CN101405011A - Methods of treating or preventing sinusitis with oxidative reductive potential water solution - Google Patents

Methods of treating or preventing sinusitis with oxidative reductive potential water solution Download PDF

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Publication number
CN101405011A
CN101405011A CNA2007800097734A CN200780009773A CN101405011A CN 101405011 A CN101405011 A CN 101405011A CN A2007800097734 A CNA2007800097734 A CN A2007800097734A CN 200780009773 A CN200780009773 A CN 200780009773A CN 101405011 A CN101405011 A CN 101405011A
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aqueous solution
described method
orp aqueous
water solution
oxidative reductive
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H·阿里米
A·古蒂雷斯
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Oculus Innovative Sciences Inc
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Oculus Innovative Sciences Inc
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Methods of using oxidative reduction potential (ORP) water solution that is stable for at least twenty-four hours in dental applications are provided. The ORP water solution can be administered to patients for the routine disinfection of the oral cavity as part of an on-going program of oral hygiene. The ORP water solution can further be used to irrigate and/or disinfect oral tissues and surfaces during dental procedures, oral surgery, or maxillo-facial surgery. Also, the ORP water solution can be administered to treat patients with damage to the oral tissues caused by disease or surgery.

Description

Use the method for oxidative reductive potential water solution treatment or prevention sinusitis
The cross reference of related application
The U.S. Provisional Patent Application US 60/760,567 that the U.S. Provisional Patent Application US that submits in present patent application request on January 20th, 2006 submitted on January 20th, 60/760,635,2006; The U.S. Provisional Patent Application US 60/760,645 that on January 20th, 2006 submitted to; Interests with the U.S. Provisional Patent Application US 60/760,557 that submitted on January 20th, 2006 intactly are incorporated herein by reference the whole of these documents.
Background of invention
The cranium hole is the air chamber in buccal, brows and the jawbone.These chambers comprise the brows district, maxillary sinus, the maxillary sinus of cheekbone inside, every side, just sieve hole between bridge of the nose rear portion and eye and the sieve skeleton that is positioned at nose upper zone and eye rear portion.Be lined with the breathing pattern epithelium in the hole, it has the following propria lamina of mucous gland of being rich in and little blood vessel.
Sinusitis is a kind of illness, the inflammation that becomes of its median sinus internal layer.Sinusitis can be for acute or chronic.Virus is the common cause of acute sinusitis, and it produces tangible inflammation.This inflammation causes nasal meatus mucus to produce to be increased and hyperemia.When the swelling of hole mucosa, air and mucus are trapped within the rear portion of hole narrow openings.This hyperemia makes individual susceptible bacteria sinusitis.The chronic inflammatory disease of nasal meatus also makes individual susceptible acute sinusitis outbreak such as allergic rhinitis (Hay Fever).Can be because of for example humidity, cold air, ethanol, the vasomotion sinusitis that spice and other environmental condition cause also makes individual susceptible sinus infection.
Most of healthy people has antibacterial in the respiratory tissues thereon, such as streptococcus pneumoniae (Streptococcus pneumoniae) and Haemophilus influenzae (Haemophilusinfluenzae).The mucus that is trapped within hole narrow openings rear portion can make the bacterial reproduction of residence and invade the hole endothelium, causes acute bacterial infection.Similarly, fungal infection can cause acute sinusitis.Although fungus is rich in environment, they are harmless to healthy people usually.Yet fungus can cause the serious disease of its immune system to the people of aspergillus hypersensitization such as aspergillus (Aspergillus).
The cause of disease of chronic sinusitis is unclear usually.Chronic sinusitis is the inflammatory diseases that usually occurs among the patient with asthma.It is caused by infectious pathogen, but, causes the aeroallergen of anaphylaxis sinusitis, and such as dust, mycete and pollen can be facilitated the generation chronic sinusitis.Also can cause chronic sinusitis case at least to the antigenic immunne response in the fungus.
The sinusitis that generally heals with medicine comprises Decongestant, antihistaminic, nonsteroid anti-inflammatory drugs, steroid, antibiotic and antiviral agents.These medicines have side effect and other defective separately.For example, nonsteroid anti-inflammatory drugs can produce bad gastrointestinal and cardiovascular side effects.In addition, anti-infective can produce anaphylaxis and can produce the environment that may cause that the antibiotic resistance bacterium occurs such as antibiotic application.Steroid has systemic side effects, and must reduce it and use preventing addiction, and because its immunosuppressive action, so must want careful use to avoid infection as immunosuppressant result appearance.When pharmacotherapy was failed, operation just became the unique alternative selection of treatment sinusitis, but operation can cause tangible pain sickness rate, and convalescent period is prolonged.Therefore, there is demand in new safety and the effective method to treatment or prevention sinusitis.
The invention provides this class methods.These and other advantage of the present invention and extra feature of the present invention are apparent from the present invention provided herein describes.
Summary of the invention
The invention provides the method for treatment or prevention patient sinusitis, this method comprises oxidation-reduction potential (ORP) aqueous solution of this patient being treated effective dose, and wherein this is solution-stabilized at least about 24 hours.The ORP stabilized aqueous solution that the present invention gives was at least about 24 hours, and preferred stablizing at least about 2 months, and is more preferably stable at least about 6 months, and most preferably stable at least about 1 year (for example more than 1 year or 1 year).
According to the present invention, for example, the ORP aqueous solution is administered to the patient goes up respiratory airway (for example upper respiratory tract) and/or one or more cranium holes, so that make one or more tissues in respiratory airway and/or the cranium hole contact the ORP aqueous solution.The cranium hole can comprise, sinus frontalis for example, maxillary sinus, sieve hole and sphenoid sinus.In one embodiment, for example, the ORP aqueous solution is administered to the patient sieves the one or more of hole, so that make one or more tissues in the sieve hole contact the ORP aqueous solution.
According to the present invention, for example, can give ORP aqueous solution by the approach of any appropriate, comprise, for example by intranasal, by oral cavity or they both.In addition, can give ORP aqueous solution with the form of any appropriate, such as liquid, spray, mixture or aerosol, and can send for example atomizing, nebulization or spraying by the method for any appropriate.In one embodiment, to have about 0.1 micron to about 100 microns, preferred 1 micron drop to about 10 microns diameter gives ORP aqueous solution.
Method of the present invention can effectively be treated or prophylaxis of acute sinusitis and chronic sinusitis, and can effectively treat or prevent because of for example anaphylaxis, and the sinusitis that asthma or inflammation cause, described inflammation influence one or more tissues in cranium hole or the last respiratory airway.The sinusitis that method of the present invention can also effectively be treated or be prevented to cause because of infection, for example infection that causes by one or more microorganisms, these microorganisms can comprise virus, antibacterial and fungus, they are preferably to ORP aqueous solution sensitivity.Susceptible virus can comprise, for example Coxsackie virus, adenovirus, rhinovirus and influenza virus.Susceptible bacteria can comprise, streptococcus pneumoniae (Streptococcuspneumoniae) for example, Haemophilus influenzae (Haemophilus influenzae), staphylococcus (staphylococci), non-pneumococcal streptococcus, Corynebacterium (corynebacterium) and anaerobe.The susceptible fungus can comprise, for example Zygomycetes (zygomycetes), aspergillus (aspergillus) and mycocandida (candida).
According to the present invention, the ORP aqueous solution can be united separately or with one or more carriers and give (for example diluting) with it.For example, can with the ORP aqueous solution with reach 25% (wt./wt. or vol./vol.) one or more suitable carriers approximately, reach 50% (wt./wt. or vol./vol.) one or more suitable carriers approximately, about 75% (wt./wt. or vol./vol.) one or more suitable carriers, reach 90% (wt./wt. or vol./vol.) one or more suitable carriers approximately, one or more suitable carriers of about 95% (wt./wt. or vol./vol.) merge.Suitable carriers can comprise, for example water (distilled water for example, sterilized water, sterile water for injection for example, Sterile Saline etc.).Suitable carriers can also comprise that one or more are described in the carrier (being incorporated herein reference the most) among the Application No. US 10/916,278.
The ORP aqueous solution that the present invention can be given gives separately or gives with at least a extra therapeutic agent (being one or more therapeutic agents of the ORP aqueous solution that gives of non-the present invention) associating (or common with it).For example, ORP aqueous solution of the present invention and one or more can be selected from antihistaminic, Decongestant, anti-infective antimicrobial drug (for example antibiotic, antiviral agents or antifungal agent), the therapeutic agent associating of anti-inflammatory agent and combination thereof or give jointly.
The accompanying drawing summary
Fig. 1 illustration produce three Room electrolyzers of typical ORP aqueous solution.
Fig. 2 illustration typical three Room electrolyzers and described to think in process of production the ionic species that produces.
Fig. 3 is for producing the schematic flow diagram of typical ORP aqueous process.
Cell survival in the human diploid fibroblasts (HDFs) that Fig. 4 A-4C has described to handle with typical 0RP aqueous solution (MCN) and hydrogen peroxide (HP), apoptosis and downright bad diagram compare.
Fig. 5 for 8-hydroxyl-2 among the HDFs that handles with typical ORP aqueous solution (MCN) and 500 μ M hydrogen peroxide (HP) '-the diagram comparison of deoxyguanosine (8-OHdG) adduct level.
Fig. 6 illustration express the cell ageing that is confirmed by beta galactosidase among typical ORP aqueous solution (MCN) and hydrogen peroxide (HP) the back HDFs of long-term contact low concentration.
Fig. 7 illustration to the effect of the antigen activation mastocyte threshing handled with the typical ORP aqueous solution (MCN) of variable concentrations.
Fig. 8 with the manner of comparison illustration effect of typical ORP aqueous solution (MCN) to the activatory mastocyte threshing of antigen handled with cromoglycate.
Fig. 9 illustration to the antigen activation handled with the typical ORP aqueous solution (MCN) of variable concentrations and the effect of Calcium ionophore (A23187)-activatory mastocyte threshing.
Figure 11 A-10B is the RNAse protection mensuration that illustration antigen in the mastocyte group of matched group and ORP aqueous solution-processing is attacked back cytokines mRNA level.
Figure 11 compares for the excretory diagram of TNF-α of the activatory mastocyte of antigen that the typical ORP aqueous solution (MCN) of using variable concentrations is handled.
Figure 12 compares for the excretory diagram of MIP1-α of the activatory mastocyte of antigen that the typical ORP aqueous solution (MCN) of using variable concentrations is handled.
Figure 13 compares for the excretory diagram of IL-6 of the activatory mastocyte of antigen that the typical ORP aqueous solution (MCN) of using variable concentrations is handled.
Figure 14 compares for the excretory diagram of IL-13 of the activatory mastocyte of antigen that the typical ORP aqueous solution (MCN) of using variable concentrations is handled.
Detailed Description Of The Invention
The invention provides prevention or treatment patient sinusitis (nasosinusitis for example, acute sinusitis, chronic sinusitis etc.) method, the method comprises oxidation-reduction potential (ORP) aqueous solution (being also referred to as peroxidating water (SOW)) of the patient being treated effective dose, and wherein this is solution-stabilized at least about 24 hours. According to the present invention, for example, the ORP aqueous solution can be administered to the upper respiratory airway (for example upper respiratory tract) of patient and/or one or more cranium holes, in order to make one or more tissue contacts ORP aqueous solution in respiratory airway and/or the cranium hole. The cranium hole can comprise, sinus frontalis for example, maxillary sinus, sieve hole and sphenoid sinus. In one embodiment, for example, the ORP aqueous solution is administered to the patient sieves the one or more of hole, in order to make one or more tissue contacts ORP aqueous solution of residing in the sieve hole.
Can with effective treatment or prevention (for example suppress outbreak, suppress to increase progressively, reduce possibility) sinusitis, comprise that the consumption of impatient property sinusitis and chronic sinusitis gives the ORP aqueous solution of the present invention. Can comprise the sinusitis that causes because of following situation according to the sinusitis of the inventive method treatment or prevention: for example contact noxious stimulus, damage, infection, inflammation, autoimmune response, hypersensitivity, asthma and allergic reaction, comprise the allergic reaction relevant with the cell histamine release.
Chronic sinusitis generally means to continue the sinusitis disease at least 3 weeks, but this inflammation can (and usually) continue several months and even several years. Allergic reaction is usually relevant with chronic sinusitis. In addition, the patient who suffers from asthma has high-frequency especially chronic sinusitis. Air amount anaphylactogen (material that causes allergic reaction), such as dust, mould and pollen cause allergic reaction (for example allergic rhinitis) usually, can facilitate thus sinusitis (particularly nasosinusitis or rhinitis). People to Studies On Fungus Allergy can be called the illness of " anaphylaxis fungal rhinosinusitis ". Pollutant in wet weather or air and the building also can affect people Yi Fasheng chronic sinusitis.
Be similar to acute sinusitis, chronic sinusitis more is common in patient with immune deficiency or mucous secretion or dyskinesia (for example immune deficiency, HIV infects, cystic fibrosis, kartagener's syndrome). In addition, chronic patients has seriousness asthma, nasal polyp and to the reaction of the Severe Asthma of aspirin and aspirin-class medicine (so-called nonsteroid anti-inflammatory drugs or NSAIDs). These patients of back have high-frequency chronic sinusitis.
The doctor can pass through medical history, physical examination, X-ray and if necessary according to MRIs or CT scan (magnetic resonance imaging and computerized tomography) diagnosis sinusitis. In the diagnosis sinusitis and after determining possible reason, the doctor can open according to reducing inflammation and the therapeutic process prescription of relief of symptoms. The treatment acute sinusitis generally need to be established the drainage of nasal meatus again, control or diminish inflammation source and alleviating pain. The doctor generally recommends decongestant to alleviate hyperemia, and antibiosis is usually controlled bacterium infection (if existence) and pain relief agents eases the pain. The doctor generally recommends decongestant to alleviate hyperemia, and antibiosis is usually controlled bacterium infection (if existence) and pain relief agents eases the pain. When making when healing with medicine failure, selectable only is the operative treatment chronic sinusitis, for example removes adenoids, removes nasal polyp, repairs the barrier film that departs from, endoscope hole operation etc. Think that giving ORP water of the present invention can be used for the treatment of chronic sinusitis, as the therapy that may avoid having more invasive, such as the alternative selection of antibiotic and operation.
Surprisingly, find that the ORP aqueous solution that the present invention gives is the mast cell threshing, namely cause the highly efficient depressor of one of the mast cell biological cascade of primary inflammation. Whether the ORP aqueous solution that the present invention gives suppresses the mast cell threshing, irrelevant by antigen or Calcium ionophore activation with them. In addition surprisingly, have been found that the ORP aqueous solution that the present invention gives suppresses proinflammatory cytokine secretion in the mast cell in non-selective mode. For example, the ORP aqueous solution of the present invention can suppress TNF-α and the MIP1-α secretion in the mast cell for example. Think that the ORP aqueous solution that the present invention gives can also suppress the proinflammatory cytokine secretion in the cell of other secrete cytokines. These ORP aqueous solution of finding that the proved invention gives should show the broad spectrum antiphlogistic effect.
It is high more about more than 50% than untreated mastocyte that the ORP aqueous solution that the present invention gives preferably suppresses the mastocyte threshing, more preferably high about more than 80% than untreated mastocyte, more preferably high about more than 90% than untreated mastocyte, and it is even more preferably high about more than 95% than untreated mastocyte, contact the ORP aqueous solution and reach 30 minutes approximately this moment, more preferably from about reaches 15 minutes and more preferably preferably reach 5 minutes approximately.According to method of the present invention, can give the ORP aqueous solution and suppress histamine secretion (for example because of threshing) by giving separately or unite with diluent (for example water or saline solution) with therapeutic modality.For example, can suppress the histamine secretion with therapeutic modality by giving compositions, wherein, for example according to reaching 50% (vol./vol.) ORP aqueous solution/diluent approximately, reach 25% (vol./vol.) ORP aqueous solution/diluent approximately, reach 10% (vol./vol.) ORP aqueous solution/diluent approximately, reach 5% (vol./vol.) ORP aqueous solution/diluent approximately and even reach 1% (vol./vol.) ORP aqueous solution/diluent ratio dilution ORP aqueous solution approximately.
The ORP aqueous solution that the present invention gives also preferably suppress TNF-α secrete about more than 50%, more preferably from about more than 60%, more preferably from about more than 70% and even more preferably from about more than 85%.In addition, the ORP aqueous solution that the present invention gives also preferably suppress MIP1-α secrete about more than 25%, about more than 50%, and more preferably from about more than 60%.In addition, the ORP aqueous solution that the present invention gives also preferably suppress IL-6 and/or IL-13 secrete about more than 25%, more preferably from about more than 50%, and more preferably from about more than 60%.According to method of the present invention, can give the ORP aqueous solution and suppress cytokine secretion by giving separately or unite with diluent (for example water or saline solution) with therapeutic modality.For example, can suppress cytokine secretion with therapeutic modality by giving compositions, wherein, for example according to reaching 50% (vol./vol.) ORP aqueous solution/diluent approximately, reach 25% (vol./vol.) ORP aqueous solution/diluent approximately, reach 10% (vol./vol.) ORP aqueous solution/diluent approximately, reach 5% (vol./vol.) ORP aqueous solution/diluent approximately and even reach 1% (vol./vol.) ORP aqueous solution/diluent dilution ORP aqueous solution approximately.
Available method treatment of the present invention or prevention sinusitis can also comprise the sinusitis that causes because of infection.In one embodiment, the invention provides the method for treatment or prevention sinusitis, wherein said sinusitis causes because of the infection that is for example caused by one or more microorganisms, and these microorganisms are selected from virus, antibacterial and fungus.Therefore, the invention provides the method for the treatment of or preventing viral sinusitis, wherein said sinusitis is relevant with the infection of one or more viruses, the ORP aqueous solution susceptible that they preferably give the patient.Susceptible virus can comprise that for example one or more are selected from HIV, Coxsackie virus, adenovirus, rhinovirus, herpesvirus, the virus of influenza virus and combination thereof.
The present invention also provides treatment or has prevented the method for bacillary sinusitis, and wherein said sinusitis is relevant with the infection that is caused by one or more antibacterials, the ORP aqueous solution that the preferred susceptible of these antibacterials gives the patient.The susceptibility antibacterial can comprise that for example one or more are selected from staphylococcus, streptococcus, Corynebacterium, the antibacterial of anaerobe and particularly streptococcus pneumoniae or Haemophilus influenzae.The present invention further provides the method for treatment or prevention fungoid sinusitis, wherein said sinusitis is relevant with the infection that is caused by one or more funguses, the ORP aqueous solution that the preferred susceptible of these funguses gives the patient.The susceptibility fungus can comprise that for example one or more are selected from Zygomycetes, the fungus of aspergillosis and mycocandida.
The present invention also provides the antibacterial of killing in the biomembrane, the method for the Pseudomonas aeruginosa in the biological example film.The present invention further provides and killed morazella catarrhalis (Moraexllacatarrhalis) and antibiotic resistance bacterium, for example the streptococcic method of penicillin resistance.The method that the present invention can use this paper to disclose is used the ORP aqueous solution than using bacitracin kill bacteria more quickly.
The present invention may further include give the ORP aqueous solution with (for example by give jointly the ORP aqueous solution with, by give the ORP aqueous solution with or by merge the ORP aqueous solution with) treat at least a extra therapeutic agent (being the therapeutic agent of the ORP aqueous solution that gives of one or more non-the present invention) of effective dose.Extra therapeutic agent can comprise that for example one or more are selected from antihistaminic, Decongestant, anti-infective (for example antimicrobial drug (for example antibiotic), antiviral agents and antifungal agent), the medicine of anti-inflammatory agent and combination thereof.
Suitable antihistaminic can comprise, diphenhydramine for example, chlorphenamine, brompheniramine, loratadine, clemastine, fexofenadine, its derivant and combination thereof.Suitable Decongestant can comprise, phenylephrine for example, and pseudoephedrine, other α-and the beta-adrenergic agonist, its derivant and combination thereof.Suitable antimicrobial drug can comprise, penicillins for example, cephalosporins or other beta-lactam, Macrolide (for example erythromycin, 6-O-erythromycin and azithromycin), fluoroquinolones, sulfonamides, Tetracyclines, aminoglycoside, clindamycin, quinolones, metronidazole, vancomycin, chloromycetin, its antibiotic effective derivant and combination thereof.Suitable antifungal agent comprises, for example, and amphotericin B, fluconazol, flucytosine, ketoconazole, miconazole, its derivant and combination thereof.Suitable antiviral agents can comprise, acyclovir for example, and amantadine, didanosine, famciclovir regains dimension, ganciclovir, valaciclovir, zanamivir, interferon, its derivant and combination thereof.Suitable anti-inflammatory agent can comprise, for example one or more anti-inflammatory agents, for example one or more anti-inflammatory steroids or one or more nonsteroid anti-inflammatory drugses (NSAIDs).Typical anti-inflammatory agent can comprise, LTRA for example, and the cyclophilin class, FK is conjugated protein, steroid and NSAIDs.
According to the present invention, for example, method that can be by any appropriate is through topical administration ORP aqueous solution, for example as liquid, and spray, mixture, aerosol or steam are for example by atomizing, nebulization or spraying etc.In one embodiment, as spray, mixture or aerosol are administered to the patient and go up respiratory airway and/or one or more cranium holes with the ORP aqueous solution.In one embodiment, when passing through atomizing, when nebulization or spraying give the ORP aqueous solution, method of the present invention comprises that the drop form to have about 1 micron extremely about 10 microns diameter gives ORP aqueous solution, so that make one or more mucosal tissues contacts ORO aqueous solution in respiratory airway or one or more cranium holes.
According to the present invention, can be by sending separately or giving ORP aqueous solution by merging (for example mixing) ORP aqueous solution and one or more suitable carriers (for example diluent).For example, the ORP aqueous solution can installed indoor mixing the (for example aerosol apparatus maybe can be allocated as mixture the device of spray) with one or more suitable carriers, and can be from installing the indoor gained mixture of sending, for example it directly is delivered to respiratory airway and/or one or more cranium holes (for example by intranasal, by oral cavity or they both).Selectively, can use the multicell device, for example two chamber devices mix the ORP aqueous solution with one or more suitable carriers (for example diluent), wherein ORP aqueous solution and carrier are resided in independent indoor and be present at them and merge and/or to mix when indoor, make ORP aqueous solution and carrier when being delivered to the patient (for example before it at once or simultaneously) merge.
Be used for atomizing, the method and apparatus of nebulization or spraying is well-known in the art.The medical treatment aerosol apparatus is used for the physiologically active liquid of dosing is sent into the suction air-flow so that the receiver sucks.For example, referring to U.S. Pat 6,598,602 (being incorporated herein by reference).The medical treatment aerosol apparatus can be operated so that produce drop, forms to have the aerosol that sucks gas.In other situation, the medical treatment aerosol apparatus is used for water droplet inject sucked air-flow so that the receiver provided the gas with proper moisture content, this is to by the mechanical respiration auxiliary device, and such as respirator, ventilator or anesthesia delivery system provide the suction air-flow particularly useful.
For example, typical aerosol apparatus is described among the WO 95/01137, and the document has been described operation so that medical drop is injected hand-control device by air-flow (suction air-flow), and described air-flow is sucked by spout by the receiver.Another example can be in U.S. Pat 5,388, find (being incorporated herein by reference) in 571, the document has been described the positive pressure respirator system, and it provides respiratory control and enhancing to the patient with respiratory insufficiency and has comprised the drop drug particles is sent aerosol apparatus into patient airway and alveolar.U.S. Pat 5,312,281 (being incorporated herein by reference) have been described ultrasonic sprayer, and it is atomized water or liquid and can adjust the size of mist according to reports at low temperatures.In addition, U.S. Pat 5,287 has been described flow velocity with variable size and pharmaceutical aerosol has been delivered to neonate, the pneumatic nebulization apparatus of child and adult output volume in 847 (being incorporated herein by reference).In addition, U.S. Pat 5,063 has been described ultrasound atomizer in 922 (being incorporated herein by reference).The ORP aqueous solution can also be deployed into aerosol form as the infection in treatment lung and/or the air flue or make the ingredient of inhaler system of the wound healing of this class body part.
In order to carry out fairly large using, suitable device can be used for the ORP aqueous solution is dispersed into gas, includes, but are not limited to humidifier, nebulizer, fogger, carburator, nebulizer, water jet and other sprayer unit.This class device allows based on successive basis allotment ORP aqueous solution.Can use in nozzle the directly ejector of mixing air and water.The ORP aqueous solution can be changed into steam, such as low-pressure steam and be released into air-flow.Can use various types of humidifiers, such as ultrasonic humidifier, steam humidifier or aerosol apparatus and evaporation humidifier.Can disperse the specific device of ORP aqueous solution to incorporate ventilating system into being used to, so that provide the ORP that extensively uses aqueous solution at whole indoor or medical health facility (for example hospital, nursing unit etc.).Can also give the ORP aqueous solution in indoor or tent maybe can give by face shield or by endoscope.
According to the present invention, as described herein, can give the ORP aqueous solution separately or, comprise itself and one or more pharmaceutically acceptable carrier, vehicle for example, adjuvant, excipient, diluent, its combination waits coupling.This class carrier preferably with the chemical species that is present in the ORP aqueous solution in one or more are compatible.The method that those skilled in the art are easy to determine appropriate formulation and give ORP aqueous solution of the present invention.Any adjustment necessary on dosage is easy to be worked out by those skilled in the art, so that according to one or more Relevant Clinical Factors, such as side effect, the overall state of an illness change of patient waits character and/or the seriousness at the treatment illness.
For example, can be by merging the ORP aqueous solution and reaching 25% (wt./wt. or vol./vol.) suitable carriers approximately, reach 50% (wt./wt. or vol./vol.) suitable carriers approximately, about 75% (wt./wt. or vol./vol.) suitable carriers, reach 90% (wt./wt. or vol./vol.) suitable carriers approximately, about 95% (wt./wt. or vol./vol.) suitable carriers and even about 99% (wt./wt. or vol./vol.) or carrier or with its dilution preparation ORP aqueous solution more suitably.Suitable carriers can comprise, for example water (distilled water for example, sterilized water, sterile water for injection for example, Sterile Saline etc.).Suitable carriers can also comprise that one or more are described in the carrier among the Application No. US 10/916,278 (being incorporated herein by reference).Exemplary formulations can comprise that for example solution is wherein used sterilized water, Sterile Saline or its combination dilution ORP aqueous solution.For example, with reaching 25% (vol./vol.) approximately, reach 50% (vol./vol.) approximately, about 75% (vol./vol.), reach 90% (vol./vol.) approximately, reach 95% (vol./vol.) approximately or reach 99% (vol./vol.) approximately or 99% above sterilized water, Sterile Saline or its combination dilution ORP aqueous solution.
Have been found that in fact ORP aqueous solution that the present invention gives does not contain the toxicity to normal structure and normal mammalian cell.The ORP aqueous solution that the present invention gives preferably can not produce on eukaryotic survival rate obviously and descend, and apoptosis is obviously increased, and can obviously not quicken cell senescence and/or can not produce tangible oxidisability DNA infringement in mammalian cell.The avirulence advantageous particularly and even may be unexpected, this be because the disinfecting power of the ORP aqueous solution that gives of the present invention almost with the hydrogen peroxide equivalence, and the toxicity of normal structure and normal mammalian cell is starkly lower than hydrogen peroxide.The ORP aqueous solution that these discovery confirmations the present invention gives comprises that for example mammal it is safe that philtrum uses.
With regard to the ORP aqueous solution that the present invention gives, cell survival rate preferably is at least about 65% at contact ORP aqueous solution after about 5-30 minute, more preferably is at least about 70% and more preferably be at least about 75%.In addition, the ORP aqueous solution that the present invention gives preferably causes only reaching approximately 10% cell, more preferably only reaches 5% cell approximately and more preferably only reach 3% cell when contact ORP aqueous solution reaches below 30 minutes or 30 minutes approximately (for example at contact ORP aqueous solution after about 30 minutes or about 5 minutes) approximately to expose the annexin-V on its cell surface.
In addition, the ORP aqueous solution that the present invention gives preferably causes about cell below 15%, the more preferably from about cell below 10% and more preferably from about the expression SA-beta galactosidase behind long-term contact OPR aqueous solution of the cell below 5%.The ORP aqueous solution that the present invention gives preferably causes the O-DNA adduct of the same section that causes under the same treatment condition with hydrogen peroxide to form, for example hydrogen peroxide causes in the cell of generally handling under condition of equivalent is lower than about 20% O-DNA adduct and forms, and is lower than that about 10% O-DNA adduct forms or about 5% or 5% following O-DNA adduct forms.
The ORP aqueous solution that the present invention gives can not produce significant RNA degraded.Therefore, from people's cell culture, extract after about 30 minutes or after contacting about 3 hours and RNA by the denaturing gel electrophoresis analysis does not generally show significant RNA degraded and generally demonstrates two normal tapes (being 28S and 18S) that are equivalent to eucaryon ribosomal RNA s at contact ORP aqueous solution, show that the ORP aqueous solution that the present invention gives makes RNA complete basically.Similarly, contact ORP aqueous solution after about 30 minutes or the RNA that from people's cell culture, extracts after contacting about 3 hours can carry out the reverse transcription of composing type people GAPDH (glyceraldehyde-3-phosphate dehydrogenase) gene and amplification (RT-PCR) and produce strong GAPDH band at the gel electrophoresis of RT-PCR product.On the contrary, handling the similar date slip of cell with HP reveals tangible RNA degraded and does not almost have GAPDHRT-PCR product (if any).
Generally speaking, can be by various differences by way of giving the ORP aqueous solution that the present invention gives, for example by non-intestinal, endoscope or directly be administered to the biological tissue surface, for example skin and/or one or more mucomembranous surfaces.Parenterai administration can comprise use, and is for example by intramuscular, subcutaneous, intravenous, and intra-arterial, in the sheath, synovial cavity is gone in the intravesical dispenser.Endoscope gives the ORP aqueous solution and can comprise and use for example conchoscope, bronchoscopy, colonoscopy, sigmoidoscopy, hysteroscopy, laparoscopy, athroscopy, gastroscopy or per urethra path.The ORP aqueous solution is administered to mucomembranous surface can be comprised, for example to hole, nose, oral cavity, trachea, bronchus, esophagus, stomach, intestinal, peritoneum, urethra, vesicle, urethra, vagina, uterus, fallopian tube, synovial membrane skin and mucocutaneous administration.Parenterai administration can also comprise by intravenous, subcutaneous, intramuscular or intraperitoneal and gives ORP aqueous solution.For example, can pass through intravenous, for example as U.S. Pat 5,334,383 and 5,622, give ORP aqueous solution described in 848 (being incorporated herein by reference), the document has been described by intravenous and has been given ORP aqueous solution treatment viral myocarditis, the method for multiple sclerosis and AIDS.
To the patient, for example the treatment effective dose that gives of mammal, particularly people should be enough to influence patient's treatment or prophylactic response in rational time limit in the context of the invention.Be easy to use method well-known in the art to determine this dosage.Those skilled in the art generally acknowledge that the concrete dosage level that is used for any particular patient depends on various potential treatment correlative factors.For example, can determine this dosage based on seriousness, weight in patients, patient age, patient body and the mental condition of the concentration of used specific ORP aqueous solution, illness, general health situation, sex, meals, administration frequency etc.Can also be based on the existence that may follow any adverse side effect that gives specific ORP aqueous solution, nature and extent is determined the size of this dosage.When possibility, expectation remains to bottom line with adverse side effect.
Can comprise the factor that concrete dosage is considered, for example, bioavailability, metabolic characteristic, administration time, route of administration, discharge rate, the pharmacodynamics relevant etc. with the specific ORP aqueous solution of particular patient.Other factors can comprise, effect or the effectiveness of ORP aqueous solution aspect the specific illness of being treated for example is before therapy processes, in the process or the serious symptom that exists afterwards etc.In some cases, can also part by using one or more algoscopys, the biological example algoscopy is measured the formation of treatment effective dose, described algoscopy is to treatment or prevents the reasonable clinical expection of effect of the specific ORP aqueous solution of specific illness.
According to the present invention, can be separately or with one or more extra therapeutic agents to the patient, for example the people gives the ORP aqueous solution that the present invention gives, so that the illness that treatment exists comprises sinusitis.Can also be by precautionary approach separately or with one or more extra therapeutic agents to the patient, for example the people gives the ORP aqueous solution that the present invention gives, described patient, for example the people has contacted one or more pathogen relevant with described illness.For example, can suitably give ORP aqueous solution of the present invention to the patient by precautionary approach, this patient contacted one or more cause infective micro-organisms (for example virus, antibacterial and/or fungus), so that the probability of the sinusitis that inhibition or reduction are relevant with patient's microorganism (and/or infection), or alleviate the seriousness that contacts the sinusitis (and/or infection) of result's generation as this class.
It will be understood by those skilled in the art that and can utilize suitable method afford ORP aqueous solution of the present invention, although and can use more than one route of administration, a kind of specific by way of providing than another kind by way of more direct and more effective.The treatment effective dose can for to the individual patient administration to reach " effect level " necessary dosage of ORP aqueous solution.For example, the treatment effective dose can be defined as the individual patient administration to reach the blood levels of ORP aqueous solution (or one or more reactive species that wherein comprise) prevention or treatment patient illness, organize the interior required consumption of level of level (for example level in one or more tissues of upper respiratory tract and/or cranium hole) and/or born of the same parents.
When effective level during as preferred administration terminal point, actual dosage and scheme can distribute according to for example pharmacokinetics, the difference of the interindividual variation of metabolism etc. and changing.Effect level can also be at ORP aqueous solution and one or more therapeutic agent, one or more anti-infectives for example, one or more " alleviants ", " regulator " or " nertralizer " (for example U.S. Patent number 5,334,383 and 5,622, disclosed in 848 (being incorporated herein by reference in full) at this), change during couplings such as one or more anti-inflammatory agents.
Suitable indicator can be used for measuring and/or the monitoring effect level.For example, can measure effect level by direct analysis (for example analytical chemistry) or by the suitable patient's sample of indirect analysis (for example using the clinical chemistry indicator) (for example blood and/or tissue).For example, can also be by directly or indirectly observing, such as the concentration of urine metabolite, the change of the labelling relevant (for example viral count with regard to viral infection) with the state of an illness, histopathology and immunochemical analyses, effect level is measured in the symptom minimizing relevant with the state of an illness etc.
Conventional ORP aqueous solution has the extremely limited shelf life, only is several hours usually.As this short-life result, use conventional ORP aqueous solution near use the time, to produce.Viewpoint from reality this means facility, and for example medical health facility is bought such as hospital is essential, stores and keep the necessary equipment of conventional ORP aqueous solution of producing.In addition, conventional technology of preparing can not be produced the permission extensive use, for example as the amount of enough commercial scale of the extensive disinfectant that is used for medical health facility.
Be different from conventional ORP aqueous solution, the ORP aqueous solution that the present invention gives is stable at least about 24 hours in its preparation back.In addition, the ORP aqueous solution that gives of the present invention generally is safe on environment and has avoided expensive disposal operations thus.The ORP stabilized aqueous solution that preferred the present invention gives at least about 1 week (1 week for example, 2 weeks, 3 weeks, 4 weeks or more than 4 weeks) and more preferably at least about 2 months.More preferably the ORP stabilized aqueous solution that gives of the present invention was at least about 6 months.Even more preferably the ORP stabilized aqueous solution that gives of the present invention at least about 1 year, and most preferably stable at least about more than 1 year, for example at least about 2 years or at least about 3 years.
Can keep being suitable for one or more application in its preparation back (for example room temperature) under the normal storage condition based on the ORP aqueous solution, for example, suppress the mastocyte threshing, suppress cytokine secretion, decontamination, sterilization, sterilization, the specific time bar of the ability of antimicrobial cleansing and wound clean is determined its stability.The stability of the ORP aqueous solution that the present invention gives can also be by under acceleration environment, measures to about 60 ℃ storage for for example about 30 ℃, and wherein the ORP aqueous solution is preferably stable reaches 90 days approximately and preferably reach 180 days approximately.
Can also determine stability based on one or more kinds (or its precursor) concentration in time that the ORP aqueous solution exists in solution in the shelf life process.Preferably with one or more kinds, for example the concentration of free chlorine maintained more than about 70% or 70% of its initial concentration in ORP aqueous solution preparation back at least about 2 months.More preferably one or more the concentration with these kinds apoplexy due to endogenous wind maintained more than about 80% or 80% of its initial concentration in ORP aqueous solution preparation back at least about 2 months.More preferably one or more the concentration with this class kind apoplexy due to endogenous wind maintained more than about 90% or 90% of its initial concentration in ORP aqueous solution preparation back at least about 2 months, and most preferably maintained more than about 95% or 95%.
Can also be based on the quantitative determination stability that is present in the organism in the sample behind the contact ORP aqueous solution.Measure organism concentration and reduce and to carry out based on any suitable organism, comprise, for example antibacterial, fungus, yeast or virus.Being used to measure stable exemplary organism can comprise, bacillus coli (Escherichia coli) for example, staphylococcus aureus (Staphylococcus aureus), white candida mycoderma (Candida albicans) and atrophy bacillus cereus (Bacillus athrophaeus) (bacillus subtilis in the past (B.subtilis)).
Can also be based on being present in the endotoxin (for example liopopolysaccharides) in the sample behind the contact ORP aqueous solution, somatomedin, the amount of cytokine and other protein and lipid reduces determines stability.
The ORP aqueous solution that the present invention gives can be used as and makes viable microbial lowering of concentration 4log (10 4) low-level disinfectant work, and also can be used as and make viable microbial lowering of concentration 6log (10 6) the high level disinfection agent work.When measuring the ORP aqueous solution that preferred the present invention gives can contact 1 minute after this solution of preparation was at least about 2 months after, produce 4log (10 4) total organism concentration reduce down.The ORP aqueous solution produces 10 when more preferably can be measured after this solution of preparation was at least about 6 months 4-10 6Organism concentration reduce.More preferably the ORP aqueous solution can be at least about 1 year behind preparation ORP aqueous solution, and most preferably surpassing about 1 year, for example at least about 2 years or produce 10 when measuring at least about 3 years 4-10 6Organism concentration reduce.
For example, the ORP aqueous solution that the present invention gives can (BioSciences Labs, Montana descend at least about 5log (10 the viable microbial sample concentration in contact in 30 seconds when measuring at least 2 months after US) at this ORP aqueous solution of preparation 5), described microorganism is selected from Pseudomonas aeruginosa (Pseudomonas aeruginosa), bacillus coli, Hai Shi enterococcus (Enterococcus hirae), Acinetobacter baumannii (Actinetobacterbaumannii), the kind of acinetobacter (Actintobacter), bacteroides fragilis (Bacteroides fragilis), clostridium perfringen (Enterbacter aerogenes), enterococcus faecalis, vancomycin resistance enterococcus faecalis (Vancomycinresistant-Enterococcus faecium) (VRE, MDR), Haemophilus influenzae (Haemophilus influenzae), acid-producing Klebsiella bacterium (Klebsiellaoxytoca), Klebsiella pneumonia (Klebsiella pneumoniae), micrococcus luteus (Micrococcus luteus), proteus mirabilis (proteus mirabilis), serratia marcescens (Serratia macrcescens), staphylococcus aureus, staphylococcus epidermidis (Staphylococcus epidermidis), staphylococcus haemolyticus (Staphylococcus haemolyticus), staphylococcus hominis (Streptococcushominis), staphylococcus saprophyticus (Staphylococcus saprophytocis), streptococcus pyogenes (Streptococcus pyogenes), white candida mycoderma.
In one embodiment, when the ORP aqueous solution that the present invention gives can be behind this ORP aqueous solution of preparation be measured at least about 2 months in contact in about 1 minute with viable microbial, comprise, but be not limited to bacillus coli, Pseudomonas aeruginosa, the sample of staphylococcus aureus and white candida mycoderma is from about 1 * 10 6With about 1 * 10 8The initial concentration of individual organism/ml is reduced to the final concentration of about 0 organism/ml.This is equivalent to about 6log (10 6) to about 8log (10 8) organism concentration reduce.When preferred ORP aqueous solution can be after preparation be measured at least about 6 months, and make bacillus coli when more preferably after preparation, measuring at least about 1 year, Pseudomonas aeruginosa, staphylococcus aureus or white candida mycoderma organism reduce 106-108.
In about 5 minutes, produce the spore suspension lowering of concentration of the Bacillusathrophaeus spore of about 6log (106) when selectively, the ORP aqueous solution that gives of the present invention can be behind this ORP aqueous solution of preparation be measured at least about 2 months.When the ORP aqueous solution that preferred the present invention gives can be behind this ORP aqueous solution of preparation be measured at least about 6 months, and produce about 106 Bacillusathrophaeus spore concentration when more preferably behind this ORP aqueous solution of preparation, measuring and descend at least about 1 year.
When the ORP aqueous solution that the present invention gives can be behind this ORP aqueous solution of preparation be measured at least about 2 months in contact 30 (30) seconds the spore suspension lowering of concentration of the Bacillusathrophaeus spore of the about 4log of generation (104).When the ORP aqueous solution that preferred the present invention gives can be behind this ORP aqueous solution of preparation be measured at least about 6 months, and produce this Bacillus athrophaeus spore concentration when more preferably after preparation, measuring and descend at least about 1 year.
When can be behind this ORP aqueous solution of preparation measuring at least about 2 months, the ORP aqueous solution that the present invention gives further to produce about 6log (10 in about 5 to about 10 minutes about contact 6) fungal spore, such as the lowering of concentration of black aspergillosis (Aspergillis niger).When the ORP aqueous solution that preferred the present invention gives can be behind this ORP aqueous solution of preparation be measured at least about 6 months, and realize 10 when more preferably after preparation, measuring at least about 1 year 6The fungal spore lowering of concentration.
When can be further measuring at least about 2 months, the ORP aqueous solution that the present invention gives further to produce about 3log (10 in about 5 to about 10 minutes about contact behind this ORP aqueous solution of preparation 6) virus, such as the lowering of concentration of human immunodeficiency virus (HIV) and adenovirus.When the ORP aqueous solution that preferred the present invention gives can be behind this ORP aqueous solution of preparation be measured at least about 6 months, and realize＞10 when more preferably after preparation, measuring at least about 1 year 3Virus concentration descend.
When can be further measuring at least about 2 months, the ORP aqueous solution that the present invention gives suppresses Mycobacterium bovis (Mycobacterium bovis) growth fully in about 5 minutes in contact behind this ORP aqueous solution of preparation.When preferred ORP aqueous solution can be behind this ORP aqueous solution of preparation be measured at least about 6 months, and realize that mycobacteria concentration suppresses fully when more preferably after preparation, measuring at least about 1 year.
The ORP aqueous solution that the present invention gives can be acidity, and is neutral or alkaline and generally can have a pH of about 1 to about 14.In this pH scope, the ORP aqueous solution is safe when being applied on the surface that for example contacts this ORP aqueous solution with appropriate amount, but can not damage surface or infringement object, such as human body skin.The pH of the ORP aqueous solution that preferred the present invention gives is about 3 to about 8.More preferably the pH of ORP aqueous solution be about 6.4 to about 7.8 and more preferably pH be about 7.4 to about 7.6.
The ORP aqueous solution that the present invention gives can have the Eo+ of-1000 millivolts (mV) extremely about+1150 millivolts (mV) approximately.This current potential is to accept or the measured value (being current potential) of the solution trend of metastatic electron, described electronics detected by metal electrode and with same solution in reference electrode relatively.Can comprise by this current potential of measured by standard techniques, for example measure and the standard reference thing, compare the current potential with millivoltmeter of ORP aqueous solution such as silver/silver chloride electrode.
The ORP aqueous solution that the present invention gives preferably has the current potential of pact-400mV to pact+1300mV.More preferably the ORP aqueous solution has about 0mV to pact+1250mV, and more preferably from about+and the 500mV current potential of pact+1250mV extremely.Even more preferably the ORP aqueous solution that gives of the present invention has pact+800mV to pact+1100mV, and most preferably from about+and the 800mV current potential of pact+1000mV extremely.
Various ions and other kind may reside in the ORP aqueous solution that the present invention gives.For example, the ORP aqueous solution can contain chlorine (for example free chlorine).Think have these kinds apoplexy due to endogenous wind one or more facilitated the ORP aqueous solution to kill various microorganisms at least, such as the disinfecting power of antibacterial and fungus and virus.Although do not wish to be subjected to the constraint of any particular theory, think that one or more of these kinds apoplexy due to endogenous wind can also facilitate the treatment of ORP aqueous solution or effects of prevention sinusitis.
Free chlorine generally comprises, but is not limited to hypochlorous acid (HClO), hypochlorite ion (ClO -),, sodium hypochlorite (NaOCl), chloride ion (Cl -), dissolved chlorine (Cl 2) and precursor.Hypochlorous acid depends on pH with hypochlorite ion's ratio.PH 7.4 times, the hypochlorous acid level generally is about 25ppm to about 75ppm.Temperature also influences the ratio that free chlorine becomes branch.
Chlorine can be present in the amount of any appropriate in the ORP aqueous solution that the present invention gives.Can be by the method for any appropriate, comprise that method well known in the art measures the level of these compositions.
The chloride content that preferably includes free chlorine and combined chloride is about 50 parts/1,000,000 (ppm) to about 400ppm.More preferably, chloride content is about 80ppm to about 150ppm.
Can measure chlorinity by means commonly known in the art, such as the DPD colorimetry (Lamotte Company, Chestertown, Maryland) or other known method, the method for setting up such as Environmental Protection Agency.In the DPD colorimetry, by making free chlorine and N, N-diethyl-p-phenylenediamine (DPD) reaction forms yellow and the calibration calorimeter measurement intensity that provides with part/1,000,000 outputs is provided.Add potassium iodide to change the pink of this solution again and obtain total chlorine number.Measure the amount of the combined chloride that exists then by deduction free chlorine from total chlorine.
The total amount that is present in the oxidation chemistry kind in the ORP aqueous solution can comprise above-mentioned chlorine kind preferably in about 2 mMs (mM) scope, and peroxidating water kind and extra kind comprise those kinds that may be difficult to measure, such as Cl -, ClO 3, Cl 2 -And ClO x
In one embodiment, the ORP aqueous solution that gives of the present invention comprises one or more chlorine kinds and/or one or more extra peroxidating water kinds.Preferred chlorine kind exists as free chlorine species.Free chlorine species can comprise and is selected from hypochlorous acid (HOCl), hypochlorite ion (OCl -), sodium hypochlorite (NaOCl)), chloride ion (Cl -), dissolved chlorine (Cl 2), one or more kinds in its precursor and composition thereof.
Total free chlorine species amount preferably is about 10ppm to about 400ppm, and more preferably from about 50ppm is to about 200ppm, and 50ppm about 80ppm extremely most preferably from about.Hypochlorous amount preferably is about 15ppm to about 35ppm.The amount of sodium hypochlorite preferably at about 25ppm to about 50ppm.
In one embodiment, the ORP aqueous solution comprises one or more chlorine kinds or one or more optional its precursors, and stable at least about 24 hours, preferably at least about 1 week, preferably at least about 2 months and preferably at least about 6 months in its preparation back.Even more preferably this class ORP stabilized aqueous solution at least about 1 year and most preferably from about more than 1 year, for example at least about 2 years or at least about 3 years.
Also preferably include the ORP aqueous solution of one or more chlorine kinds, one or more extra peroxidating kinds (for example one or more oxygen kinds, dissolved oxygen) or one or more its precursors, and it has about 6 to about 8 pH.The pH of more preferably this ORP aqueous solution is about 6.2 to about 7.8 and most preferably from about 7.4 to about 7.6.The ORP aqueous solution that typical the present invention gives can comprise, for example about 15ppm is to about 35ppm hypochlorous acid, about 25ppm is to about 50ppm sodium hypochlorite, make these compositions have about 6.2 to about 7.8 pH, and can stablize at least about 1 week, for example at least about 2 months, at least about 6 months, at least about 1 year or about more than 1 year, for example at least about 2 years or at least about 3 years.
Although never limit the present invention, think that control pH and other variable (for example salinity) can provide stable ORP aqueous solution, it comprises one or more chlorine kinds, optional hydrogen peroxide or its precursor, such as hypochlorous acid and hypochlorite ion.
The ORP aqueous solution that the present invention gives preferably comprises the water kind of one or more oxidations, and they can produce free radical (such as hydroxyl) when contact ferrum.ORP water can be chosen the chemical compound that comprises that one or more generate in its production process wantonly, such as sodium hydroxide (NaOH), chlorine dioxide (ClO 2), peroxide (hydrogen peroxide (H for example 2O 2) and ozone (O 3), but, reported sodium hydroxide, chlorine dioxide, hydrogen peroxide and ozone can react with hypochlorite, thereby make it obtain consuming and producing other chemical species.
Can pass through oxidation-reduction reaction, for example the ORP aqueous solution that gives by electrolytic process or redox reaction production the present invention wherein is used for electric energy producing one or more chemical modifications at aqueous solution.The typical method that is used for preparing suitable ORP aqueous solution is described in for example U.S. Patent Application Publication No. US 2005/0139808 and US 2005/0142157 (being incorporated herein by reference).
In electrolytic process, import electric energy and by water with current forms from any to another transmission charge.Exist for electric current being produced and continuing, should have electric charge carrier in the water, and should have the power that makes carrier movement.Electric charge carrier can they can be cation and anion for electronics or with regard to solution with regard to metal and quasiconductor.Reduction reaction takes place on negative electrode, and oxidation reaction takes place on anode.Think that some reduction at least and the oxidation reaction that take place are described among the International Application No. WO 03/048421A1.
The water that produces on anode used herein is called anode water, and the water that produces on negative electrode is called negative electrode water.Anode water generally comprises the kind of the oxidation that is produced by cell reaction, and negative electrode water generally comprises reductive kind from reaction.Anode water generally has low pH, and general about 1 to about 6.8.Anode water preferably comprises various forms of chlorine, comprises, for example, chlorine, chloride ion, hydrochloric acid and/or hypochlorous acid or one or more its precursors.Also preferably there are various forms of oxygen, comprise, for example, oxygen and optional peroxide and/or ozone or one or more its precursors.Negative electrode water generally has high pH, and general about 7.2 to about 11.Negative electrode water can comprise hydrogen, hydroxyl and/or sodium ion.
The ORP aqueous solution that the present invention gives can comprise the mixture of anode water (for example water that produces) and negative electrode water (for example water that produces) in the cathode chamber of electrolyzer in the anode chamber of electrolyzer.The ORP aqueous solution that preferred the present invention gives comprises and for example accounts for the negative electrode water of about 10% volume of this solution to the consumption of about 90% volume.More preferably negative electrode water is present in the ORP aqueous solution with about 10% volume to the amount of about 50% volume, and about 20% volume that more preferably accounts for this solution is to about 40% volume, and for example about 20% volume of this solution is to about 30% volume.In addition, anode water may reside in the ORP aqueous solution, and for example consumption accounts for about 50% volume of this solution to about 90% volume.Typical ORP aqueous solution can comprise the anode water of about 10% volume to the negative electrode water of about 50% volume and about 50% volume to about 90% volume.Can use three Room electrolyzers shown in Fig. 1 to produce anode water and negative electrode water.
The preferred use comprises the anode chamber, the ORP aqueous solution that cathode chamber and the production the present invention of salt solution chamber between anode and cathode chamber give, wherein merge in anode and the negative electrode water at least some, make the ORP aqueous solution comprise anode water and negative electrode water.Can be used to prepare typical ORP aqueous solution typical case's three Room electrolyzers sketch map as shown in Figure 2.
Electrolyzer 100 has anode chamber 102, cathode chamber 104 and salt solution chamber 106.Salt solution chamber is between anode chamber 102 and cathode chamber 104.Anode chamber 102 has inlet 108 and outlet 110 is flow through anode chamber 100 to allow water.Cathode chamber 104 has inlet 112 similarly and outlet 114 is flow through cathode chamber 104 to allow water.Salt solution chamber 106 has inlet 116 and outlet 118.Electrolyzer 100 preferably includes the chamber that holds all parts.
Anode chamber 102 and salt solution chamber are isolated from each other by anelectrode 120 and cation exchange membrane 122.Anelectrode 120 can with anode chamber's 102 adjacent positioned, wherein film 122 is between anelectrode 120 and salt solution chamber 106.Selectively, film 122 can with anode chamber's 102 adjacent positioned, wherein anelectrode 120 is between film 122 and salt solution chamber 106.
Cathode chamber 104 is isolated from each other by negative electrode 124 and cathode ion exchange film 126 with salt solution chamber.Negative electrode 124 can with cathode chamber 104 adjacent positioned, wherein film 126 is between negative electrode 124 and salt solution chamber 106.Selectively, film 126 can with cathode chamber 104 adjacent positioned, wherein negative electrode 124 is between film 126 and salt solution chamber 106.
Electrode preferably is made of metal so that allow voltage potential to be applied between anode chamber and the cathode chamber.Metal electrode is generally planar and has with similar size of ion exchange membrane and cross section surface long-pending.Configured electrodes so that the most of contact in the surface of ion exchange parts its separately the anode chamber and the water in the cathode chamber.This can make ionic species in salt solution chamber, moves between anode chamber and the cathode chamber.Preferably, electrode has passage or the hole that electrode surface is evenly passed through in a plurality of positions.
Potential source is connected with negative electrode 124 so that the reduction reaction in oxidation reaction in the inductive anode chamber 102 and the cathode chamber 104 with anelectrode 120.
The ion exchange membrane 122 and 126 that uses in the electrolyzer 100 can be made of the material of any appropriate, so that allow ion, such as chlorion (Cl -) exchange and saline solution between salt solution chamber 106 and anode chamber 102, such as sodium ion (Na +) exchange between salt solution chamber 106 and cathode chamber 104.Anode ion exchange membrane 122 and cathode ion exchange film 126 can be made by the material of identical or different structure.The preferred anodes ion exchange membrane comprises fluorinated polymer.Suitable fluorinated polymer comprises, for example perfluorinated sulfonic acid polymer and copolymer are such as perfluorinated sulfonic acid/PTFE copolymer and perfluorinated sulfonic acid/TFE copolymer.Ion exchange membrane can be made of monolayer material or multilamellar.Suitable ion exchange membrane polymer can be included in one or more ion exchange membrane polymer under the Nafion trade mark.
The anode chamber 102 of electrolyzer 100 and the water source of cathode chamber 104 can be suitable water supply arbitrarily.Water can maybe can be chosen in from municipal water supply and use preceding pretreatment in the electrolyzer.Preferably, pretreated water and be selected from demineralized water, pure water, distilled water and deionized water.More preferably, the ultra-pure water of pretreated water source for using the reverse osmosis purifier apparatus to obtain.
The saline solution that is used for brine chamber 106 can comprise the saline solution that comprises the suitable ionic species that produces the ORP aqueous solution arbitrarily.Preferably, saline solution is sodium chloride (NaCl) saline solution, is also referred to as saline solution usually.Other suitable saline solution can comprise other chloride salt, and such as potassium chloride, ammonium chloride and magnesium chloride and other halogen are such as potassium and bromine salt.Saline solution can wrap saliniferous mixture.
The solution of salt can have the concentration of any appropriate.For example, saline solution can be for saturated or spissated.Preferred salt solution is saturated nacl aqueous solution.
Fig. 2 illustration think be used for the various ionic speciess that three Room electrolyzers related to the present invention produce.Three Room electrolyzers 200 comprise anode chamber 202, cathode chamber 204 and salt solution chamber 206.When suitable electric current was put on anode 208 and negative electrode 210, the ion that is present in the saline solution that flows through salt solution chamber 206 migrated into the water that flows through anode chamber 202 and cathode chamber 204 respectively by cathode ion exchange film 212 and anode ion exchange membrane 214.
Cation migrates to the negative electrode water 218 that flows through cathode chamber 204 from the saline solution 216 that flows through salt solution chamber 206.Anion migrates to the anode water 220 that flows through anode chamber 202 from the saline solution 216 that flows through salt solution chamber 206.
Preferred salt solution 216 is sodium-chloride water solution (NaCl), and it comprises sodium ion (Na +) and chloride (Cl -) ion.Na +Cation migrates to negative electrode water 218 from saline solution 216.Cl -Anion migrates to anode water 220 from saline solution 216.
Sodium ion and chlorion can further react in anode chamber 202 and cathode chamber 204.For example, chlorion can with various oxonium ions in the anode water 220 and other kind (for example oxygen containing free radical, the O of being present in 2, O 3) react and generation ClOn-and ClO -Other reaction also can be carried out in anode chamber 202, comprises the formation oxygen-derived free radicals, hydrion (H +), oxygen (for example is O 2), ozone (O 3) and peroxide.In cathode chamber 204, hydrogen (H 2), sodium hydroxide (NaOH), hydroxide ion (OH -) and other group can form.
The equipment that makes up generation ORP aqueous solution is to comprise at least two three Room electrolyzers.Electrolyzer comprises the anode chamber separately, cathode chamber and with anode chamber and the isolated salt solution chamber of cathode chamber.This equipment comprises anode water that collection is produced by electrolyzer and the mixing channel of the part negative electrode water that produced by one or more electrolyzers.Preferably, this equipment comprises that further the salt recirculating system is to allow to be supplied to the saline solution recirculation of electrolyzer salt solution chamber.Be used to use two electrolyzers produce the ORP aqueous solutions typical method sketch map as shown in Figure 3.
Process 300 comprises two three Room electrolyzers, particularly first electrolyzer 302 and second electrolyzer 304.305 shift from the water source, pumping, or allotment water is to the anode chamber 306 of first electrolyzer 302 and the anode chamber 310 and the cathode chamber 312 of cathode chamber 308 and second electrolyzer 304.Advantageously, this process can produce about 1 liter/minute to about 50 liters/minute ORP aqueous solution.Can increase this production capacity by using extra electrolyzer.For example, can be with 3,4,5,6,7,8, three Room electrolyzers are used to increase the output of the ORP aqueous solution that the present invention gives more than 9,10 or 10.
The anode water that produces in anode chamber 306 and the anode chamber 310 is collected in the mixing channel 314.The part negative electrode water that produces in cathode chamber 308 and cathode chamber 312 is collected in the mixing channel 314 and with anode water and merges.Discard the rest parts negative electrode water that in this process, produces.Can make negative electrode water optional, after this join mixing channel 314 through gas trap 316 and/or gas trap 318.Gas trap is removed gas, such as the hydrogen that forms in negative electrode water in process of production.
Mixing channel 314 can be chosen wantonly and be connected with recirculation pump 315 so that allow anode water and part negative electrode water uniform mixing from electrolyzer 302 and 304.In addition, mixing channel 314 can be chosen wantonly and comprise the suitable device that is used to monitor ORP aqueous solution level and pH.By pump 317 the ORP aqueous solution is shifted so that be applied to mixing channel position or its contiguous sterilization or sterilization from mixing channel.Selectively, the ORP aqueous solution can be allocated into one or more suitable containers, for example shipment is to remote position (for example warehouse, hospital etc.).
Process 300 further comprises the saline solution recirculating system so that saline solution is provided to the salt solution chamber 322 of first electrolyzer 302 and the salt solution chamber 324 of second electrolyzer 304.In salt bath 320, prepare saline solution.By pump 321 salt is transferred to salt solution chamber 322 and 324.Preferably, saline solution at first flows through salt solution chamber 322 successively, flows through salt solution chamber 324 subsequently.Selectively, can simultaneously saline solution be pumped to two salt solution chamber.
Before returning salt bath 320 again, saline solution can flow through the heat exchanger 326 in the mixing channel 314.So that control the temperature of ORP aqueous solution as required.
The ion that is present in the saline solution exhausts in first electrolyzer 302 and second electrolyzer 304 in time.Can regularly in mixing channel 320, add extra ion source changes anode water and negative electrode water over to replacement ion.Can use extra ion source, for example keep the constant pH of saline solution, it may descend in time (promptly becoming acidity).Extra ion source can comprise that for example, salt is such as sodium chloride for the chemical compound of any appropriate.Preferably, sodium hydroxide is joined in the mixing channel 320, so that replace the sodium ion (Na that changes anode water and negative electrode water over to +).
The ORP aqueous solution can be changed over to one or more suitable containers after its preparation, for example be used to distribute and be sold to end user's sealed container, and described end user is such as healthcare facility, comprise hospital for example, nursing unit, the doctor's office, outpatient's Surgicenter, dental clinic etc.Suitable containers can comprise, for example keeps the sealed container of the aseptic and the stability of the ORP aqueous solution that keeps in the container.Container can be made of any material compatible with the ORP aqueous solution.Preferred container does not generally react with one or more ions or other kind that are present in the ORP aqueous solution.
Preferably, container is made of plastics or glass.Plastics can be rigid, can be stored on the top of the shelf with Bedpan.Selectively, what container can be for flexibility, the container of being made by flexiplast for example is such as flexible pouch.
Suitable plastic can comprise, polypropylene for example, polyester terephthalate (PET), polyolefin, cycloolefin, Merlon, ABS resin, polyethylene, polrvinyl chloride and composition thereof.Preferably, container comprises one or more polyethylene kinds, and they are selected from high density polyethylene), low density polyethylene (LDPE) (LDPE) and linear low density polyethylene (LLDPE).Most preferably container is made by high density polyethylene (HDPE).
Container preferably has the opening that allows allotment ORP aqueous solution.Sealed container opening in any suitable manner.For example, can or fill in sealed container with four spiral covers.Choose wantonly and can further use paper tinsel layer sealed open.
The gas of sealed container headroom can be air or other suitable gas arbitrarily, preferably its not with the ORP aqueous solution in one or more kinds reactions.Suitable headspace gas can comprise, nitrogen for example, oxygen and composition thereof.
The inflammation that the ORP aqueous solution that the present invention gives can also be used for the treatment of or prevent cell-mediated inflammation and cause because of autoimmune response includes, but are not limited to SLE, autoimmune thyroiditis, sarcoidosis, inflammatory bowel, rheumatoid arthritis and rheumatic fever.The ORP aqueous solution that the present invention gives can be used for the treatment of or prevent the inflammation that causes because of infection, for example be selected from virus because of one or more, the inflammation that the infection that antibacterial and fungi microbe cause causes comprises allergy and the inflammation of autoimmune-mediation of causing because of infection.
The inflammation that the ORP aqueous solution that the present invention gives can also be used for the treatment of or prevention is relevant with the upper respiratory tract illness.When inflammation is relevant with the upper respiratory tract illness, preferably with the ORP aqueous solution for example as spray, mixture, aerosol or steam are administered to air flue, so that contact is by airway tissue on one or more of illness infringement.The method of any appropriate comprises that one or more route of administration as herein described can be used for the ORP aqueous solution is delivered to air flue, so that treat or prevent one or more upper respiratory tract illness of the present invention.
The ORP aqueous solution that the present invention gives can also be used for prevention or treat the inflammation that influences respiratory airway tissue on one or more (nose tissue for example as described herein) or lung tissue.This class illness can comprise, pharyngitis for example, asthma etc., their available ORP solution prevention of the present invention or treatments.
With regard to pharyngitis, according to estimates the whole world all at doctor's clinic, have 1 to 2% among clinic and the emergency room prescription on individual diagnosis person because of due to the pharyngitis.In the U.S. and Mexico, think that pharyngitis and tonsillitis account for 1,500 ten thousand and 1,200 ten thousand prescription on individual diagnosis persons every year respectively.These cases generally cause because of various antibacterials and virus.In addition, belong to can significantly the raise risk of rheumatic fever among the weak crowd of the pharyngitis that causes and tonsillitis because of A family beta hemolytic streptococcus; Yet, only think that 5 to 15% pharyngitis case is caused by this antibacterial and remaining acute case is to cause because of antibacterial and the virus that does not almost have the epidemiology dependency.The case of back trends towards in several days the self limiting healing and can not leave over sequela.
Empirical tests a large amount of doctors in the whole world all can indistinguishably hold according to antibiotic prescription and be used for acute pharyngitis.This situation all can take place every day, usually because the patient tends to require potent antibiotics.Regrettably, be difficult to set up streptococcal pharyngitis/tonsillitic definite clinical diagnosis and use antibiotic therapy acute pharyngitis/tonsillitic cost/benefit ratio to have query.In some country, such as Mexico, spend in the antibiotic cost and spend in government's resource of losing the job day as the disease consequence on expenditure remarkable, all these have all represented the great consumption aspect national budget.
Think that method of the present invention provides treatment or prophylaxis of acute pharyngitis/tonsillitic safety, complementary therapy effective and with low cost.Acute pharyngitis/tonsillitic experiential therapy can be from giving ORP aqueous solution of the present invention, and according to Streptococcus development or quick test result's difference, if desired, can only bring into use antibiotic at after this 48-72 hour.The ORP aqueous solution that the present invention gives can make antibiotic use postpone thus, and alleviates patient's symptom simultaneously, and quickens patient's recovery, as long as acute pharyngitis/tonsillitis is not from A family Streptococcus.ORP aqueous solution of the present invention also can shorten the clinical response time limit and reduce the sickness rate of recurrence with the impatient property of treatment streptococcus pharyngitis/tonsillitic assistance application.
The inflammation that the ORP aqueous solution can also be used for the treatment of or prevention is relevant with allergy that the present invention gives.Historically, allergy is classified as one of 4 types of can cause important diseases thus.The ORP aqueous solution that the present invention gives can also be used for the treatment of and/or prevent one or more in (for example suppress outbreak, suppress to increase progressively or reduce probability) this class reaction.The I allergy generally because of can cause with the antibodies that combines mastocyte or basophilic granulocyte (referring to Kumar etc., Robbins﹠amp; Cotran Pathologic Basis of Disease, 2004, pp.193-268 is incorporated herein by reference).The I type is reflected at contact and takes place in antigenic several minutes of the individuality of antigen sensibilization in advance.In the people, the reaction of I type is by the IgE mediation with the high affinity Fc receptor on mastocyte or the basophilic granulocyte.
Mastocyte effect in the allergy of I type is even more important, because they reside in the tissue under hematochezia pipe and the neural epithelial surface.At atopic dermatitis, observed a plurality of clinical symptoms are differently produced by the IgE-antigenic stimulus of the mastocyte of invaded tissue by being arranged in allergic rhinitis and the atopic asthma.At present such as the pathogenetic acceptable viewpoint of this class illness of atopic asthma be anaphylactogen by cause pulmonary mastocyte (MCs) with IgE in the early stage release of what is called reaction such as histamine, leukotrienes, prostaglandins, kininis, platelet activating factor (PAF) wait this amboceptoid to start (referring to pp.193-268 such as Kumar).These amboceptors are induced bronchoconstriction and are strengthened vascular permeability and the mucus generation thus.According to this model, after the mastocyte activation, the various cytokines of those emiocytosises comprise tumor necrosis factor (TNF-α), IL-4, IL-5 and IL-6, they participate in the local recruitment and the activation of other inflammatory cell, such as the eosinophilic granulocyte, and basophilic granulocyte, T lymphocyte, platelet and mononuclear phagocyte.These cells of raising facilitate inflammatory reaction to take place thus, can become spontaneous then and the aggravation symptoms of asthma.This late phase response facilitated in the inducing peripheral tissue the long-term inflammatory reaction that changes (Kumar etc., pp.193-268).Clinically, the reaction of I type can have local action, such as allergic rhinitis, or general action, as what find in anaphylaxis, this anaphylaxis self shows pruritus, urticaria, RD and circulatory failure.
The allergy of II type by be oriented on the cell surface and the crack, extracellular in antigenic antibody-mediated.These antibody can instruct lysis or cause target molecule opsonic action (for the endocytosis of other cell is prepared).Selectively, antibody can be oriented to and the activating cell surface receptor.The illness that causes because of the reaction of II type comprises infusion reaction, Graves disease (thyrotoxicosis), drug reaction, pernicious anemia and acute rheumatic fever.In rheumatic fever, form at streptococcal antigen, but organize, such as the antibody of cardiac valve generation cross reaction with the people.
The allergy of III type is caused by immune complex, and these immune complexs are antibody and other host immune system albumen, and most typical is the combination of complement protein.The normal function of antibody is combination and activating complement.Yet when the macromole immune complex that produces is not fully added man-hour, they can cause the histologic lesion that continues.Macrophage and PMNLs can be activated and cause these cells to discharge poisonous chemical substance by immune complex.The reaction of immune complex can be for partial and can produce illness, such as arthus reaction or cause general disease, such as some aspect of serum sickness or systemic lupus erythematosus (sle) (SLE).
The allergy of IV type is cell-mediated and is called delayed hypersensitivity sometimes.The allergy of IV type is by the T cell mediated and often cause granulomatous reaction to form.In granulomatous reaction, the macrophage form that is called epithelioid cell is attempted digestion antigen, but failure.Antigenic persistency causes release of cytokines, and they attract extra lymphocyte, thereby produces the chronic inflammatory disease focus.This focus has the cytotoxic t-lymphocyte of high concentration, and they discharge flanking cell is had toxic granzyme and perforin.The allergy of IV type is the outstanding composition of autoimmune disease, all logical sequence of Jaeger like that syndrome, sarcoidosis and contact dermatitis.
Pathological state can merge dissimilar allergy.In autoimmune disease, host antigen stimulates allergy, and the host is caused serious consequence.For example, in SLE host, antigen induction is at the II type reaction of hemocyte, and the reaction of III type causes blood vessel and glomerule infringement.In addition, also in iatrogenic (iatragenic) illness, such as observing allergy in drug reaction and the transplant rejection.Transplant rejection comprises the composition of II type and the allergy of IV type.
The ORP aqueous solution that the present invention gives can also be used for prevention or treatment is infected, one or more infectious pathogens for example, the infection that causes such as infective micro-organisms.This quasi-microorganism can comprise, virus for example, antibacterial and fungus.Virus can comprise that for example one or more are selected from adenovirus, herpesvirus, Coxsackie virus, HIV, rhinovirus, the virus of coronavirus and influenza virus.Antibacterial can comprise that for example one or more are selected from bacillus coli, Pseudomonas aeruginosa, the antibacterial of staphylococcus aureus and mycobacterium tuberculosis (Mycobateriumtuberculosis).Fungus can comprise that for example one or more are selected from white candida mycoderma, the fungus of bacillus subtilis and atrophy bacillus cereus.
The ORP aqueous solution that the present invention gives can also be effective to adenovirus.The ORP aqueous solution that the present invention gives is preferably contacting the ORP aqueous solution after about 20 minutes, more preferably realize after about 10 minutes greater than about 2 in contact after about 15 minutes and more preferably in contact, be preferably greater than approximately 2.5, more have choosing to descend greater than about 3 log-10 adenovirus carrying capacity.Contacting the ORP aqueous solution after about 15 minutes, more preferably after contacting about 10 minutes and more preferably after contact 5 minutes, the ORP aqueous solution that the present invention gives can also reduce the HIV-1 virus load effectively, preferably reach greater than about 2, more preferably greater than about 2.5, even the log attenuation quotient of choosing greater than about 3 log-10 arranged more.
According to method of the present invention, give the prevention of ORP aqueous solution or treat to infect to be used to prevent or treatment and the relevant sinusitis of infection (or the tissue of being encroached on) as described herein.
The ORP aqueous solution that the present invention gives can also be used to handle the tissue of damage or infringement, is for example undertaken by the ORP aqueous solution of organizing the contact treatment effective dose that makes one or more damages or infringement.The method of any appropriate all can be used for the tissue of contact damage or infringement, so that handle the tissue of damage or infringement.For example, can be by handling the tissue of damage or infringement, so that make the ORP aqueous solution of the tissue contact effective dose of damage or infringement with the flushing of ORP aqueous solution.Can be as described herein with the ORP aqueous solution as steam or spray or by aerosolization, atomization or atomizing give, so that the ORP aqueous solution of damage or damaging tissue's contact treatment effective dose.
The ORP aqueous solution that the present invention gives can be used for handling, for example because of the tissue of surgical injury or infringement.For example, the ORP aqueous solution can be used to handle the tissue that has damaged or damaged because of otch.In addition, the ORP aqueous solution can be used to handle the tissue of performing the operation, burn hemostasis, amputation, radiation, chemotherapy and combination damage or infringement because of operation on oral cavity, transplant operation, implant surgery, graft.Operation on oral cavity can comprise for example dental operation, such as root canal, and exodontia, gums operation etc.
The ORP aqueous solution that the present invention gives can be used for handling because of one or more burns, galling, and wearing and tearing, scratch, rash, ulcer pierces through wound, and its combination waits not necessarily the damage that caused by operation or the tissue of infringement.The ORP aqueous solution that the present invention gives can be used to handle the tissue of the damage of infection or infringement or the damage that causes because of infection or the tissue of infringement.This class infects can be selected from virus as described herein such as one or more, the microorganism of antibacterial and fungus because of one or more infectious pathogens cause.
According to the present invention, the tissue that gives ORP aqueous solution treatment damage or infringement can also be used for prevention or treatment and this damage or the relevant sinusitis of infringement (or tissue of damage or infringement).
The ORP aqueous solution that the present invention gives can also be as eradicating various environment, the for example microorganism in health care and the medical treatment device zone, comprise antibacterial, the disinfectant of virus and spore is so that carry out disinfection to surface and armarium, and be applied to wound care, the medical treatment device sterilization, food sterilization, medical worker, hospital, the hand disinfection of family of consumer and anti-biological terror.The ORP aqueous solution can be used for disinfecting surface, is for example undertaken by the ORP aqueous solution that makes surface contact infection amount.Can use the method contact surface of any appropriate.For example, can be by coming contact surface, so that to this surface sterilization with ORP aqueous solution flushing surface.In addition, can lead to mistake as described herein with the ORP aqueous solution as steam or spray or by aerosolization, atomization or atomizing are applied to the surface and come contact surface, so that disinfecting surface.In addition, can use cleaning as described herein wiping the ORP aqueous solution be applied to the surface.By disinfecting surface, can remove infective micro-organisms from the surface.Selectively (or in addition), the ORP aqueous solution that the present invention gives can be applied to the surface so that barrier to infecting is provided, thus disinfecting surface.
Described surface can comprise one or more biological surfaces, one or more abiotic surface and combinations thereof.Biological surface can comprise, for example, one or more body cavitys, such as the oral cavity, hole chamber, cranial cavity, abdominal cavity and intrathoracic tissue.Intraoral tissue is drawn together, oral cavity tissue for example, gingival tissues, tongue tissue and throat tissue.Biological tissue can also comprise muscular tissue, osseous tissue, organ-tissue, mucosal tissue, vascular tissue, nervous tissue and combination thereof.Abiotic surface comprises, for example, and device, prosthetic device and the medical treatment device that can perform the operation and implant.According to method of the present invention, can be to the internal organs that may in operation process, expose, internal organs, the aseptic of surgical environments is for example kept in the surface sterilization of muscle etc.
The ORP aqueous solution can also be applied to people and/or animal so that treat various illness, include, but are not limited to following situation in one or more relevant inflammation: the cleaning agent of operation/open wound; Skin pathogens sterilization (for example being used for antibacterial, mycoplasma, virus, fungus, Protein virus); The war wound sterilization; Wound healing promotes; Burn-healing promotes; The gastric ulcer treatment; Wound irrigation; Dermatophytes; Psoriasis; The athlete foot; Blood-shot eye illness and other ocular infection; Ear infection (for example swimmer's ear); Lung/nose/sinus infection; With other medical applications on human or animal body.The ORP aqueous solution further describes in U.S. Patent Application Publication No. USU 2002/0160053 as the application of histiocyte growth promoter and (is incorporated herein by reference).
Can be by the ORP aqueous solution control of using with the present invention, reduce, the organism of killing or eradicating includes, but are not limited to Pseudomonas aeruginosa, bacillus coli, the Hai Shi enterococcus, Acinetobacter baumannii, the kind of acinetobacter, bacteroides fragilis, clostridium perfringen, enterococcus faecalis, vancomycin resistance enterococcus faecalis (Vancomycin resistant-Enterococcusfaecium) (VRE, MDR), vancomycin resistance escherichia coli, Haemophilus influenzae, acid-producing Klebsiella bacterium, Klebsiella pneumonia, micrococcus luteus, proteus mirabilis, serratia marcescens, staphylococcus aureus, staphylococcus epidermidis (Staphylococcus epidermidis), staphylococcus haemolyticus (Staphylococcus haemolyticus), staphylococcus haemolyticus (Staphylococcus hominis), staphylococcus saprophyticus (Staphylococcussaprophyticus), streptococcus pneumoniae, streptococcus pyogenes, Salmonella choleraesuls (Salmonella choleraesuis), shigella dysenteriae (Shingelladysenteriae) and other susceptible bacteria and yeast, Trichophyton mentagrophytes (Trichophyton mentagrophytes) for example, white candida mycoderma and candida tropicalis.ORP aqueous solution of the present invention can also be used for control, kills or eradicate virus, comprises, adenovirus for example, human immunodeficiency virus (HIV), rhinovirus, influenza (for example influenza A), hepatitis (for example hepatitis A), coronavirus (causing the poverty-stricken syndrome of serious acute respiratory (SARS)), rotavirus, respiratory syncytial virus, herpes simplex virus, varicella zoster virus, rubella virus and other susceptible virus.
The ORP aqueous solution that the present invention uses can also be used for controlling the allergen activity that is present in environment.In this respect, anaphylactogen generally comprises non-antibacterial, fungus, yeast or virus can in the susceptible human or animal, cause adverse immune response or anaphylactoid any material.The common physiological reaction of asthma after for contact one or more in this class anaphylactogen.Anaphylactogen can be (promptly from that live or dead organism) or (for example non--life such as the textile) of non--survival of survival, and may reside in the environment, for example, and in family and/or working space.
Can be with can comprising that the ORP aqueous solution is handled based on proteinic family anaphylactogen, for example, animal skin, skin and feces, family's dust, weeds, grass, tree, demodicid mite and pollen.Zoo-anaphylactogen can comprise, for example, and cat epithelium, Canis familiaris L. epithelium, horsehair scurf bits, ox hair scurf bits, dog dander, Cavia porcellus epithelium, Goose feather, mouse epithelial, mouse retention, rat epithelium and rat urine.
The occupation anaphylactogen can comprise that for example, high molecular reagent is such as the native protein that generally derives from plant or animal proteinum; With the low-molecular-weight chemical substance, such as vulcabond and other material of in some textile, finding.Other the chemical anaphylactogen that may reside in the working space can comprise, for example, and anhydride, antibiotic, timber dust and dyestuff.A large amount of protein can comprise plant gum for the occupational anaphylactogen, enzyme, animal proteinum, insecticide, vegetable protein and leguminous plant.
Can be described in Korenblat and Wedner with the extra anaphylactogen that the ORP aqueous solution is handled, Allergy Theory and Practice (1992) and Middleton, Jr. is among the Allergy Principles and Practice (1993).
The ORP aqueous solution can be sterilized and sterilize in any suitable manner.For example, for to medical treatment or dental instruments sterilization and sterilization, can keep the apparatus contact ORP aqueous solution time enough time limit and reduce to desired level so that will be present in the level of the organism on the apparatus.
For to crust sterilization and sterilization, can will directly be applied to crust from the ORP aqueous solution in the container (wherein storing this ORP aqueous solution).For example, the ORP aqueous solution can be toppled over, spraying, or directly be applied to crust.Can use suitable substrate then, such as cloth, fabric or napkin are coated on crust with the ORP aqueous solution.In hospital application, substrate is preferably aseptic.Selectively, can at first the ORP aqueous solution be applied to substrate, such as cloth, on fabric or the napkin.Can make moistening substrate contact crust then.Selectively, can it be applied to crust by the as described herein ORP aqueous solution is dispensed in the air.Can in a similar way the ORP aqueous solution be applied to humans and animals.
Can also use the cloths for cleaning that comprises water-fast substrate and ORP aqueous solution as herein described to use the ORP aqueous solution, wherein the ORP aqueous solution be allocated on substrate.Can apply with ORP aqueous solution dipping, cover, or be applied on the substrate.Preferably, with ORP aqueous solution pretreatment substrate, after this with cloths for cleaning dispensing end user.
The substrate that is used for cloths for cleaning can be the water-fast adsorbent or the adsorbent material of any appropriate.Various materials can be used as substrate.It should have enough wet strengths, abrasivity, suspension property (loft) and porous.In addition, substrate should not produce harmful effect to the stability of ORP aqueous solution.Example comprises the non-knitting substrate, knitting substrate, aquation entanglement substrate and sponge.
Substrate can have one or more layers.Every layer can have identical or different structure and abrasiveness.Different structures can be because of using different combinations of materials or using different production methods or its combination causes.Substrate is not answered water-soluble or is separated in water.Substrate can provide the carrier that the ORP aqueous solution is delivered to handled surface thus.
Substrate can be monolithic non-knitting or multi-disc non-knitting thing.Non-knitting thing sheet can be by the timber slurry, synthetic fibers, and natural fiber and admixture thereof constitute.The synthetic fibers that are used for substrate can include, but are not limited to polyester, artificial silk, nylon, polypropylene, polyethylene, the mixture of other cellulosic polymer and this fibrid.The non-knitting thing can comprise non-knitting fibre plate material, comprises molten blowing, form altogether, and carrier gas, the rotation combination, wet carrying, in conjunction with the Web materials of combing, aquation (be also referred to as rotation tangle) material and the combination thereof of tangling.These materials can comprise synthetic or natural fiber or its combination.Binding agent can be chosen wantonly and be present in the substrate.
The example of suitable non-knitting water insoluble substrates comprises 100% cellulose Wadding Grade 1804 from Little RapidsCorporation, from the 100% polypropylene pin of AmericanNon-wovens Corporation towards material NB 701-2.8-W/R, from the cellulose of Ahlstrom Fibre Composites and the admixture of synthetic fibers-Hydraspun 8579a with from the 70%Viscose/30%PES Code 9881 of PGI Nonwovens Polymer Corp.The additional examples that is applicable to the non-knitting substrate of cloths for cleaning is described in U.S. Pat 4,781,974,4,615,937,4,666,621 and 5,908,707 and International Patent Application Publication No. WO 98/03713, among WO 97/40814 and the WO 96/14835 (being incorporated herein by reference).
Substrate can also be made by knit materials, such as cotton fiber, and Cotton Gossypii/nylon admixture or other textile.Be used to make the regenerated cellulose of sponge, polyurethane foam etc. also can be suitable for.
The liquid load ability of substrate should be at least about the 50%-1000% of its dry weight, most preferably at least about 200%-800%.It is expressed as 1/2 to 10 times of carrying capacity of substrate weight.Substrate weight can change, but be not limited to about 0.01 to about 1,000 gram/square metre, 25 to 120 gram/m most preferably 2(being called " basis weight ") and general production to sheet or net are cut it, and be die-cut, or be divided into suitable shape and size.Cloths for cleaning preferably has certain wet tensile strength, but is not limited to about 25 to about 250 newton/m, more preferably from about 75-170 newton/m.
Can the allotment of ORP aqueous solution be existed by suitable arbitrarily method, dipping, coating covers, or is applied on the substrate.For example, can handle the each several part of substrate with the ORP aqueous solution of dispersion amount.Preferably, with the ORP aqueous solution the continuous net-shaped thing of substrate material is carried out disposed of in its entirety.The whole net of substrate material can be immersed the ORP aqueous solution.Selectively, because the substrate net is that be wound or level and smooth in non-knitting substrate production process, can or measure on net the spraying of ORP aqueous solution.Manufacturer is used in the ORP aqueous solution dipping in its container or is coated with the laminate portion that backing material downcut and be divided into size separately.
Cloths for cleaning generally can comprise extra composition so that improve the characteristic of rag.For example, cloths for cleaning can further comprise polymer, surfactant, and polysaccharide, the polycarboxylic acids esters, polyvinyl alcohol, solvent, chelating agen, buffer agent, thickening agent, dyestuff, coloring agent, spice and composition thereof is so that improve the characteristic of rag.These optional members should not produce harmful effect to the stability of ORP aqueous solution.The case description that can choose the various compositions that comprise wantonly in cloths for cleaning is in U.S. Pat 6,340, in 663,6,649,584 and 6,624,135 (being incorporated herein by reference).
Can be respectively with heat insulation or can gluing thermoplastic twine thing (such as polyethylene, mylar etc.) outward and seal cloths for cleaning of the present invention respectively.Rag can also be packaged as a large amount of multilamellars so that allocate more economically.Can be by the ORP aqueous solution of at first the multilamellar substrate being put into allotter and substrate layer contact the present invention being given.Selectively, can make cloths for cleaning form successive net by being applied to the ORP aqueous solution on the substrate in process of production and then moistening substrate being written into allotter.
Allotter includes, but are not limited to have the jar of cutting out thing or has the bucket of cutting out thing.The thing of closing on the allotter is to make moistening rag and external environment condition isolated and prevent that liquid component from volatilizing too early.
Allotter can be made by any suitable material all compatible with the ORP aqueous solution with substrate.For example, allotter can be by plastics, such as high density polyethylene (HDPE), and polypropylene, Merlon, polyethylene terephthalate (PET), polrvinyl chloride (PVC) or other duroplasts are made.
Can make the shallow opening of the continuous net-shaped thing of rag, most preferably by closing thing by allotter top.Telling the mode of the rag of Len req or size then from net expects.Can be at allotter top configuration blade, jagged edge or net cut into other apparatus of required size, with regard to limiting examples, folding when in fact wherein shallow opening works as incisxal edge.Selectively, can be with the continuous net-shaped thing indentation of rag, folding, segmentation is bored a hole or part is cut into even or non-homogeneous size or length, can avoid the demand to sharp-pointed incisxal edge then.In addition, can intersect the insertion rag, so that the next one is taken in the taking-up of a rag out of.
Can go into environment such as air dispersion with ORP aqueous solution of the present invention selectively by gaseous medium.Can the ORP aqueous solution be dispensed into air by the mode of any appropriate.For example, the drop and the dispersion that can make the ORP aqueous solution form any appropriate size entered the room.
With regard to small-scale application, can be by comprising the spray bottle allotment ORP aqueous solution of standpipe and pump.Selectively, the ORP aqueous solution can be packaged in the aerosol container.Aerosol container can comprise the product of allotment, propellant, container and valve.Valve can comprise actuating device and soak pipe.Can allocate container contents by hold-down transmission device.Various compositions in the aerosol container should be compatible with the ORP aqueous solution.Suitable propellant can comprise the liquefaction halocarbon, hydrocarbon or hydrocarbon-hydrocarbon admixture or Compressed Gas, and such as carbon dioxide, nitrogen or nitrous oxide.Aerosol systems preferably produces the drop of about 0.15 μ m to about 5 μ m sizes.
For some application, the ORP aqueous solution can be chosen wantonly and comprise bleach.Bleach can comprise, the chemical compound that substrate is brightened or bleach.The ORP aqueous solution that contains bleach can use in family laundering, so that to antibacterial and pathogenic bacteria sterilization and sterilization and make the medicated clothing blast.Suitable bleach includes, but are not limited to chloride bleach and contains the bleach of peroxide.The mixture of bleach can also be joined in the ORP aqueous solution.Preferably can bleach be joined in the ORP aqueous solution with the form of aqueous solution.
Suitable chloride bleach can comprise, chlorine for example, hypochlorite, N-chlorine compound and chlorine dioxide.Preferably, the chloride bleach that joins in the ORP aqueous solution is sodium hypochlorite or hypochlorous acid.Other suitable chloride bleach comprises, chlorine for example, calcium hypochlorite, bleaching liquid (for example calcium hypochlorite and calcium chloride water), bleaching powder (calcium hypochlorite for example, calcium hydroxide, the mixture of calcium chloride and hydrate thereof), hypochlorous acid two magnesium, lithium hypochlorite, Efficacious Disinfeitant and composition thereof.
Can in any suitable manner bleach be joined in the ORP aqueous solution.Preferably can at first prepare the aqueous solution that comprises bleach.(for example can use the home bleaching agent
Figure A20078000977300421
Bleach) or the preparation of the chloride bleach in other suitable source or other bleach contain the aqueous solution of bleach.Bleaching agent solution and ORP aqueous solution can be merged then.
Can bleach be joined in the ORP aqueous solution with any suitable amount.The ORP aqueous solution that preferably contains bleach is to human or animal's skin nonirritant.The total chlorion content that preferably contains the ORP aqueous solution of chlorine bleaches can be about 1000ppm to about 5000ppm, and preferably about 1000ppm is to about 3000ppm.The pH that contains the ORP aqueous solution of chlorine bleaches preferably is about 8 to about 10, and Eo+ preferably be about+700mV is to pact+800mV.
The further illustration of the following example the present invention, certainly, should not be considered as limiting by any way its scope.
Embodiment 1-3
These embodiment confirm the specific characteristic of the ORP aqueous solution that the present invention uses.According to the sample of ORP aqueous solution among the methods analyst embodiment 1-3 as herein described, so that measure the ion be present in every kind of sample and the physical characteristic and the level of other chemical species.To chlorine dioxide, the result that ozone and hydrogen peroxide obtain is based on the code test that is used to measure this class kind, but can represent different kinds, can also produce the positive test result.In addition, reported chlorine dioxide, the reaction of ozone and hydrogen peroxide and hypochlorite causes it to consume and other chemical compound (for example HCl and O 2) produce.To the pH of every kind of sample of ORP aqueous solution, Eo+ (ORP) and the ionic species that exists are listed in the table 1.
The physical characteristic of table 1.ORP aqueous sample and the ionic species of existence
Embodiment 1 Embodiment 2 Embodiment 3
pH 7.45 7.44 7.45
ORP(mV) +879 +881 +874
Total Cl -(ppm) 110 110 120
In conjunction with Cl -(ppm) 5 6 6
The ORP aqueous solution has suitable being used for for example sterilizes, and inflammation is cleaned and/or prevented and/or treated to sterilization, sinusitis, the physical characteristic of peritonitis or infection.
Embodiment 4-10
These embodiment show the not commensurability bleach of interpolation in ORP aqueous solution of the present invention.Especially, these embodiment confirm the antimicrobial acivity and the fabric bleaching ability of compositions.
Use distilled water preparation 10%
Figure A20078000977300431
Liquid lime chloride.Use 10% liquid lime chloride to prepare following solution then: 80%ORP aqueous solution/20% bleach (embodiment 4); 60%ORP aqueous solution/40% bleach (embodiment 5); 40%ORP aqueous solution/60% bleach (embodiment 6); 20%ORP aqueous solution/80% bleach (embodiment 7); With 0%ORP aqueous solution/100% bleach (embodiment 8).Two kinds of contrast solutions also are used for comparison, the ORP aqueous solution (embodiment 10) that comprises 100%ORP aqueous solution/0% bleach (embodiment 9) and have 0.01%Tween 20 disinfectant.Measure the physical characteristic of these samples, particularly pH, Eo+ (ORP), total chlorine (Cl-) content and hypochlorous acid (HClO-) content and test chlorine dioxide content and peroxide content the results are shown in it in table 2.
The physical characteristic of table 2.ORP aqueous solution/bleach compositions
pH ORP Total Cl -(ppm) HClO - (ppm)
Embodiment 4 8.92 +789 1248 62
Embodiment 5 9.20 +782 2610 104
Embodiment 6 9.69 +743 4006 80
Embodiment 7 9.86 +730 4800 48
Embodiment 8 9.80 +737 5000 50
Embodiment 9 7.06 +901 64 32
Embodiment 10 6.86 +914 51 26
The big grain chloride ion that adds as the ingredient of bleach has stoped the accurate mensuration of chlorine dioxide and peroxide level, as specifying expression with n.d..In addition, the result that chlorine dioxide and peroxide are obtained is based on the code test that is used to measure this class kind, but can represent different kinds, can also produce the positive test result.In addition, reported chlorine dioxide, the reaction of ozone and hydrogen peroxide and hypochlorite causes it to consume and other chemical compound (for example HCl and O 2) produce.Confirm that as these embodiment the hypochlorous acid level of ORP aqueous solution of adding and do not add bleach is similar.
Use bacillus subtilis black subspecies (Bacillus subtilis var.niger) spores (available from SPS Medical of Rush, the ATCC#9372 of New York) that the sample of embodiment 4-10 is carried out the test of high spore counting.The spore suspension is concentrated (by evaporating) to 4 * 10 in aseptic cover 6Individual spore/100 microlitres.100 microlitre spore suspension samples are mixed separately with the sample of 900 microlitre embodiment 4-10.Sample is at room temperature hatched 1 to 5 minute time limit described in table 3.Shown in time point, the sample that 100 microlitres are hatched is at bed board on each TSA flat board and hatched 24 hours under 35 ℃ ± 2 ℃, after this measures the quantity that produces bacterium colony on each bed board.The contrast bed board shows initial spore suspension＞1 * 10 6Individual spore/100 microlitres.To when different incubation time, be listed in the table 3 by bacillus (Bacillus) spore concentration (as the meansigma methods of twice mensuration) of different samples.
Table 3. bacillus spore concentration
1 minute 2 minutes 3 minutes 4 minutes 5 minutes
Embodiment 4 ＞＞1000 411 1 0 2
Embodiment 5 ＞＞1000 1000 1 0 0
Embodiment 6 ＞＞1000 ＞＞1000 ＞1000 22 0
Embodiment 7 ＞＞1000 ＞＞1000 ＞1000 15 0
Embodiment 8 ＞＞1000 ＞＞1000 ＞1000 3 1
Embodiment 9 ＞＞1000 74 0 0 0
Embodiment 10 ＞＞1000 239 3 0 0
Confirm that as these results when bleach concentration (as 10% bleach aqueous solution) increased, the amount of the bacillus spore of being killed was reduced the sample of hatching 2-3 minute.Yet with regard to hatching 5 minutes sample, bleach concentration can not influence killing of bacillus spore.In addition, the result confirms that interpolation 0.01% detergent can not reduce killing of spore in the ORP aqueous solution.
Sample to embodiment 4-10 carries out the fabric bleaching test.The fabric that specimen is used is 100% the artificial silk child short-sleeved sweater with navy blue dyestuff paster.2 square inches dyed fabric sheet is put into the 50mL plastic tube.Cover every fabric with the solution example among the embodiment 4-10.To be listed in the table 4 up to the elapsed time of full bleaching as the acquisition of measuring that bleaches by fabric.
Table 4. is up to the time of fabric sample full bleaching
Embodiment Time
Embodiment 4 39 minutes
Embodiment
5 23 minutes
Embodiment
6 18 minutes
Embodiment 7 19 minutes
Embodiment 8 10 minutes
Embodiment 9 ＞6 hours
Embodiment
10 ＞6 hours
As what these embodiment confirmed, when the ORP concentration of aqueous solution increases in compositions, increase up to the time of realizing full bleaching.
Embodiment 11
The purpose of this research is to estimate the safety of typical ORP aqueous solution Microcyn when the rabbit nasal cavity is gone in administration as drop.33 rabbit random division are become 2 groups, I and II group.I group (18 animals) gives test article as matched group and to II group (15 animals).At-1 day or the 0th day, record body weight and blood sample collection were used to select the analysis of parameter.In the time of the 0th day, give I treated animal with 500 μ L Sterile Salines, and give 500 μ L test article (under 50% concentration) n treated animal (annuals).Twice of every day gone into right nostril as drop with reference substance and test article administration.1-6 days according to same way as to animals administer.Every day is by special pharmacology and/or the toxicology effect of noting nose observation animal.When stopping, research writing down body weight weekly.In the time of the 7th day, select 1/3rd animals in every group to be used for blood sampling, put to death and postmortem.Remaining animal was continued medication to the 14th day, select this moment half animal to be used for blood collection, put to death and postmortem from every group.In the time of the 21st day, after 7-days convalescent periods), collection remains the blood of animal and puts to death them and do postmortem.The nasal mucosa sample of gathering from two nostrils from every animal is used for histopathological analysis.
Postmortem is made up of the gross examination of skeletal muscle to respiratory tract.Get complete nasal meatus with the bone that is connected and be fixed in the buffered formalin.Gather also that any visible abnormal sample is used for histopathological examination in the respiratory tract.Three biopsy samples of each nostril (right side of processing and untreated left side) check (preceding, in and posterula).The microscope histopathological examination of nasal mucosa comprises: the integrity of epithelium, the existence of epithelium cilium or disappearance, the existence of inflammatory cell infiltration, edema goblet cell, gland hypertrophy, the change of blood vessel quantity or feature and any other change or observed result.
Will be relatively from the result of test group (observed result in life, comprise nostril examine the result, body weight, hemanalysis, postmortem situation and histopathology result substantially) and matched group.Test group and with between the animal of saline treatment at there was no significant difference aspect the slight stimulation.
Embodiment 12
The present embodiment illustration can be used to measure the clinical research of typical ORP aqueous solution treatment pharyngitis effectiveness.
A kind of this class ORP aqueous solution that is used for this research is called " Microcyn 60 ", in the recent period it is introduced Mexico market as antibacterial.According to the standard available from Secretariat of Health ofMexico, Microcyn 60 is for having sterilization, sterilization and the active neutral pH peroxide solution of Wound antibiotic.Microcyn 60 is by the preparation of pure water and salt (NaCl), have low concentration sodium (＜55ppm) and chlorine (＜80ppm), the pH of 7.2 to 7.8 scopes and the Eo+ of 840mV to 960mV.Only produce a kind of Microcyn 60 of concentration and need not activation or dilution.
By by inverse osmosis, make it carry out this solution of aquatic product that obtains by the electrochemical gradient that high voltage and sodium chloride generate then.In this manner, be chosen in the reactive specy that forms in the multicell that generates electrochemical gradient in a controlled manner so that generate Microcyn 60.Product is the solution with controlled free-radical content, and described free radical provides high oxidation-reduction potential, and (+840mV is to+960mV) and thus high antimicrobial acivity.
Think that hypochlorous acid and sodium hypochlorite are the abundantest composition that is rich among the Microcyn 60, other composition is lower such as the concentration of chlorion etc.Although the applicant does not wish to be subjected to the constraint of particular theory, think that disinfective action not necessarily needs only to depend on the amount of chlorine, and may depend on kind and/or oxygen or its one or more its precursors of active oxygen.In addition, and opposite with the peroxide solution reported in other document, and Microcyn 60 has neutral pH (6.4-7.8), does not have corrosion and storage-stable and reaches 2 years.All these features all make it can produce peroxide solution, and agent is effective and compatible with the application on no life and biological surface (for example tissue) as high level disinfection for it.
Accelerated stability test is verified can be stored in Microcyn 60 under the various condition of different temperatures, and 4 to 65 ℃, and in 2 year time limit, can not lose its antimicrobial activity.Even can under disadvantageous relatively condition, store and allocate Microcyn 60, and can not lose its antibacterial activity.On the contrary because deficient in stability, so must conventional solution use special-purpose and expensive device or near the place to use, for example hospital's production is so that be used to find purpose with this solution.
Because only produce a kind of Microcyn 60 of concentration, so the dosage of Microcyn 60 can only change on applied volume/unit are skin.In toxicologic study, Microcyn 60 dosage that generally are applied to intact skin about 0.05 to about 0.07mL/cm 2Between change; In acute dermal toxicity research and skin irritation research, can be to reach 8.0mL/cm 2 Dosage use Microcyn 60, and those are about 0.09mL/cm what be applied to deep wound research 2The Microcyn 60 of dosage.
Carry out toxicologic study, wherein used single administration Microcyn 60 local contact intact skins 4 to 24 hours.The evaluation of rat deep wound was repeatedly used Microcyn 60 at 7 day in the time limit process, every day 1 or 2 times.
The rabbit intact skin is carried out two kinds of researchs, so that estimate the effect of Microcyn 60 aspect acute irritation and dermal toxicity.When the necropsy of any rabbit that contacts Microcyn 60, all do not find clinical symptom, skin irritation or skin abnormality.
In rat, estimate from the part and the systemic-toxic sign of local application Microcyn 60 to deep wound.Do not observing unusual, significant difference aspect hematochemistry parameter or the blood cell mathematic(al) parameter, when postmortem, do not observing unusual yet.The skin irritation classification around the place of application and the histopathology of wound and tissue all show between the wound handled with Microcyn 60 and those wounds with the matched group of saline solution processing and have any difference.
Also by injection in the mouse peritoneum being estimated the general toxicity of Microcyn 60.For this reason, by intraperitoneal by way of the Microcyn 60 that gives 5 injected in mice single doses (50mL/kg).According to same way as, give the saline solution (0.9% sodium chloride) of 5 control group mice injection single doses (50mL/kg).In this research, in any animal of the Microcyn 60 that accepts the intraperitoneal single dose, both do not observed mortality rate, do not observe any general toxicity evidence yet, this shows LD 50Be higher than 50mL/kg.
Give Microcyn 60 by oral administration to rat, so that any intrinsic toxicity effect of its absorption and sign product.In this research, give single dose (4.98mL/kg) to 3 rat of Sprague-Dawley strain by esophagus.In the postmortem of any animal of the Microcyn 60 of contact single port clothes dosage, both do not observe mortality rate, do not had clinical symptom or unusual yet.
Also in rabbit, estimated the probability of the eye stimulation of local application Microcyn 60.In any animal of topical contact Microcyn 60, both not observed the eye stimulation, do not observe any other clinical symptom by eye yet.
By sucking by way of rat is used Microcyn 60 so that measure by sucking potential acute toxicity.All animals all show very slight or slight activity minimizing and perpendicular hair after contact, but they are all asymptomatic in the time of second day.When contacting the animal postmortem of Microcyn 60 by suction, do not observe mortality rate or unusual.
In Cavia porcellus, use improved closed diaphragm method (Buehler) probability of sensitization of skin to be estimated to Microcyn 60.Control animals after single processing is attacked and all do not observe stimulation using the present invention to handle in the animal (by inducing processing) of attacking post-evaluation.These studies confirm that Microcyn 60 can not cause sensitivity response.
Therefore, when by oral and suck by way of or when being applied in intact skin, the open skin wound in deep, the conjunctival sac by peritoneal injection Microcyn 60, do not show the untoward reaction relevant with product.Handle skin and mucosa in thousands of patients with the very different wound of character after, its sterilization and cosmetic result are also splendid.Therefore, the Microcyn60 of local application should be effectively in this clinical trial and can fully tolerate.
Microcyn 60 is packaged in the transparent 240mL PET air-tight bottle.This product stock is kept stable at ambient temperature and in this class bottle reach 2 years.From the characteristic of its high biology safety, Microcyn 60 can be discarded safely, and for example emptying is gone into sump and do not had pollution or corrosive harm.
Use Microcyn 60 to carry out repeatedly microbiological test in the U.S. and Mexico.Antibacterial above 90% just is uprooted in former seconds of contact.Antibiotic and the antifungal activity that Microcyn 60 is shown in this standard is summarised in the table 5.
Table 5. is killed the time
Antibacterial Catalog number (Cat.No.) Onset time (minimizing is lower than 99.999%)
Pseudomonas aeruginosa ATCC 25619 1 minute
Staphylococcus aureus ATCC 6538 1 minute
Escherichia coli (E.coli) ATCC 11229 1 minute
S.typhi CDC 99 1 minute
The white candida mycoderma ATCC 1 minute
Bacillus subtilis 9372
Low spore (10 4) 10 minutes
High spore (10 6) 15 minutes
According to PAHO[Pan-American Health Organization]/the WHO scheme kills the spore ability test.
The viricidal activity of verified Microcyn 60 and confirmed it to monocyte hyperplasia Li Site bacterium (Listeriamonocytogenes), the activity of methicillin resistance staphylococcus aureus (MRSA) and Mycobacterium bovis in the research that the U.S. carries out to HIV.Therefore, confirmed that Microcyn 60 can eradicate antibacterial, fungus, virus and spore when the administration that conduct is recommended when contacting in 1 to 15 minute.
In this research, recruitment has the acute pharyngitis/tonsillitis that is caused by A family beta hemolytic streptococcus genus and 40 patients that do not receive treatment as yet.Choice criteria is as follows: the age is 12 to 40 years old and has in the following symptom two or more: the oropharynx burn feeling; Odynophagia; Pharyngeal erythema or tonsil rubescent (be with or without and ooze out); The cervical lymph node disease; With belong to antigen immune by A family beta hemolytic streptococcus and measure positive (StrepA Test-Abbott Labs).Culling level is as follows: generate heat＞38 ℃; Bronchospasm (clinical eliminating); Serious cough; Sinusitis-rhinitis (clinical eliminating); Esophageal reflux (clinical eliminating); 2 weeks were used antibiotic before research; Participate in 8 weeks in the end in addition-patient of kind of clinical research; Rheumatic fever; Post-streptococcal glomerulonephritis; Severe chronic heart disease; Serious kidney, liver or pulmonary insufficiency; With gestation or lactogenic.
When this research began, the patient can use the medicine of following such as antipyretic and this class of analgesic, and comprise acetaminophen and aspirin, but do not comprise anti-inflammatory agent, such as ibuprofen, Mesulid, cox 2 inhibitor or steroid.Before entering any specific procedure of this research, the patient must obtain written informed consent.
Evaluate patient in three times are gone to a doctor.In going to a doctor for the first time, the patient shows acute pharyngitis/tonsillitis clinically and gets case history and carry out medical inspection, and pharyngeal exudate is measured and got in the tachysynthesis of Streptococcus.Announcing suitable and after the informed consent signature, opening according to 30 seconds oropharynx cleanings and 5mL Microcyn 60 prescription separately to the patient.These flushings were carried out once every 3 hours, amounted to every day 4 times, continue 3 days.
Carrying out the second time in back 72 hours in use Microcyn 60 processing goes to a doctor.In going to a doctor for the second time, estimate clinical progress and the side effect of Microcyn 60.Get new pharyngeal exudate and determine whether to use antibiotic or alleviating medicine to continue treatment according to clinical development.After 10 days, go to a doctor for the third time so that get rid of the patient.
For qualified and carry out clinical evaluation in this research, the A family beta hemolytic streptococcus that every patient must exist culture to confirm belongs to pharyngitis/tonsillitis.All patients must all patients must will carry out separately 18 times 30 seconds and the flushing of 5mL Microcyn 60 or carried out maximum 24 flushings at 72 hours at interval.
The major parameter of effect is than 3 orders of magnitude of culture decline that giving to get behind the Microcyn 60 in the starting culture bacterial loads.Carried out this bacteriology's assessment in back 72 hours in use Microcyn 60 processing.The minor parameter of effect is the improvement of clinical report, and lay special stress on pharyngalgia and dysphagia alleviate.In prescription on individual diagnosis 1,2 and 3, report clinical symptoms.
Estimate toleration according to the untoward reaction report.Untoward reaction is defined as any symptom statement of the patient who accepts the Microcyn60 processing, in processing procedure, relates to or do not relate to antibacterial.
By bacteriologist bacteriology's efficacy outcomes (main effect standard) is proposed, irrelevant with clinical symptoms.In going to a doctor for the first time, carry out beta hemolytic streptococcus according to Schedule of Evaluations and before giving Microcyn 60 and belong to antigen and initial pharyngeal exudate culture test (going to a doctor 1).Draw materials for the 60 back second time of carrying out pharyngeal exudate in 72 hours and cultivate (going to a doctor 2) giving Microcyn.All cultures are done antimicrobial spectrum so that determine antibacterial to penicillin, erythromycin, the toleration of clarithromycin and lincomycin by the test of standard diffusion disc.Bacteriology's effect is defined as starting culture and gives the count of bacteria decline between the Microcyn 60 back cultures of getting in 72 hours 3 orders of magnitude.
Bacteriology's depletion is expressed as the processing count of bacteria in culture in back 72 hours and descends 3 below the order of magnitude.Write down uncertain reaction in those cases, wherein the sample transhipment was postponed more than 48 hours, in those cases, swab is not immersed the transhipment culture medium, or in those cases, sample is lost.These cases are got rid of outside this research and with new case replacement, finish up to the patient of 40 selections.
When the patient finishes Microcyn 60 dispensers and after going to a doctor for the second time, begin to follow up a case by regular visits to or the report period.In this evaluation,, the patient is categorized as according to clinical progress and the side effect that may exist:
If initial sign and symptom do not eliminate as yet or sb.'s illness took a turn for the worse at the whole body with General Symptoms, treatment failure so.In these cases, open according to oral antibiotic prescription, such as procaine benzylpenicillin, clarithromycin or azithromycin, its dosage or service time for treatment doctor indication and 1 all inner evaluations they.
If the symptom and the sign that are present in the prescription on individual diagnosis 1 are eliminated, and are clinical cure so.In the case that these acute processes disappear, get rid of the patient and be reported to healing clinically.In any case, all require the patient in 1 week, to check prescription on individual diagnosis for the third time.
Uncertain progress.Any clinically may be because of any good former thereby without the patient's who estimates progress; For example, coinfection, if or estimate carry out evening extremely, promptly more than 72 hours.In these cases, during the patient still can be included in and research and analyse, as long as can write down 72 hours time pharynx exudate and culture result.
The statistical analysis that uses in clinical research has considered that all accept the patient of at least 18 each Microcyn 60 flushings in 30 seconds in 72 hour time limit.This identical standard is considered as comprising any patient of toleration in analyzing.The main standard of efficiency analysis is fallen 3 orders of magnitude of counting decline for the beta hemolytic streptococcus subordinate in the cultivation of carrying out when using Microcyn 60 to handle back 72 hours.Carry out statistical analysis by Wilcoxon pairing sample survey.The statistical analysis of ANOVA check the carrying out clinical variable of usage quantity parameter.Patient's the minimum quantity of estimating is 30 patients.
Untoward reaction takes place for any opposite medical condition in clinical research patient who gives drug products or experimenter, and it is not necessarily relevant with this medicine on reason.Therefore, untoward reaction can be temporary transient and the sign (comprising unusual laboratory discovery) of using relevant any disadvantageous of drug products and not expecting, no matter whether symptom or disease are regarded as relevant with this application.The situation about being pre-existing in that will worsen in research process is reported to untoward reaction.
The temporary transient stopped treatment of random time in 72 hours processes that untoward reaction intensity is moderate in the severe situation.Determine treatment by the treatment doctor subsequently.According to present embodiment, confirm the effectiveness of ORP aqueous solution treatment sinusitis of the present invention thus.
Embodiment 13
Present embodiment confirms the viricidal activity of typical ORP aqueous solution to adenovirus-serotype 5.With regard to present embodiment, use adenovirus (Ad) carrier based on adenovirus hominis 5 types, it is E1a-, part is that E1-b and part lack for E3-.Preparation is contained in the shuttle plasmid (pAd-Track) that pCMV transcribes green fluorescent protein (GFP) reporter gene under the control.In electroreception attitude antibacterial, carry out the homologous recombination of this pShuttle plasmid and AdEasy 1 plasmid.The clone who has insert by restriction endonuclease digestion test.In case confirm, just change super spirial plasmid DNA over to the DH10B cell and increase on a large scale.The recombiant plasmid transfection of in the culture medium that does not contain serum (OptiMEM-GIBCO), cultivating 293 cells (ATCC 1573) and digesting subsequently with Pad..Detect the cytopathic effect of infection cell, gather and with three freezing and thaw cycle cracking.With AdenoPure post (BD Clontech), according to the explanation purification gained virus (AdGFP) of manufacturer.Quantitatively viral by OD 260/280.Ultimate yield is 1.52 * 10 11Pfu/mL.
Use is used the flow cytometry of fluorescent activation and is estimated the effect of ORP aqueous solution in the adenovirus of deactivation encoding green fluorescent protein gene (AdGFP) based on the test of the fluorescent emission detection of the HeLa cell of the AdGFP that detects self-infection contrast AdGFP virus or ORP aqueous solution-processing.Use 7.5 * 10 from start to finish 7Pfu/mL (being 150m.o.i.) infects the HeLa cell.Under used experimental condition, cell shows under light microscopy normally.The background fluorescence of measuring in matched group HeLa cell is 0.06%.After having infected contrast AdGFP, 88.51% HeLa cellular expression GFP.Behind contact ORP aqueous solution, decline is inversely proportional to adenovirus infection and time of contact.Therefore, the virus of ORP aqueous solution- processing 1,5 and 10 minutes only can be respectively at 2.8%, 0.13% and 0.09% HeLa cellular expression GFP.Consider autofluorescence under all test conditions and initial virus load (promptly 7.5 * 10 7Pfu), infectious titer is 6.6 * 10 in control group A dGFP-HeLa 7Pfu.Handling with the ORP aqueous solution in the group of virus, the infectious titer when virus contact ORP aqueous solution 1,5 and 10 minutes is respectively 2.0 * 10 6, 5.2 * 10 4With 2.2 * 10 4Therefore, the log-10 attenuation quotient when virus contact ORP aqueous solution 1,5 and 10 minutes is 1.5,3.1 and 3.5.These results show jointly virus contact ORP aqueous solution realizing aspect the log-10 of the virus load decline in 5 minutes＞3.
Embodiment 14
Present embodiment confirms to be used to sterilize the kill the virus effectiveness of the lip-deep United StatesEnvironmental of abiotic surround Protection Agency scheme typical case ORP aqueous solution to HIV.
The SF33 bacterial strain of HIV-1 is used for this research.Use PHA (3 μ g/mL, Sigma) and the human IL-2 (20U/mL Roche) will activate 3 days from the peripheral blood lymphocytes of healthy donors in the HUT culture medium.Washed cell and use the SF33 strain infection.Collected supernatant at the 4th and 6 day and test p24HIV-1 antigen by ELISA (Beckman Coulter).At room temperature with centrifugal 20 minutes supernatant of 3000RPM so that remove cell and cell debris.Take out supernatant, five equilibrium and virus is stored under-80 ℃ is till using the same day.
Under 37 ℃, refrigerated aliquot was melted 2 minutes, after this use at once.The continuous log10 dilution liquid (1 to-5) of use in the HUT culture medium.By 0.2ml virus inoculation thing evenly is coated with exhibition at 55cm 2The preparation viromembrane is gone up in aseptic polystyrene culture dish bottom.At room temperature make viromembrane air-dry in (21 ℃) and the biological safety cabinet, show visible drying (20 minutes) up to them.(can duplicate and cause cytopathic effect in order to ensure virus strains (SF33), use to remain in the HUT culture medium, but moist viral suspension repeat this operation).
Make matched group film contact 2ml HUT culture medium 5 minutes.Scrape then and get and virus dilution.At room temperature make independent exsiccant film contact 2ml ORP aqueous solution 5 minutes separately.After time of contact, scrape make even plate and its inclusions that suspends again.Promptly be engraved in virus dilution in the HUT culture medium-ORP water solution mixture (10: 1).Detect the infectivity of the continuous log diluent of this gained suspension.(in order to control the ORP aqueous solution direct cytotoxic effect possible to the MT-2 cell, the MT-2 cell culture is gone in serial dilution 2ml ORP aqueous solution aliquot (10: 1 to 10: 5) and inoculation in culture medium).
In infectivity is measured, MT-2 cell line is used as indicating clone.This strain shows that cytopathic effect is formed by sincitia and forms when having infected HIV-1.Give 4 micropore inoculation 0.2ml every kind of diluent from the suspension of lytic virus again of test group (dissolving again) and matched group (dissolving again) with control medium with the ORP aqueous solution.Only inoculate test media for the cell matched group that does not infect.At 37 ℃ and 5%CO 2Under hatch culture.
By ELISA every 2 days regularly to culture to having or not existing cytopathic effect and having the scoring of p24-HIV-1 antigen.Use the experimental infection of contrast HIV-1 to show that cytopathic effect and Ag p24 albumen are released in the supernatant that infects the MT-2 culture.On the contrary, realizing log attenuation quotient＞3 aspect the virus load in HIV-15 minute with the processing of ORP aqueous solution, as what when contacting in 5 minutes, in the MT-2 culture, measure by two kinds of algoscopys.These results show that thus efficacy levels requires consistent with EPA to the HIV-1 viricidal activity of inanimate surfaces.
Embodiment 15
Present embodiment confirms the effect to the viability of human diploid fibroblasts (HDFs) of typical ORP aqueous solution and hydrogen peroxide (HP).In order to study this potential toxicity, make HDFs at external contact ORP aqueous solution and hydrogen peroxide (HP).Known HP has toxicity to eukaryotic cell, thereby has increased apoptosis and downright bad and reduced cell viability.In the present embodiment, be determined at cell viability, apoptosis and the necrosis of pure ORP aqueous solution of contact and 5 and 30 minutes HDFs of 880mM HP (concentration that is used for the HP germicidal applications).
The HDF culture is available from three kinds of different foreskins, collects they and common stored refrigerated to be used for this research purpose.Only diploid cell is used for all experiments.When cell cycle analysis, the DNA diploidy is defined as single G0-G1 peak and the corresponding G2/M peak of gathering from least 20,000 sample of total that existence has CV＜/=7%.Fig. 4 A-4C has disclosed the result, wherein describes 5 and 30 minutes time of contact respectively with white and black bar.In the same cell group, undertaken analyzing in these parameters, wherein use: A) 7-aminoactinomycin D (7AAD) by flow cytometry; B) annexin V-FITC; And C) propidium iodide.Fig. 4 A-4C has disclosed the percent value that is expressed as meansigma methods ± SD (n=3).
Cell survival rate behind contact ORP aqueous solution and HP is respectively 75% and 55% (Fig. 4 A).If contact extends to 30 minutes, cell survival rate further drops to 60% and 5% respectively so.Obviously the ORP aqueous solution is by the necrosis induction cell death, because 15% cell has all mixed propidium iodide (Fig. 4 C) twice time in flow cytometry.As if apoptosis is not the mechanism of ORP aqueous solution inducing cell death, because only the cell of 3% ORP aqueous solution-processing has exposed annexin-V (apoptosis labelling) (Fig. 4 B) at cell surface.This percentage ratio in fact with matched group in measure similar.On the contrary, HP after contacting 5 and 30 minutes respectively in the cell that 20% and 75% handles necrosis induced and in 15% and 20% cell cell death inducing.These results show jointly (undiluted) ORP aqueous solution to the toxicity of HDFs far below the HP bacteriocidal concentration.
Embodiment 16
Present embodiment confirm typical ORP aqueous solution with respect to hydrogen peroxide (HP) to oxidisability DNA infringement among the HDFs and dna adduct 8-hydroxyl-2 '-effect of deoxyguanosine (8-OHdG) formation.Being known in and producing the 8-OHdG adduct in the cell is the labelling of oxidative damage on the DNA specificity residue.In addition, the high cellular level and the mutation of this adduct, carcinogenesis is relevant with cell ageing.
Fig. 5 is illustrated in matched group and handles, and the ORP aqueous solution is handled and HP-handles the 8-OHdG adduct level that existed afterwards in 30 minutes in the DNA of HDFs sample.After exposure (T0, white bars) or extract DNA attacking after date 3 hours (T3, black bar) at once.Dna digestion and use the ELISA test kit is measured the 8-OHdG adduct according to the explanation of each manufacturer.With numeric representation (ng/mL) is meansigma methods ± SD (n=3).Contact ORP aqueous solution can not make in 30 minutes hatches after 30 minutes the adduct in the cell of handling and forms and increase than matched group.On the contrary, handle with 500 μ M HP and the quantity of 8-OHdG adduct increased about 25 times than the cell of matched group-processing or ORP aqueous solution-processing in 30 minutes.
The cell of ORP aqueous solution-processing can reduce 8-OHdG adduct level, as long as it kept 3 hours in the DMEM that is replenishing behind the contact ORP aqueous solution.Although allow 3 hour identical convalescent period, the cell that HP-handles still provides than the cell of matched group-processings or the processing of ORP aqueous solution Duos about 5 times adduct.These results confirm that jointly short term contact ORP aqueous solution can not induce significant DNA oxidative damage.These results show that also the ORP aqueous solution can not induce mutation or carcinogenesis in external or body.
Embodiment 17
The typical ORP aqueous solution of the long-term contact of present embodiment confirmation low concentration and HP are to the effect of HDFs.Known eremacausis stress-induced cell is crossed presenility.In order to simulate the oxidative stress of prolongation, make ORP aqueous solution (10%) or the HP (5 μ M) of elementary HDF culture at the medium-term and long-term contact of 20 population doublings processes low concentration.The expression of SA-beta galactosidase and activity formerly with body in relevant with external aging course.In the present embodiment, in the expression that makes HDF contact ORP aqueous solution or HP1 month post analysis SA-beta galactosidase continuously.To the results are depicted among Fig. 6.By in the 20 power microscope visuals field, blue cell being carried out the expression of analysis of accounts SA-beta galactosidase.(with regard to dyeing pattern embodiment) referring to the A group.The B group demonstrates only HP processing and quickens cell ageing, as (n=3) shown according to the cell quantity of overexpression SA-beta galactosidase.HP with low dosage handles the SA-beta galactosidase expression that has increased in 86% cell for a long time, and can not induce this protein overexpression with the processing of ORP aqueous solution.Can from present embodiment, reach a conclusion the inducer that ORP aqueous solution and acellular are old and feeble too early.
Embodiment 18
Present embodiment confirms the effectiveness of typical ORP aqueous solution (Mycrocyn) in suppressing the mastocyte threshing.Mastocyte has been known as the Primary Actor in the I type allergy disease.In spontaneous dermatitis, observed various clinical symptom is confined to differently produced by the mastocyte in the invaded tissue because of the IgE-antigenic stimulus in allergic rhinitis and the atopic asthma.Present acceptable atopic asthma pathogenesis viewpoint be anaphylactogen in so-called reaction in early days by causing that the pulmonary mastocyte (MCs) with I gE discharges amboceptor and starts this process, described amboceptor is such as histamine, leukotrienes, prostaglandins, kininis, platelet activating factor (PAF) etc.These amboceptors are induced bronchoconstriction and are strengthened vascular permeability and the mucus generation thus.According to this model, after the mastocyte activation, those cells are secreted various proinflammatory cytokines late, comprise tumor necrosis factor (TNF-α), IL-4, IL-5 and IL-6, they participate in the local recruitment and the activation of other inflammatory cell, such as the eosinophilic granulocyte, basophilic granulocyte, the T lymphocyte,, platelet and mononuclear phagocyte.These cells of raising facilitate inflammatory reaction to take place thus, can become spontaneous then and the aggravation symptoms of asthma.This late phase response has facilitated in the inducing peripheral tissue the long-term inflammatory reaction that changes (referring to Kumar etc., pp.193-268).
The antigenic stimulus of mastocyte takes place the receptor (Fc ε RI receptor) that IgE has a high-affinity by activation, this receptor in conjunction with the multimerization albumen of IgE and subsequently can the bonded IgE of factor receptor and the interaction of specific antigen assemble.Its structure comprises 4 peptide species, and promptly IgE is in conjunction with the α chain, β chain and two kinds of γ chains that disulfide bond closes of its signal conducting power that is used to increase, and they are for by the main signal transducer based on the activation primitive of the immunity receptor tyrosine (ITAM) of coding.Used the mastocyte (BMMC) of bone marrow derived, the rat leukaemia is RBL 2H3, mice and rat peritoneum mastocyte and other mast cell line, such as MC-9 characterized by to the crosslinked activatory signal conduction of this receptor by way of.In them, exist antigen to cause the mastocyte threshing at all in conjunction with IgE, the calcium mobilization, cytoskeleton is reset and different transcription factor (NFAT, NF κ B, AP-1, PU.1, SP1, Ets etc.) activation, these transcription factor activating cell factor genes are transcribed, and produce thereby stop cytokine.
Load monoclonal anti-dinitrophenol,DNP IgE (300ng/ 1,000,000 cells) in 4 hours processes under 37 ℃ ripe Mus mastocyte BMMC.Remove culture medium and cell is suspended in physiological buffer (in the Tyrode buffer/BSA) again.With the ORP aqueous solution (in its Microcyn embodiment) of variable concentrations cell was handled 15 minutes down at 37 ℃ then.Remove buffer and cell is suspended in fresh Tyrode ' s/BSA again and hatched at 37 ℃ that the antigens (with the link coupled people's albumin of dinitrophenol,DNP) with variable concentrations stimulate in the process in following 30 minutes.By β-hexosaminidase determination of activity in by the supernatant of irritation cell and precipitation, use is determined threshing (having confirmed that β-hexosaminidase is arranged in the identical particle that mastocyte comprises histamine) based on the chrominance response of the ability of the different carbohydrates of this enzyme hydrolysis.Result (Fig. 7) confirms to use the ORP aqueous solution that increases concentration significantly to reduce threshing.
Surprisingly, ORP aqueous solution (Microcyn) to the inhibitory action of mastocyte threshing at least with the antiallergic chemical compound sodium cromoglicate (Intel of clinical effectively " mast cell stabilizers " and establishment TM) observed result is similar.Once more according to by β in the precipitation of irritation cell and the supernatant-hexosaminidase activity, use based on the chrominance response of the ability of the different carbohydrates of this enzyme hydrolysis and determine threshing.Use or do not use sodium cromoglicate (Intel TM) preincubate 15 minutes stimulates the cell that has loaded anti--DNP monoclonal IgE.Cromoglycate is not higher than ORP aqueous solution (comparison diagram 7 and Fig. 8 at the effectiveness aspect the minimizing threshing; Both all make threshing reduce at least about 50%).
Embodiment 19
Present embodiment confirms the activatory inhibitory action of mastocyte that typical ORP aqueous solution causes Calcium ionophore.
Stimulate mastocyte by the inductive calcium current amount of activation Calcium ionophore.Used the mastocyte (BMMC) of bone marrow derived, the rat leukaemia is RBL 2H3, mice and rat peritoneum mastocyte and other mast cell line, such as MC-9 characterized by the activatory signal conduction of Calcium ionophore by way of.In them, the calcium mobilization causes mastocyte threshing (for example histamine release) at all, and cytoskeleton is reset and different transcription factor (NFAT, NF κ B, AP-1, PU.1, SP1, Ets etc.) activation, these transcription factor activating cell factor genes are transcribed, thereby stop cytokine generation and secretion.
Load monoclonal anti-dinitrophenol,DNP IgE (300ng/ 1,000,000 cells) in 4 hours processes under 37 ℃ ripe Os Mus marrow-deutero-mastocyte BMMC.Remove culture medium and cell is suspended in physiological buffer (in the Tyrode buffer/BSA) again.With the ORP aqueous solution (Microcyn) of variable concentrations cell was handled 15 minutes down at 37 ℃ then.Removing buffer and cell being suspended in fresh Tyrode ' s/BSA again and hatching in following 30 minutes in the process at 37 ℃ stimulates with Calcium ionophore (100mM A23187).By by β-hexosaminidase determination of activity in the supernatant of irritation cell and the precipitation, use based on the chrominance response of the ability of the different carbohydrates of this enzyme hydrolysis and determine threshing (having confirmed that β-hexosaminidase is arranged in the identical particle that mastocyte comprises histamine).Result (Fig. 8) confirms to use the ORP aqueous solution that increases concentration significantly to reduce threshing.
These results suggest ORP aqueous solution is the nonspecific inhibitor of histamine release.Therefore, ORP aqueous solution even under variable concentrations-suppress the mastocyte threshing, this has nothing to do with stimulus object (for example antigen or ionophore).Although do not expect to be subjected to any theory constraint, the ORP aqueous solution can change secretion by way of system on plasma membrane and/or cytoskeleton level.Because think that the mechanism of action of ORP aqueous solution is nonspecific, so think that ORP aqueous solution antigen has potential widely clinical practice.
Embodiment 20
Present embodiment confirms the effect that typical ORP aqueous solution is transcribed the cytokine gene of mastocyte.
Figure 10 A and 10B are that the variable concentrations ORP aqueous solution of using by oneself is handled mastocyte 15 minutes and further measured with the RNA enzyme protection of antigenic stimulus as described in example 20 above.After stimulation, (RNAeasy kit Qiagene) extracts mRNA and use standard reagent box condition (Clontech, Becton﹠amp to use affinity chromatographic column; Dickinson) carry out the RNAse protection and measure, produce so that detect the mRNA of the different cytokines after antigen is attacked.These cytokines comprise TNF-α, LIF, IL13, M-CSF, IL6, MIF and L32.
Figure 10 A and 10B represent that ORP aqueous solution (Microcyn) antigen in mastocyte can not change the cytokines mRNA level after attacking, and be irrelevant with ORP aqueous solution that is used to test or antigen concentration.
In this research, after the antigenic stimulus of using variable concentrations, short scorching gene transcription thing level (i.e. the rna content of the mastocyte of Ci Jiing) does not change in the mastocyte of ORP aqueous solution-processing.Therefore, the secretion that the ORP aqueous solution suppresses these cytokines by way of, do not transcribe but do not influence it.
Embodiment 21
Present embodiment confirms that typical ORP aqueous solution is active to the excretory inhibition of the mastocyte of TNF-α.
Handle mastocyte 15 minutes and further use antigenic stimulus as described in example 20 above with variable concentrations ORP aqueous solution.After this, replace tissue culture medium (TCM) and different time during the time limit (2-8 hour) collect the fresh culture sample so that measure the TNF-alpha levels.Freezing sample and further commodity in use ELISA test kit (Biosource) are according to the explanation analysis of manufacturer.
Figure 11 represents after the antigenic stimulus that from ORP aqueous solution-processing cell TNF secretion-α obviously descends than untreated cell to the level of culture medium.
Therefore, the ORP aqueous solution suppresses the TNF-α secretion of the mastocyte of antigenic stimulus.The clinical observation result unanimity of the inflammatory reaction in these results and the different wounds after the application of ORP aqueous solution can alleviate surgical operation.
Embodiment 22
Present embodiment confirms that typical ORP aqueous solution is active to the excretory inhibition of the mastocyte of MIP1-α.
Handle mastocyte 15 minutes and further use antigenic stimulus as described in example 20 above with variable concentrations typical case's ORP aqueous solution (Microcyn).After this, replace tissue culture medium (TCM) and when the different time time limit (2-8 hour), collect the fresh culture sample, so that measure the MIP1-alpha levels.Freezing sample and further commodity in use ELISA test kit (Biosource) are according to the explanation analysis of manufacturer.
Figure 12 represents after the antigenic stimulus that from ORP aqueous solution-processing cell secretion MIP1-α obviously descends than untreated cell to the level of culture medium.
Therefore, the ORP aqueous solution suppresses the MIP1-α secretion of the mastocyte of antigen-stimulation.These results can alleviate behind the surgical operation the observed clinical effectiveness unanimity of inflammatory reaction in the different wounds with using the ORP aqueous solution.
To measure the excretory similar result of study of IL-6 and IL-13 is depicted in Figure 13 and 14.
Embodiment 20-23 and present embodiment confirm that further the ORP aqueous solution can suppress the early stage and late phase allergic responses by the crosslinked startup of IgE receptor.
Embodiment 22
Present embodiment confirms the safety of typical ORP aqueous solution (Microcyn) when spraying into the rabbit nasal cavity.
42 rabbit are divided into 4 groups at random: I, II, III and IV group (table 6).Following processing rabbit: in the time of the 0th day, I group rabbit is given Sterile Saline and gives benzalkonium chloride to II group rabbit.In the time of the 0th day, III and IV are organized the Microcyn that rabbit gives 40ppm and 80ppm respectively in addition.All goods are gone into right naris by the nasal spray administration.In the time of the 7th day, behind the 8th dosage, from every group, get 1/3rd rabbit and put to death and postmortem.To administration every day of remaining animal, put to death during by the 14th day and postmortem from every group half residue animal.In the time of the 21st day, after 7 days, put to death residue rabbit and postmortem in not administration.
Table 6.
Figure A20078000977300631
From every rabbit, gather from the nasal mucosa sample in two nostrils and in formalin and preserve to be used for histopathological analysis.The tissue that finishing formalin is preserved is embedded in the paraffin, cuts into slices and dyes with h and E.Extensive standardized veterinary pathologist has been checked all above-mentioned tissues.Nasal cavity is cut into slices on three levels, be called nasal cavity I, II and III level and an evaluation left side and right side.The I level is top section, has, but is not that whole sections comprise the hair follicle that contains epithelium.Be lined with stratified squamous epithelium in most of this district.The II level be about apart from the nostril backward 1/3 and comprise vomeronasal organ and turbinates major part.The III level be about apart from the nostril backward about 2/3 and generally include the turbinates fraction.Estimate the epithelial integrity of every grade of nasal cavity, epithelium cilium, inflammatory cell, edema, goblet cell, glandular hyperplasia and blood vessel.The following classification of carrying out of will cutting into slices: the change that " minimum " representative is minimum and need careful detecting to identify usually; " appropriateness " is little, but the infringement that is easy to identify; " moderate " is the extensive or big infringement that does not occupy the major part of tissue; " significantly " is big and occupies the seriousness infringement of organizing major part.
The in-house pathological change of nose is generally limited to II and III level and just observed in the time of the 14th day, but except that the 7th day the time rabbit of IV group.In the time of the 14th day, with I or II group rabbit in observed result relatively the time, the minimum focus epithelium necrosis to appropriateness with dosage indifference takes place in some rabbit from III and IV group, hypertrophy and/or epithelium cilium atrophy incidence rate or seriousness increase.What follow the epithelium infringement is focus lymphocyte inflammatory cell infiltration, and its existence continues to the 21st day.In the time of the 21st day, the infringement of the epithelium of necrosis or cilium atrophy is no longer observed in the treatment rabbit.This moment, the focal epithelial hyperplasia of observed minimum level in two sections was regarded as renewal/restorative change, because it is in the treatment phase process of this research.The rabbit of some Microcyn-treatment had goblet cell hypocellularity or goblet cell hypertrophy when 21 day time limit, but these change with in matched group, find those do not have different.The lymphocyte inflammatory infiltration is the main discovery when 21 day experimental period finished.Single matched group rabbit had the focus epithelium necrosis of minimum level in the time of the 21st day, it is considered as accidental discovery.
Do not exist minimum to the incidence rate of appropriateness infringement or the obvious dosage dependent interaction of seriousness.Appropriate lymphocytic infiltration is regarded as normally and the change of the expection relevant with healing/recovery with focal epithelial hyperplasia.Although the right naris of all rabbit is gone in the Microcyn administration, there is not actual variance aspect the infringement pattern/incidence rate between each side.
Present embodiment confirm every day to the rabbit intranasal give 40 or 80ppm Microcyn by the end of treatment in the time of 14 days (but not being 7 days) produced the downright bad infringement of minimum or appropriate focus nasal epithelium, hypertrophy and/or the atrophy of epithelium cilium.
Embodiment 24
Originally studies confirm that typical ORP aqueous solution Dermacyn avirulence.
This research is carried out according to ISO 10993-5:1999 standard causing Cytotoxic probability so that measure typical ORP aqueous solution Dermacyn.The filter disc that will have 0.1mL Dermacyn is placed on the agarose surface, thereby directly is pressed on the monolayer l cell (L-929).At 37 ℃ with 5%CO arranged 2Exist and hatch the cytotoxicity infringement of observing the preparation sample after 24 hours down.Observed result and positive control and negative control sample are compared.The sample that contains Dermacyn does not demonstrate any lysis or Cytotoxic evidence, and positive and carry out of negative control as expecting.
Based on this research, infer that Dermacyn can not produce cytotoxic effect to mouse fibroblast cell.
Embodiment 25
Use 16 rats to carry out this research so that estimate the local tolerance of typical ORP aqueous solution Dermacyn and to the histopathology effect of wound bed in the through thickness skin wound healing model.Tried to form wound on the both sides of rat.In agglutination, in the left side or right side bark fetching skin section (for example being respectively Dermacyn-handles and saline-processing).
Estimate the trichroism dye liquor-painted section and the II collagen type stained at Dermacyn and saline-processing surgical wound position by extensive standardized veterinary pathologist.Estimate breeding as connective tissue of section, fibroblast form and collagen protein form, and have new epidermis on the cross section, 2 collagen type expressions of inflammation and skin ulcer degree.
These discoveries show Dermacyn fully tolerance in rat.In skin biopsy, there be not the histopathology infringement relevant with processing from side wound (being respectively Dermacyn-handles and saline-processing), saline treatment and in wound site that Dermacyn handles, do not have relevant histopathology difference, show that the Dermacyn-processing is fully tolerated.At saline-processing and Dermacyn TMThere was no significant difference between 2 collagen types of the wound location of-processing are expressed shows that Dermacyn has no adverse effects to fibroblast or collagen protein processing in wound healing process.
Embodiment 26
Present embodiment confirms that typical oxidation-reduction potential water Microcyn of the present invention is as the effectively application of antimicrobial solutions.
Use the Microcyn oxidation-reduction potential water to carry out external time-kill evaluation.The attack suspension of 50 kinds of different microbial strains is estimated (ATCC) clinical isolates of bacterial strain and 25 those identical type-as Tentative Final Monograph of Microcyn-25 US mode culture collection center (American Type Culture Collection), Federal Register, on June 17th, 1994, vol.59:116 is described in the pg.31444.Contacting Microcyn 30 (30) seconds, one (1) minute, three (3) minutes, five (5) minutes, seven (7) minutes, nine (9) minutes, ten one (11) minutes, ten three (13) minutes, measure after ten five (15) minutes and 20 (20) minutes from each percentage ratio of attacking in the initial colony of bacterial strain and reduce and Log 10Reduce.Carry out all agar bed boards in duplicate and under 99% (v/v) concentration, estimate Microcyn.All tests are all according to as carrying out among the 21C.F.R.Part58 of Good Laboratory Practices.
The result of evaluation when contact in 30 seconds summarized above-mentioned external time-killed to following table, and all have reduced the above test colony of 5.0Log10 labelling:
Table 7.30-killing in vitro second
Sequence number Microbe species Initial colony (CFU/mL) Contact back colony (CFU/mL) Log 10Reduce Reduce percentage ratio
1 Acinetobacter baumannii (ATCC#19003) 2.340×10 9 ＜1.00×10 3 6.3692 99.9999
2 Acinetobacter baumannii clinical isolates BSLI#061901Ab3 1.8150×10 9 ＜1.00×10 3 6.2589 99.9999
3 Bacteroides fragilis (ATCC#43858) 4.40×10 10 ＜1.00×10 3 7.6435 99.9999
4 Bacteroides fragilis clinical isolates BSLI#061901Bf6 2.70×10 10 ＜1.00×10 3 7.4314 99.9999
5 White candida mycoderma (ATCC#10231) 2.70×10 10 ＜1.00×10 3 6.3345 99.9999
6 White candida mycoderma clinical isolates BSLI#042905Ca 5.650×10 9 ＜1.00×10 3 6.7520 99.9999
7 Clostridium perfringen (ATCC#29007) 1.2250×10 9 ＜1.00×10 3 6.0881 99.9999
8 Clostridium perfringen clinical isolates BSLI#042905Ea 1.0150×10 9 ＜1.00×10 3 6.0065 99.9999
9 Enterococcus faecalis (ATCC#29212) 2.610×10 9 ＜1.00×10 3 6.4166 99.9999
1 0 Enterococcus faecalis clinical isolates BSLI#061901Ef s2 1.2850×10W ＜1.00×10 3 6.1089 99.9999
1 1 Enterococcus faecalis VRE, MDR (ATCC#51559) 3.250×10 9 ＜1.00×10 3 6.5119 99.9999
1 2 Enterococcus faecalis clinical isolates BSLI#061901Efm1 1.130×10 9 ＜1.00×10 3 6.0531 99.9999
1 3 Bacillus coli (ATCC#11229) 5.00×10 8 ＜1.00×10 3 5.6990 99.9998
1 4 Bacillus coli clinical isolates BSLI#042905Ec1 3.950×10 8 ＜1.00×10 3 5.5966 99.9997
1 5 Bacillus coli (ATCC#25922) 6.650×10 8 ＜1.00×10 3 5.8228 99.9998
1 6 Bacillus coli clinical isolates BSLI#042905Ec2 7.40×10 8 ＜1.00×10 3 5.8692 99.9998
1 7 Haemophilus influenzae (ATCC#8149) 1.5050×10 9 ＜1.00×10 4 5.1775 99.9993
1 8 Haemophilus influenzae clinical isolates BSLI#072605Hi 1.90×10 9 ＜1.00×10 4 5.2788 99.9995
1 9 Acid-producing Klebsiella bacterium MDR (ATCC#15764) 1.120×10 9 ＜1.00×10 3 6.0492 99.9999
2 0 Acid-producing Klebsiella bacterium clinical isolates BSLI#061901Ko1 1.810×10 9 ＜1.00×10 3 6.2577 99.9999
2 1 Klebsiella pneumonia ozena subspecies (Klebsiellla pneumoniae subsp.ozaenae) (ATCC#29019) 1.390×10 9 ＜1.00×10 3 6.1430 99.9999
2 2 Klebsiella pneumonia clinical isolates BSLI#061901Kpn2 9.950×10 8 ＜1.00×10 3 5.9978 99.9999
2 3 Micrococcus luteus (ATCC#7468) 6.950×10 8 ＜1.00×10 3 5.8420 99.9999
2 4 Micrococcus luteus clinical isolates BSLI#061901M12 1.5150×10 9 ＜1.00×10 3 6.1804 99.9999
2 5 Proteus mirabilis (ATCC#7002) 1.5950×10 9 ＜1.00×10 3 6.2028 99.9999
2 6 Proteus mirabilis clinical isolates BSLI#061901Pm2 2.0950×10 9 ＜1.00×10 3 6.3212 99.9999
2 7 Pseudomonas aeruginosa (ATCC#15442) 6.450×10 8 ＜1.00×10 3 5.8096 99.9999
2 8 Pseudomonas aeruginosa clinical isolates BSLI#072605Pa 1.3850×10 9 ＜1.00×10 3 6.1414 99.9999
2 9 Pseudomonas aeruginosa (ATCC#27853) 5.550×10 8 ＜1.00×10 3 5.7443 99.9999
3 0 Pseudomonas aeruginosa clinical isolates BSLI#061901Pa2 1.1650×10 9 ＜1.00×10 3 6.0663 99.9999
3 1 Serratia marcescens (ATCC#14756) 9.950×10 8 ＜1.00×10 3 5.9978 99.9999
3 2 Serratia marcescens clinical isolates BSLI#042905Sm 3.6650×10 9 ＜1.00×10 3 6.5641 99.9999
3 3 Staphylococcus aureus (ATCC#6538) 1.5050×10 9 ＜1.00×10 3 6.1775 99.9999
3 4 Staphylococcus aureus clinical isolates BSLI #061901Sa1 1.250×10 9 ＜1.00×10 3 6.0969 99.9999
3 5 Staphylococcus aureus (ATCC#29213) 1.740×10 9 ＜1.00×10 3 6.2405 99.9999
3 6 Staphylococcus aureus clinical isolates BSLI #061901Sa2 1.1050×10 9 ＜1.00×10 3 6.0434 99.9999
3 7 Staphylococcus epidermidis (ATCC#12228) 1.0550×10 9 ＜1.00×10 3 6.0233 99.9999
3 8 Staphylococcus epidermidis clinical isolates BSLI #072605Se 4.350×10 8 ＜1.00×10 3 5.6385 99.9998
3 9 Staphylococcus haemolyticus (ATCC#29970) 8.150×10 8 ＜1.00×10 3 5.9112 99.9999
4 0 Staphylococcus haemolyticus clinical isolates BSLI#042905Sha 8.350×10 8 ＜1.00×10 3 5.9217 99.9999
4 1 Staphylococcus hominis (ATCC#27844) 2.790×10 8 ＜1.00×10 3 5.4456 99.9996
4 2 Staphylococcus hominis clinical isolates BSLI#042905Sho 5.20×10 8 ＜1.00×10 3 5.7160 99.9998
4 3 Staphylococcus saprophyticus (ATCC#35552) 9.10×10 8 ＜1.00×10 3 5.9590 99.9999
4 4 Staphylococcus saprophyticus clinical isolates BSLI#042905Ss 1.4150×10 9 ＜1.00×10 3 6.1508 99.9999
4 5 Streptococcus pneumoniae (ATCC#33400) 2.1450×10 9 ＜1.00×10 4 5.3314 99.9995
4 6 Streptococcus pyogenes (ATCC#19615) 5.20×10 9 ＜1.00×10 3 6.7160 99.9999
4 7 Streptococcus pyogenes clinical isolates BSLI#061901Spy7 2.5920×10 9 ＜1.00×10 3 6.4141 99.9999
Be lower than 5.0Log although measure its microorganism minimizing 10But Microcyn also shows remaining three antimicrobial acivities that are not included in the kind in the table 8.More particularly, 30 seconds contact Microcyn are with streptococcus pneumoniae colony (clinical isolates; BSLI#072605Spn1) reduced 4.5Log 10More than, be detectability at this kind.In addition, when attacking with candida tropicalis (ATCC#750), Microcyn has surpassed 3.0Log in the microorganism minimizing that contact showed after 30 seconds 10In addition, when attacking with candida tropicalis (BSLI#042905Ct), Microcyn has surpassed 3.0Log in the microorganism minimizing that contact showed after 20 minutes 10
The typical consequence of this external time-kill evaluation shows that the Microcyn oxidation-reduction potential water shows quick (promptly being lower than 30 seconds in the most of situation) antimicrobial acivity at the wide spectrum attack micro organisms.The gram positive bacteria of 50 kinds of evaluations has 47 kinds to reduce 5.0Log after 30 seconds contacting described product in the micropopulation of gram negative bacteria and yeast specie 10More than.
Embodiment 27
Present embodiment represented the typical oxidoreduction water of the present invention Microcyn with
Figure A20078000977300691
The antimicrobial acivity of chlorhexidine gluconate solution 4.0% (w/v) and 0.9% sodium choride irrigation (USP) relatively.
Use as described in example 29 above
Figure A20078000977300692
Chlorhexidine gluconate solution 4.0% (w/v) and 0.9% sodium chloride rinse solution (USP) carry out external time-kill evaluation as the reference product.To 10 US mode culture collection centers (American Type Culture Collection) of being described in Tentative Final Monograph especially (ATCC) the bacterial strain suspension estimate every kind of reference product.Microcyn about record among the embodiment 29 reduces the data that the microbial activity analysis is gathered then.
The Microcyn oxidation-reduction potential water will attack 5 kinds of micropopulations in the bacterial strain be reduced to right
Figure A20078000977300693
The observed level of chlorhexidine gluconate solution.Microcyn and
Figure A20078000977300694
All provide after 30 seconds above 5.0Log at the following bacterial strain of contact 10Microorganism reduce: bacillus coli (ATCC#11229 and ATCC#25922), Pseudomonas aeruginosa (ATCC#15442 and ATCC#27853) and serratia marcescens (ATCC#14756).In addition, as shown in table 9, Microcyn is by providing 5.8420Log after contact in 30 seconds 10Reduce the splendid antimicrobial acivity that shows micrococcus luteus (ATCC#7468).Yet, with
Figure A20078000977300695
The direct micrococcus luteus of comparing (ATCC#7468) is active and impossible, because after contact in 30 seconds, Described colony is reduced to the test detectability (in this concrete situation, reach 4.8Log 10More than).Notice that aseptic 0.9% sodium chloride rinse solution has reduced 0.3Log with above-mentioned 6 kinds of bacterial strain micropopulations separately after contact in complete 20 minutes 10Below.
The Microcyn oxidation-reduction potential water provides 4 kinds the antimicrobial acivity that test is attacked in the bacterial strain to surpass
Figure A20078000977300701
Effect with sodium choride irrigation: enterococcus faecalis (ATCC#29212), staphylococcus aureus (ATCC#6538 and ATCC#29213) and staphylococcus epidermidis (ATCC#12228).Evaluation result has been summarized external time to these 4 kinds-killed to following table:
Table 8. comparing result
Figure A20078000977300702
Figure A20078000977300711
This external time very nearly the same-kill evaluation result confirm the Microcyn oxidation-reduction potential water not only show with
Figure A20078000977300712
Very nearly the same at bacillus coli (ATCC#11229 and ATCC#25922), Pseudomonas aeruginosa (ATCC#15442 and ATCC#27853), the antimicrobial acivity of serratia marcescens (ATCC#14756) and micrococcus luteus (ATCC#7468), and provide to enterococcus faecalis (ATCC#29212) more effective processing of staphylococcus aureus (ATCC#6538 and ATCC#29213) and staphylococcus epidermidis (ATCC#12228).Just as shown in table 9, the Microcyn illustration plant apoplexy due to endogenous wind antimicrobial reaction (promptly being lower than 30 seconds) faster at some.In addition, contact Microcyn causes that the microorganism of listed all kinds totally reduces in the table 8.
Embodiment 28
Present embodiment confirms the effectiveness of ORP aqueous solution to penicillin resistance streptococcus pneumoniae (ATCC 51915).
It is dull and stereotyped and at 35-37 ℃ and CO to inoculate a plurality of BAP by the test frozen cultures 2Under hatch and prepared the culture of streptococcus pneumonia thing in 2-3 days.After hatching, change 3-7mL sterile diluent/culture medium over to each agar bed board and scrape and get so that suspend this organism.Collect from all dull and stereotyped suspensions and change sterile tube over to and with 4.0McFarland Standard relatively.Filter this suspension and vortex mixed before being used for test operation by sterile gauze.
0.1ml organism suspension inoculum is joined in 49.9ml Microcyn or the contrast material.When each contacts the phase, by vortex mixed test mixing thing.Make the test mixing thing expose 15 seconds down at 25.0 ℃, 30 seconds, 60 seconds, 120 seconds, 5 minutes and 15 minutes.
From the test mixing thing, take out the 1.0ml sample and join 9.0ml and represent to neutralize in the nertralizer of 100 times of diluents of inoculation test mixing thing.The aliquot of 100 times of neutralization inoculations of 5ml test mixing thing is gone on the 0.45 microlitre filter of using 10ml Butterfield buffer pre-wetted.With about 50mL Butterfield buffer flushing filter, take out and change over to the BAP bed board from instrument with sterile manner.1: 10 serial dilution of refabrication and in duplicate with among 1 (1.0) ml and aliquot bed board on BAP of the 10-3-10-4 diluent of inoculation test mixing thing.
Hatched 48 ± 4 hours at the 35-37 ℃ of cultivation bed board that antibacterial gone down to posterity down and among the C02.To go down to posterity and cultivate bed board, check after this 2-8 ℃ of following cold preservation 2 days.After hatching and storing, the growth that exists on the visualization agar bed board.Counting colony-forming units and survivor's quantity when being determined at each open-assembly time.Suitably check shows that the representational subculture of growth is so that confirm test organism.
Typical case's ORP aqueous solution Microcyn 25.0 ℃ following 15 seconds, 30 seconds, 60 seconds, 120 seconds, show after 5 minutes and 15 minute contact time＞99.93197279% penicillin resistance streptococcus pneumoniae (ATCC 51915) minimizing.
Embodiment 29
The purpose of present embodiment is to use the bacterial suspension algoscopy to measure the microbial activity of typical ORP aqueous solution (Dermacyn) and bacitracin.
Dermacyn is an alternate products, need not thus to dilute in test process.Bacitracin is for being diluted to the rehydration concentrated solution of 33 unit/ml.
2.5 * 10 7The spore suspension that is purchased of the atrophy bacillus cereus (B.atropheus) of/ml is used for test.In addition, fresh suspension of preparation Pseudomonas aeruginosa and staphylococcus aureus and use spectrophotometric determination can be accepted to guarantee titre.
9 microlitre test substances are joined in the 100ul microorganism suspension.The test mixing thing is remained on the time of contact that is used for 20 seconds, 5 minutes and 20 minutes under 20 ℃.1.0ml test mixing thing (complete mixture) is joined in the 9.0ml nertralizer 20 minutes (Here it is primary neutralization pipe or ONT).The neutral test mixing thing of 1.0ml bed board on Tryptic Soy Agar with duplicate 5 minutes and 20 minute contact time.Extra diluent and coating bed board are used for 20 seconds time point, so that obtain isarithmic flat board.
All bed boards are hatched under 30 ℃-35 ℃ amount to 3 days and hatch post-evaluation in every day.In order to measure the micro organism quantity of contact Dermacyn and bacitracin in the test suspension process, if carry out that 4 10-doubly dilute and suitable, according in duplicate with 2 kinds of final diluent bed boards of 1.0ml.
When Derma cyn shows at all time points when the use test organism is attacked during to nourishing type bacterium with at 5 and 20 minutes time points to the elimination fully (＞4log minimizing) of spore.Bacitracin only produces the minimizing of about 1log.Microcyn shows the to a certain degree minimizing to spore when 20 seconds time points.Bacitracin does not demonstrate the evidence that reduces antibacterial or spore colony with time limit testing time.
Embodiment 30
Present embodiment confirms the effectiveness of two kinds of typical ORP aqueous solutions (M1 and M2) to the antibacterial in the biomembrane.
The parental strain that is used for all researchs is Pseudomonas aeruginosa PA01.Make all plankton bacterial strains be grown in the minimal medium (2.56gNa2HPO4 that shakes bottle of the 220rpm under 22 ℃ in aerobic mode, 2.08g KH2PO4,1.0g NH4Cl, 0.04g CaCl2 2 H2O, 0.5g MgSO4 7H2O, 0.1mg CuSO4 5H2O, 0.1mg ZnSO4 H2O, 0.1mgFeSO4 7H2O and 0.004mg MnCl2 4H2/ liter, pH 7.2) in.As described below making in the minimal medium of biofilm development under 22 ℃.Glutamic acid (130mg/ liter) is used as sole carbon source.
Make biofilm development (Sauer etc., J.Bacteriol.184:11401154 (2002) is incorporated herein by reference) as mentioned above.In brief, 22 ℃ down will be once siloxanes pipe internal surface by the constant current tube reactor assembly be used to cultivate biomembrane.3 days (ripe-1 stage) of growth under flox condition, 6 days (ripe-2 stages) and 9 days (scatter stage) back collection of biological film.By along whole length extruded tube from inner surface collection of biological theca cell, cause from the chamber, extruding cell material.Gained cell paste is collected on ice.Before sampling, from pipe, purify bulk liquid to prevent the phytoplankton cells of interference separation.
By using serial dilution bed board counting the quantitative measurement plankton of CFU and the group size of biomembrane cell.In order to carry out this, the different time of contact SOSs after the time limit from the inner surface the collection of biological film.By use Olympus BX60 microscope (Olympus, Melville, NY) and-100 amplification A100PL object lens by viewed in transmitted light biomembrane image once by growing in the flow cell.(CA) image is caught in exposure with 30-ms for Optronics Inc., Galena to use Magnafire cooling three-chip belt charge-coupled device camera.In addition, (Zeiss, Heidelberg Germany) carry out the CONFOCAL SCANNING LASER MICROSCOPE inspection to use LSM 510Meta inverted microscope.Use LD-Apochrome 40-/0.6 lens and LSM 510Meta software (Zeiss) to obtain image.
The biomembrane of in 60 minutes handle M1-being handled is observed 2-log and is reduced.This discovery shows that using M1 to handle every 10.8 minutes (+/-2.8 minutes) just makes the biomembrane survival rate reduce by 50%.
Table 9.M1 kills
Figure A20078000977300741
Yet total M2 surpasses M1 to a certain extent at the effectiveness of killing aspect the biomembrane, because the result shows every 4.0 minutes (+/-1.2 minutes), uses M2 to handle and just causes the biomembrane survival rate to descend 50%.
Table 10.M2 kills
Figure A20078000977300751
Therefore, ORP water is effective to the antibacterial in the biomembrane.
All lists of references with this paper citation comprise open source literature, and patent application and patent are incorporated herein by reference, and its citation degree is with identical with the degree that especially every piece of document intactly is incorporated herein by reference respectively.
Unless this paper has in addition in indication or the context opposite statement is arranged, otherwise the term " a kind of (a) " that (especially in the context in following claim) uses in describing context of the present invention and " a kind of (an) " and " described (the) " and similar indicant are regarded as covering odd number and plural number.Unless otherwise stated, otherwise term " comprises ", and " having ", " comprising " and " containing " is regarded as open-ended term (promptly meaning " including, but are not limited to ").Unless otherwise stated, otherwise numerical range described herein only specifies as relating separately to the stenography of each the single value that belongs to this scope, and each single value is introduced this description, just as being incorporated herein them identical respectively.Unless otherwise stated or opposite indication arranged in the context, otherwise implement all methods as herein described with any suitable order.Unless request is arranged in addition, otherwise the application of any and all embodiment provided herein or exemplary language (for example " such as ") only specifies and illustrates the present invention better, but do not hint scope of the present invention is limited.Language in this description should be considered as showing that any not key element of request is that enforcement is essential to the invention.
This paper has described the preferred embodiments of the invention, comprises the present inventor is become known for implementing preferred forms of the present invention.The version of those preferred embodiments it will be apparent to those skilled in the art when reading foregoing description.If present inventor's expection is suitable, those skilled in the art use this class version, and the present inventor specifies and can implement the present invention in the special mode of describing among the non-embodiment.Therefore, the present invention includes the modification that applicable law allowed and the equivalents of all its themes described in the claim that await the reply.In addition, unless otherwise stated or opposite indication is arranged in the context, otherwise the present invention includes its combination in any of the above-mentioned key element in might version.

Claims (48)

1. the method for prevention or treatment patient sinusitis, this method comprises the oxidative reductive potential water solution of described patient being treated effective dose, wherein this solution-stabilizedly had a pH of about 6.4 to about 7.8 at least about 24 hours and this solution.
2. the described method of claim 1 comprises giving oxidative reductive potential water solution to last respiratory airway.
3. the described method of claim 1 comprises making in the respiratory airway one or more organize catalytic oxidation reduction potential aqueous solution.
4. the described method of claim 1 comprises making and organizes catalytic oxidation reduction potential aqueous solution in one or more cranium holes.
5. the described method of claim 4, wherein one or more cranium holes are selected from sinus frontalis, maxillary sinus, sieve hole and sphenoid sinus and combination thereof.
6. the described method of claim 1 comprises giving oxidative reductive potential water solution to one or more sieve holes.
7. the described method of claim 1 comprises making in the sieve hole one or more organize catalytic oxidation reduction potential aqueous solution.
8. the described method of claim 1 comprises by intranasal giving oxidative reductive potential water solution.
9. the described method of claim 1 comprises that the one or more openings by oral cavity or nose give oxidative reductive potential water solution.
10. the described method of claim 1 comprises with liquid, spray, and mixture, the form of aerosol or steam is sent oxidative reductive potential water solution.
11. the described method of claim 1, wherein by aerosolization, atomization or atomizing give oxidative reductive potential water solution.
12. the described method of claim 1 wherein gives oxidative reductive potential water solution to have about 0.1 micron drop form to about 100 micron diameters.
13. the described method of claim 1, wherein said sinusitis are acute sinusitis.
14. the described method of claim 1, wherein said sinusitis are chronic sinusitis.
15. the described method of claim 1, wherein said sinusitis causes because of anaphylaxis.
16. the described method of claim 1, wherein said sinusitis causes because of asthma.
17. the described method of claim 1, wherein said sinusitis causes because of infection.
18. the described method of claim 17, wherein said infection is selected from virus because of one or more, and the microorganism of antibacterial and fungus causes.
19. the described method of claim 18, wherein said infection is selected from Coxsackie virus because of one or more, adenovirus, and the virus of rhinovirus and influenza virus causes.
20. the described method of claim 18, wherein said infection is selected from streptococcus pneumoniae (Streptococcus pneumoniae) because of one or more, Haemophilus influenzae (Haemophilusinfluenzae), staphylococcus, non-streptococcus pneumoniae property staphylococcus, the antibacterial of Corynebacterium (corynebacterium) and anaerobe causes.
21. the described method of claim 18, wherein said infection is selected from Zygomycetes (zygomycetes) because of one or more, and the fungus of aspergillus (aspergil1us) and mycocandida (candida) causes.
22. the described method of claim 1 wherein gives oxidative reductive potential water solution with one or more carriers that reach 25% approximately.
23. the described method of claim 1 wherein gives oxidative reductive potential water solution with one or more carriers that reach 50% approximately.
24. the described method of claim 1 wherein gives oxidative reductive potential water solution with one or more carriers that reach 75% approximately.
25. the described method of claim 1 wherein gives oxidative reductive potential water solution with one or more carriers that reach 90% approximately.
26. the described method of claim 1 wherein gives oxidative reductive potential water solution with one or more carriers that reach 95% approximately.
27. the described method of claim 1 wherein gives oxidative reductive potential water solution with one or more carriers that reach 99% approximately.
28. the described method of claim 22, wherein said one or more carriers are selected from sterilized water, saline and combination thereof.
29. the described method of claim 23, wherein said one or more carriers are selected from sterilized water, saline and combination thereof.
30. the described method of claim 24, wherein said one or more carriers are selected from sterilized water, saline and combination thereof.
31. the described method of claim 25, wherein said one or more carriers are selected from sterilized water, saline and combination thereof.
32. the described method of claim 26, wherein said one or more carriers are selected from sterilized water, saline and combination thereof.
33. the described method of claim 27, wherein said one or more carriers are selected from sterilized water, saline and combination thereof.
34. the described method of claim 1, wherein the pH of oxidative reductive potential water solution is about 7.4 to about 7.6.
35. the described method of claim 1, wherein oxidative reductive potential water solution is stable at least about 2 weeks.
36. the described method of claim 1, wherein oxidative reductive potential water solution is stable at least about 2 months.
37. the described method of claim 1, wherein oxidative reductive potential water solution is stable at least about 6 months.
38. the described method of claim 1, wherein oxidative reductive potential water solution is stable at least about 1 year.
39. the described method of claim 1, wherein oxidative reductive potential water solution comprises and accounts for the negative electrode water of this liquor capacity about 10% to about 50% consumption.
40. the described method of claim 1, wherein oxidative reductive potential water solution comprises and accounts for the negative electrode water of this liquor capacity about 20% to about 40% consumption.
41. the described method of claim 1 wherein comprises and accounts for this liquor capacity about 50% anode water to about 90% consumption.
42. the described method of claim 1, wherein oxidative reductive potential water solution comprises and accounts for this liquor capacity about 10% to the negative electrode water of about 50% consumption with account for this liquor capacity about 50% anode water to about 90% consumption.
43. the described method of claim 1, wherein oxidative reductive potential water solution comprises at least a free chlorine species, and it is selected from hypochlorous acid, hypochlorite ion, sodium hypochlorite, chlorite ion and combination thereof.
44. the described method of claim 1, wherein oxidative reductive potential water solution comprises about 15ppm to about 35ppm hypochlorous acid.
45. the described method of claim 1, wherein oxidative reductive potential water solution comprises 25ppm to about 50ppm sodium hypochlorite.
46. the described method of claim 1, wherein oxidative reductive potential water solution comprises about 15ppm to about 35ppm hypochlorous acid, and about 25ppm is about 50ppm sodium hypochlorite extremely, about 6.2 to about 7.8 pH, and this is solution-stabilized at least about 1 week.
47. the described method of claim 1, wherein oxidative reductive potential water solution has the current potential of pact-400mV to pact+1300mV.
48. the described method of claim 1 further comprises giving at least a antihistaminic that is selected from, Decongestant, the additional therapeutic agent of anti-infective and anti-inflammatory agent and combination thereof.
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