (animalis), subspecies animal (subspecies animalis), bifidobacterium infantis (Bifidobacterium infantis), bifidobacterium longum (Bifidobacterium longum), bifidobacterium breve (Bifidobacterium breve), Lactobacillus acidophilus (Lactobacillus acidophilus), lactobacillus plantarum (Lactobacillus plantarum), Lactobacillus casei (Lactobacillus casei), lactobacillus delbrueckii (Lactobacillus delbrueckii), lactobacillus delbrueckii subspecies bulgaricus (Lactobacillus Delbrueckii subspecies bulgaricus), Lactococcus lactis (Lactococcus lactis), Lactococcus lactis Lactic acid subspecies (Lactococcus lactis subspecies lactis), streptococcus lactis (Streptococcus Lactis), streptococcus thermophilus (Streptococcus thermophilus), bifidobacterium lactis (Bifidobacterium Lactis), bifidobacterium breve (Bifidobacterium breve), Pediococcus acidilactici (Pediococcus ) and Lactobacillus helveticus (Lactobacillus hetveticus) aciditactici；Alternatively,
(b) gramnegative bacterium, selected from the group being made up of：Klebsiella oxytoca (Klebsiella oxytocia), Shigella flexneri (Shigella flexneri), xanthomonas campestris (Xanthomonas campestris) and fluorescence Pseudomonad (Pseudomonas flourescens).
90. according to the method described in claim 86, wherein the lysate and/or the activation of lysate fraction it is at least one or A variety of TLR or NLR.
91. according to the method described in claim 86, wherein the lysate and/or lysate fraction activate at least two TLR And/or NLR.
92. according to the method described in claim 86, wherein the lysate and/or lysate fraction activate at least three kinds of TLR And/or NLR.
93. according to the method described in claim 86, wherein the lysate and/or lysate fraction activation TLR2, TLR3, At least one of TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2 or a variety of.
94. according to the method described in claim 86, wherein the lysate and/or lysate fraction activate TLR2 and TLR4.
95. according to the method described in claim 86, wherein the lysate and/or lysate fraction activation TLR2, TLR3, Two or more in TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2.
96. according to the method described in claim 86, wherein the lysate and/or lysate fraction activation TLR2, TLR3, It is three or more in TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2.
97. a kind of Therapeutic combinations, the combination include：
(a) compositions are cracked, it includes
(i) can activate at least one or more of toll samples receptor (TLR) or Nod samples receptor (NLR) bacterial lysate and/or Lysate fraction；
(ii) it is used to enhance the optional accelerating agent that the composition absorbs；With
(iii) it is used to increase the optional carrier of the composition volume；With
(b) one or more medicaments；
Wherein, while or apply the cracking compositions and one or more medicaments in any order, and wherein, pass through The cracking compositions and one or more medicaments are applied by identical or different administration method.
98. according to the Therapeutic combinations described in claim 97, wherein the cracking compositions are through sublingual or oral administration.
99. a kind of pharmaceutical preparation, it includes following combinations：
(a) compositions are cracked, it includes
(i) can activate at least one or more of toll samples receptor (TLR) or Nod samples receptor (NLR) bacterial lysate and/split Solve object fraction；
(ii) it is used to enhance the optional accelerating agent that the composition absorbs；With
(iii) it is used to increase the optional carrier of the composition volume；With
(b) one or more medicaments.
100. according to the Therapeutic combinations described in claim 97 or the pharmaceutical preparation described in claim 99, wherein described one kind Or various medicaments are selected from the group being made up of：
Anticonvulsants, motion stimulant, bisfentidine, muscarine antagonist；Chelating agent, prostaglandin analogue, amino water Poplar hydrochlorate, the drug for influencing immune response, irritant purgative, influences bile composition and drug, the bile of flowing at corticosteroid Acid sequestering agent, proton pump inhibitor, opioid, opioid receptors antagonist, antalgesic, is slept at Dopamine D2 receptor Dormancy drug, cardiac glycoside, phosphodiesterase inhibitors, thiazide, diuretics, Potassium-sparing diuretic, aldosterone antagonists, osmotic diuresis Agent, antiarrhythmic medicament, beta-adrenoceptor blocking drug object, hypertension drug, the medicine for influencing renin-angiotensin system Object, nitrate, calcium blockers, antianginal drug, peripheral vasodilator agent, parasympathomimetic agent, anti-coagulants, nucleoprotamine, Antiplatelet drug, fibrinolytic drug object, Antifibrinolytic agents, regulation and control Lipid pharmaceutical, omega-fatty acid chemical combination Object, CNS drugs, anti-infectives, or another drug selected from the group being made up of：Benzetropine, the third ring pyridine are stood than piperazine It steps on, amantadine, bromocriptine, pergolide, Entacapone, Tolcapone, selegiline, Pramipexole, budesonide, Fu Mote Sieve, quetiapine fumarate, Olanzapine, pioglitazone, montelukast, zoledronic acid, Valsartan, Latanoprost, irbesartan, Clopidogrel, atomoxetine, Dexamfetamine, ritalin, modafinil, bleomycin, D actinomycin D, daunorubicin, she reach than Star, rice Tobramycin, mitoxantrone, azacitidine, capecitabine, Cladribine, clofarabine, cytarabine, fludarabine, fluorine Uracil, gemcitabine, mercaptopurine, methopterin, nelarabine, pemetrexed, Raltitrexed, thioguanine, apomorphine, times Ta meter Song, cortisone, deflazacort, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, Triamcinolone acetonide, ring P0-357, sirolimus, tacrolimus, interferon-' alpha ' and interferon beta.
101. according to the Therapeutic combinations described in claim 97 or the pharmaceutical preparation described in claim 99, wherein described one kind Or various medicaments are selected from the group being made up of：
Selected from by atropine sulfate, dicyclomine hydrochloride, scopolamine butylbromide, propantheline bromide, alverine citrate and salt The Anticonvulsants of the group of sour mebeverine composition；
Motility excitant selected from the group being made of metoclopramide and domperidone；
Bisfentidine selected from the group being made of for fourth and ranitidine cimetidine, famotidine Buddhist nun；
Muscarine antagonist；
Chelating agent selected from the group being made of two citric acid trisodium citrate and ulcerlmin；
Prostaglandin analogue；
Aminosalicylate selected from the group being made of Balsalazide sodium, mesalazine, Olsalazine and salicylazosulfapyridine；
Corticosteroid selected from the group being made of beclomethasone dipropionate, budesonide, hydrocortisone and prednisolone；Choosing The influence immune response for the group that free cyclosporin, mercaptopurine, methotrexate (MTX), adalimumab and infliximab form Drug；
Irritant laxative selected from the group being made of Bisacody, dihydroxy anthraquinone, more library esters and guttalax；
Influence the drug of bile composition and flowing；
Selected from by cholestyramine resin, Oxyphencyclimine, camylofin, mebeverine, Trimebutine, rociverine, dicyclomine, it is double oneself Wei Lin, difemerine, piperidolate, benzene oxazolone, Mepenzolate, Pipenzolate, glycopyrronium bromide, Ao Fen Australia amine, monodral, second Amine too woods, proparacaine, Otilonium Bromide, Tridihexethyl, isopropylamine, hexocyclium, Poldine, Bei Funing, diphemanil, for not Iodine ammonium, prifinium bromide, timepidium bromide, benzene piperazine dimension woods, papaverine, Drotaverine, moxaverine, 5-HT3 antagonists, 5-HT4 swash Dynamic agent, fenpiprane, diisopromine, Chlorbenzoxamine, Pinaverium Bromide, fenoverine, idanpramine, proxazole, A Erwei Woods, Trepibutone, isometheptene, caroverine, 1,3,5-trihydroxybenzene, silicone, recipavrin, atropine, hyoscyamine, Anisodus luridus Alkali, butylscopolamine, epoxytropine tropate, methyl atropine, fentonium bromide, Cimetropium Bromide and main Dopamine D2 receptor composition Group bile acid sequestrant；
Matter selected from the group being made of Omeprazole Sodium, Lansoprazole sodium, Pantoprazole Sodium, esomeprazole sodium and RABEPRAZOLE SODIUM Sub- pump inhibitor；
Opioid and opioid receptors antagonist；
Selected from by paracetamol, Diclofenac, difunisal, Etodolac, fenoprofen, Flurbiprofen, brufen, Indomethacin, Ketoprofen, ketorolac, Meclofenamic Acid, mefenamic acid, Meloxicam, Nabumetone, naproxen, oxaprozin, Phenylbutazone, piroxicam, sulindac, tolmetin sodium, celecoxib, buprenorphine, butorphanol, codeine, hydrocodone, hydrogen Coffee ketone, levorphanol, pethidine, methadone, morphine, Nalbuphine, Oxycodone, Oxymorphone, pentazocine, propoxyhene and C16H25NO2 The antalgesic of the group of composition；
Selected from by nitrazepam, Flurazepam, Lip river antrypol, Lormetazepam, Temazepam, Zaleplon, zolpidem, zopiclone, Chloraldurate, trichloroethyl phosphate, clormethiazole, Quazepam, triazolam, estazolam, Clonazepam, alprazolam, Ai Si Zopiclone, ramelteon, Trazodone, amitriptyline, doxepin, benzodiazepine, melatonin, diphenhydramine and grass The sleep drug of the group of medicine therapeutic agent composition；
Cardiac glycoside selected from the group being made of digoxin and foxalin；
Phosphodiesterase inhibitors selected from the group being made of Enoximone and milrinone；
Thiazide selected from the group being made of bendroflumethiazide, chlorthalidone, Cyclopenthiazide, her that amide, metolazone and Xi Pa amine With related diuretics；
Diuretics selected from the group being made of frusemide, bumetanide and Torasemide；
Potassium-sparing diuretic selected from the group being made of Amiloride, triamterene, eplerenone and spirolactone and aldosterone Antagonist；
Osmotic diuresis agent；
Selected from what is be made of adenosine, Amiodarone Hydrochloride, disopyramide, flecainide acetate, propafenone hydrochloride and lidocaine hydrochloride The antiarrhythmic medicament of group；
Selected from by Propranolol, atenolol, acebutolol, complete bisoprolol fumarate salt, Carvedilol, celiprolol, Ai Si Luo Er, Eibar Luo Er, metoprolol tartrate, Nadolol, Nebivolol, oxprenolol, pindolol, Sotalol and thiophene The beta-adrenoceptor blocking drug object of the group of Luo Er compositions；
Selected from by pacifying for health, Bosentan, diazoxiide, hydralazine, iloprost, minoxidil, silaenafil, Xi Tasheng Smooth, sodium nitroprussiate, clonidine, ethyldopa, moxonidine, guanethidine monosulfate, Doxazosin, indoramin, prazosin, spy Draw the hypertension drug of the group of azoles piperazine, benzene oxygen aniline and phentolamine mesilate composition；
Selected from by captopril, Cilazapril, enalapril maleate, fosinopril, Imidapril, lisinopril, not former times Puli, perindopril tert-butylamine salt, quinapril, Ramipril, Trandolapril, Candesartan Cilexetil, Eprosartan, according to shellfish The influence renin angiotensin of the group of Sha Tan, Losartan, olmesartan medoxomil, Telmisartan, Valsartan and aliskiren composition The drug of system；
Selected from by glyceryl trinitrate, isosorbide dinitrate, Ismo 20, Amlodipine Besylate Tablet, your sulphur Zhuo, felodipine, isradipine, lacidipine, Lercanidipine, nicardipine, nifedipine, Nimodipine, verapamil, she cuts down Nitrate, calcium channel blocker, the antianginal drug of fixed, nicorandil and ranolazine composition the group of mine-laying；
Selected from the periphery for the group being made of Cilostazol, inositol niacin alcohol ester, moxisylyte, naftidrofuryl oxalate and pentoxifylline Blood vessel dilatation and related drugs；
Selected from by dopamine, Dopexamine, ephedrine, aramine, noradrenaline acid tartrate, tartaric acid norephedrine With the parasympathomimetic agent of the group of benzene ephedrine composition；
Selected from by heparin, bemiparin, dalteparinSodium, Enoxaparin, tinzaparin, danaparoid, bivalirudin, lepirudin, Epoprostenol, fondaparin, neodicoumarin, acenocoumarin, phenindione, dabigatran etcxilate, razaxaban and nucleoprotamine The anti-coagulants and nucleoprotamine of the group of sulfate composition；
Selected from what is be made of Abciximab, aspirin, clopidogrel, persantine, eptifibatide, prasugrel and tirofiban The antiplatelet drug of group；
Selected from the group being made of Alteplase, Reteplase, streptokinase, Tenecteplase, urokinase, etamsylate and Trenaxmine Fibrinolytic drug object and Antifibrinolytic agents；
Selected from by Atorvastatin, Fluvastatin, Pravastatin, rosuvastatin, Simvastatin, colesevelam, cholestyramine resin, Colestipol, ezetimibe, Bezafibrate, ciprofibrate, fenofibrate, Gemfibrozil, acipimox, niacin, ω -3 fat The regulation and control Lipid pharmaceutical of the group of fat acid compound, ethanolamine oleate and sodium tetradecyl sulfate composition；
Selected from by benperidol, chlorpromazine, Flupentixol, haloperidol, levomepromazine, pericyazine, perphenazine, pimozide, chlorine Pyrazine, promazine, Sulpiride, triperazine, Zuclopenthixol, Amisulpride, Aripiprazole, Clozapine, Olanzapine, Pa Panli Ketone, kui gentle ziprasidone, Risperidone, Sertindole, Zotepine, Flupentixol, fluphenazinum, Olanzapine embonate, pipotiazine Palmitate, risperidone, Zuclopenthixol, carbamazepine, sodium vedproate, valproic acid, lithium carbonate, lithium citrate, amitriptyline, Clomipramine, dosulepin, imipramine, lofepramine, nortriptyline, trimipramine, Mianserin, Trazodone, nardil, different card Wave hydrazine, parnitene, Moclobemide, Citalopram, escitalopram, Prozac, Fluvoxamine, Paxil, Sertraline, Ah Ge Meilating, Duloxetine, Flupentixol, Mirtazapine, Reboxetine, tryptophan, Venlafaxine, atomoxetine, fill in rice Bright, methylphenidate, modafinil, Ai Si licarbazepines, Oxcarbazepine, ethymal, Gabapentin, pregabalin, scheme for lacosamide, drawing Not triazine, Levetiracetam, phenobarbital, Puli's rice ketone, phenytoinum naticum, rufinamide, Tiagabine, Topiramate, sabril, azoles Silt amine, Ropinirole, rotigotine, compound aniline dopamine, levodopa, compound karr DOPA, Rasagiline, Si Laiji Orchid, Entacapone, Tolcapone, amantadine, orphenadrine, procyclidine, benzhexol, haloperidol, Piracetam, Riluzole, Tetrabenazine, Acamprosate, disulfiram, Bupropion, varenicline, buprenorphine, lofexidine, donepezil, galanthamine, The CNS drugs of the group of Memantine hydrochloride and rivastigmine composition；
Selected from by penicillin, ospen, flucloxacillin, temocillin, Amoxicillin, ampicillin, amoxicillin, multiple Square flucloxacillin, Piperacillin, Ticarcillin, Pivmecillinam, cephalosporins, Cefaclor, cefadroxil, cephalo ammonia Benzyl, Cefixime, cefotaxime, Cefradine, cefotaxime, cefuroxime, ertapenem, Imipenem, Meropenem, ammonia Qu Nan, tetracycline, demethylchlortetra cylinum, Doxycycline, lymecycline, minocycline, terramycin, tigecycline, gentamicin, fourth Amine kanamycins, neomycin, tobramycin, erythromycin, azithromycin, clarithromycin, Ketek, clindamycin, chloramphenicol, Fusidic Acid, vancomycin, teicoplanin, Daptomycin, Linezolid, Quinupristin, polymyxin E, compound sulfonamide methyl Isoxazole, sulphadiazine, trimethoprim, capreomycin, seromycin, ethambutol, isoniazid, pyrazinamide, Rifabutin, Rifampin, streptomysin, dapsone, Clofazimine, metronidazole, Tinidazole, Ciprofloxacin, lavo-ofloxacin, Moxifloxacin, naphthyridines Acid, promise fluorine draw star, Norfloxacin, furantoin, methenamine hippurate, anphotericin, anidulafungin, Caspofungin, fluorine Health azoles, Flucytosine, griseofulvin, Itraconazole, ketoconazole, mikafen, nystatin, posaconazole, Terbinafine, volt Vertical health azoles, Abacavir, Didanosine, emtricitabine, Lamivudine, stavudine, tenofovir disoproxil, Zidovudine, A Zha That Wei, darunavir, fosamprenavir, indinavir, Luoping Nai Er, Nai Feinawei, Ritonavir, inverase, tipranavir, Efavirenz, etravirine, nevirapine, enfuirtide, Maraviroc, Merck, acyclovir, famciclovir, isopropyl Inosine, cidofovir, Ganciclovir, phosphonic acid, valganciclovir, Aldoforwe ester, Entecavir, is replaced than husband valaciclovir Fixed, amantadine, Oseltamivir, zanamivir, palivizumab, Ribavirin, Artemether, chloroquine, Mefloquine, primaquine, Chloroguanide, pyrimethamine, quinine, fortimicin, diloxanide chaff, flagyl, Tinidazole, mepacrine, stibii natrii gluconas, Ah Support cuts down the anti-infectives for the group that quinone, penta amidine of edetic acid(EDTA), mebendazole and piperazine form；
Selected from by benzetropine, the third ring pyridine, Biperiden, amantadine, bromocriptine, pergolide, Entacapone, Tolcapone, department Come lucky orchid, Pramipexole, budesonide, Formoterol, quetiapine fumarate, Olanzapine, pioglitazone, montelukast, azoles to come Phosphonic acids, Latanoprost, irbesartan, clopidogrel, atomoxetine, Dexamfetamine, ritalin, modafinil, is won Valsartan Bleomycin, D actinomycin D, daunorubicin, idarubicin, rice Tobramycin, mitoxantrone, azacitidine, capecitabine, carat are bent Shore, clofarabine, cytarabine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methopterin, nelarabine, training are U.S. bent Plug, Raltitrexed, thioguanine, apomorphine, betamethasone, cortisone, deflazacort, dexamethasone, hydrocortisone, first What base prednisolone, prednisolone, Triamcinolone acetonide, cyclosporine, sirolimus, tacrolimus, interferon-' alpha ' and interferon beta formed The other medicines of group.
102. a kind of preparation, it includes
(a) compositions are cracked, the cracking compositions include
(i) can activate at least one or more of toll samples receptor (TLR) or Nod samples receptor (NLR) bacterial lysate and/or Lysate fraction；
(ii) it is used to enhance the optional accelerating agent that the composition absorbs；With
(iii) it is used to increase the optional carrier of the composition volume；With
(b) the people's anti-TNF alpha antibodies or its antigen-binding fragment or tnf inhibitor detached.
103. according to the preparation described in claim 102, wherein people's anti-TNF alpha antibodies or its antigen-binding fragment are A Da The wooden monoclonal antibody.
104. according to the preparation described in claim 103 prepare for treat subject rheumatoid arthritis (RA), late Hair property RA or psoriatic arthritis drug in purposes.
105. a kind of rheumatoid arthritis (RA), method of Delayed onset RA or psoriatic arthritis for treating subject, The method includes to the subject apply therapeutically effective amount according to the preparation described in claim 102.
106. according to the method described in claim 105, wherein by people's anti-TNF alpha antibodies or its antigen-binding fragment with double All dosage regimens are applied to the subject.
107. according to the method described in claim 105, wherein by people's anti-TNF alpha antibodies or its antigen-binding fragment with 30mg or higher dosage is applied to the subject.
108. according to the method described in claim 105, wherein the TNF α inhibitor is TNF α fusion protein.
109. according to the method described in claim 108, wherein the TNF α fusion protein is Etanercept.
110. according to the method described in claim 105, wherein the anti-TNF alpha antibodies or its antigen-binding fragment are Ying Fuli Former times monoclonal antibody or goli mumab.
111. according to the method described in claim 105, wherein the anti-TNF alpha antibodies or its antigen-binding fragment are A Damu Monoclonal antibody.
112. according to the method described in claim 105, wherein the anti-TNF alpha antibodies or its antigen-binding fragment are A Damu Monoclonal antibody.
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Families Citing this family (5)

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Publication number Priority date Publication date Assignee Title
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CN116042490B (en) * 2023-03-03 2023-09-01 善恩康生物科技（苏州）有限公司 Composite probiotics for resisting fatigue and improving exercise capacity as well as preparation method and application thereof
CN116735756A (en) * 2023-08-08 2023-09-12 天津辰欣药物研究有限公司 Detection method for measuring 3-bromopropylamine hydrobromide impurity in peama Bei Teqi starting material by gas chromatography

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104144693A (en) * 2012-01-16 2014-11-12 E·麦肯纳 Compositions and methods for the treatment of hepatic diseases and disorders

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104144693A (en) * 2012-01-16 2014-11-12 E·麦肯纳 Compositions and methods for the treatment of hepatic diseases and disorders

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
G ZIMMERMAN等: "Post-traumatic anxiety associates with failure of the innate immune receptor TLR9 to evade the pro-inflammatory NFκB pathway", 《TRANSLATIONAL PSYCHIATRY》 *
MARIA DE LOS ANGELES PINEDA等: "A randomized, double-blinded, placebo-controlled pilot study of probiotics in active rheumatoid arthritis", 《MEDICAL SCIENCE MONITOR》 *
P.SIEBLER ET 等: "Immunization with the immunoregulatory saprophytic bacterium, Mycobacterium vaccae, enhances fear extinction in adult male Sprague Dawley rats", 《24TH ANNUAL MEETING OF INTERNATIONAL BEHAVIORAL NEUROSCIENCE SOCIETY》 *
R RAU: "Adalimumab (a fully human anti-tumour necrosis factor a monoclonal antibody) in the treatment of active rheumatoid arthritis: the initial results of five trials", 《ANNALS OF THE RHEUMATIC DISEASES》 *
XINYAN PENG等: "Protective Effects of Lactobacillus plantarum NDC 75017 Against Lipopolysaccharide-Induced Liver Injury in Mice", 《INFLAMMATION》 *

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