CN101242793A

CN101242793A - Antiviral heat treatment

Info

Publication number: CN101242793A
Application number: CNA2005800210028A
Authority: CN
Inventors: 格里特·岩·范霍斯特; 彼特拉斯·蒂奥多拉斯·德哈恩
Original assignee: PRODUVATION BV
Current assignee: PRODUVATION BV
Priority date: 2004-06-25
Filing date: 2005-06-24
Publication date: 2008-08-13
Also published as: BRPI0512513A; WO2006002949A2; EP1778140A2; CA2572248A1; MXPA06015149A; JP2008503291A; WO2006002949A3; AU2005259451A1; ZA200700190B

Abstract

A method for treating viral infections in vivo in subjects in need of such treatment by applying heat to affected body tissue, use of an apparatus to provide heated moist gas or heated liquids to affected body tissue that is infected with a virus and apparatuses capable of providing heat to a body part that is infected with a virus.

Description

Antiviral heat treatment

The present invention relates to field of medicaments.More particularly, the present invention relates to heat to treat the method for viral infection to the organ that contains viral load or body part, can be to the device of described organ or body part heating, and their purposes.Particularly, the present invention is applicable to the opposing and the treatment of viral infection, organ as skin and so on, internal organs and body part such as respiratory system (lung), female genital tract (as cervix uteri), health is acral as hands, foot, and masculinity and femininity sexual organ such as penis, scrotum, external genital and public area.

Virus is to be present in intracellular parasite specially, need be wrapped in usually in the protein coat by the biochemical mechanism ability reproducible of host cell and the hereditary material of transmitted virus, and the outside also has one deck lipid envelope sometimes.

From the angle of structure and hereditary complexity, viral difference is very big, and some viruses contain the rna gene group of the minority gene of only encoding, and other viruses then contain the nearly DNA genome of 200 genes of coding.Virus combines with host cell by special receptor.After entering host cell, virus is removed decapsidate, and nucleic acid is released and expresses, and produces virus protein.Viral genome is duplicated, and is assembled into new progeny virion (virion) and discharges the cell that then infects the next door.Virus enters cell in mucosal sites usually.Duplicate usually and carry out in epithelial surface, some viral infection also can be duplicated by viremia, and promptly virion enters systemic circulation and infects its hetero-organization through circulating propagation.

Based on the total standpatter's pattern recognition of a large amount of Institute of Micro-biology that comprise virus, eukaryote has formed a large amount of antimicrobial defense mechanisms.Double-stranded RNA (dsRNA) is one of this type of molecular pattern.In the mammalian cell, the inductive defense reaction of dsRNA can produce by inducing interferon, and interferon is that a class can be by suppressing viral gene expression and promoting the infected cell apoptosis to weaken the protein of virus disseminating.Inductive another antiviral response of dsRNA is called RNA in regnum animale and disturbs (RNA interference, RNAi), then be called PTGS (post-transcriptional gene silencing in plant kingdom, PTGS) or RNA silence (Fire et al.Nature1998,391,806-81 1; Ding, Curr.Opin.Biotechnology 2000,11,152-156; Hutvhger and Zamore Curr.Opin.Gen.Dev 2002,12,225-232).The key characteristic of RNAi is its significant sequence-specific: the infected biology that dyes produces dsRNA and replys, and optionally degrades on sequence and the homologous mRNA of dsRNA elicitor.Therefore, RNAi not only can be used for blocking virus expression specifically, also can block host gene specifically and express after introducing homology dsRNA.The center initiation factors molecule of RNA silence is (long-chain) dsRNA molecule, and these molecules are fragment that DICER be degraded to 21～23nt by the nuclease that is target spot with dsRNa.These short interfering rnas s (siRNAs) is a target spot with cognate rna s subsequently, and generation RNA induces reticent complex, and (RNA-initiated silencing complex, RISC) Jie Dao degraded produce a small amount of endochylema target RNA.If target RNA is viral genome, anti-genome or mRNA, the inductive RNA of RNAi degraded can specific inhibition in addition fully blocking virus duplicate.Conversely, if target RNA derives from cell, then RNAi can (post-translationally) block homogenic expression after translation.

In order to overcome the host RNA silence, it has been found that the reticent inhibitive factor of a large amount of plant virus coding RNAs (RNA silencing suppressors, RSS).International publication number is reticent inhibitive factor of RNA and the application in plant thereof that a kind of plant virus source has been described in the application of publication of WO 98/44097, WO 01/38512 and WO 02/057467.WO 02/057301 has described the RSS in a kind of plant virus source and the application in zooblast thereof, people's such as while Li article (Li etal., Science 296:1319-1321,2002) a kind of insect viruses source RSS and the activity in plant and insect cell thereof have been described.International publication number WO 04/035796 has described the application of vertebrate viruse and the application in animal thereof.People's such as Li research (Proc.Natl.Acad.Sci.USA2004,101,1350-1355) show that NS1 and E3L albumen that mammal influenza virus and vaccinia virus are encoded respectively can suppress antiviral rna silence in the drosophila cell, this result has supported the effect that RNAi reacts as natural anti-virus forcefully in plant cell and other non-plant eukaryotic cells.

Another kind of host anti-virus defence is heating.It has been generally acknowledged that heating mainly utilize many biological invasions than the narrower temperature range of bodily tissue tolerance thereby to temperature raise more sensitivity promptly because of overheated before tissue suffers damage dead this fact.Heating also comes stimulating immune system by the generation that increases antibody and interferon.

Some studies show that the replication in vitro of virus can be suppressed because of temperature raises.For example, and Sweet etc. (Br.J.Exp.Path.1978,59,373-380) find that the influenza virus A of growing can deactivation when the temperature of heating in the organic culture of ferret turbinates.This that the result of study of the ferret that is subjected to this viral infection is also supported Sweet etc. found.In some animals, ferret isolation or the treatment of use antipyretic can be suppressed the inductive heating of viral infection.Observed the control animal that the lower decrease speed of the average virus titer of nasal cavity washing liquid of animal of temperature is slower than fever (Husseini et al. (1982) J.of Infectious Diseases Vol.145,520-524).So just find to have dependency relation between the virus titer of body temperature and influenza virus A.(Antimicr.Agents and Chemoth.1999, Vol.43 822-829) have studied the influence that simple hyperthermic treatment (HT) (20 minutes, 45 ℃) is duplicated in the Hela cell ERC group virus to Conti etc.When discovery is used in virus replication circulation moment, HT in vitro inhibition surpass 90% virus replication.

Can cause the virus of common cold to comprise rhinovirus and Coxsackie virus, it duplicates mainly and carries out on the epithelial cell of upper respiratory tract.It is the well known home remedy that is used for upper respiratory tract infection that steam sucks.This typically relates to places one bowl of very hot water, on cover towel, then that head is low to towel, keep a period of time, normally 5～20 minutes.Can add nasal decongestant or other aromatics in the water.Aromatic oil stimulates the mucosa of respiratory tract slightly, and mucus and salivation are increased, and throat pain and nasal congestion are alleviated.One of existing device of these application is rhinotherm by name ^TMDevice.This disclosure of the Invention described in the publication application of publication number WO 03/97143 a kind of substituted device of relieve common colds, this device blows to nasal cavity with the thermal current of negative ionization.

Though steam sucks some symptoms that also are usually used in relieve common colds, the proof steam sucks has the evidence of any curative effect very limited to lysis.One piece of summary that is used for the treatment of (comprising 20～30 minutes treatment of one or many) common cold about hot dampness is reached a conclusion, although evidence suggests symptom is eased, but there is not objective improvement (Singh M.Heated as aspects such as virus shedding or nose washing liquid virus titers in final result mensuration, humidified air for the cornmon cold (CochraneReview) .In.The Cochrane Library, Issue 2,2004).Therefore, although high temperature is proved convincingly external that to the inhibition effect of virus replication heating still is difficult to determine to the therapeutic value that the body inner virus infects struggle.

The inventor is surprised to find that, with the similar zooblast faciation ratio under the normal body temperature, it is temperature when being higher than normal body temperature that temperature raises, the RNAi increased activity of some animal reservoir's cell masses.Based on this understanding, the intravital virus replication of reply that heats to treat of organ that inventor's supposition is infected by the virus or body part has inhibitory action, might be enough to opposing or treatment viral infection.The inhibition that makes virus replication will produce enough degree, the temperature that needs organ or body part are higher 2 ℃ and keep the time of long enough synthetic to induce from the albumen of thermal induction gene than normal physiological body temperature at least.These conditions raise in-house RNAi and obtain prolonging, and mean that the ability that silent gene is obtained by RNAi keeps elevated levels can reach about 96 hours or more of a specified duration, usually between about 6 hours to about 96 hours.Typically, be unlikely to Tai Gao so that tissue is exposed to cause under the heating-up temperature and organizes under the nonviable condition at higher temperature (with respect to the situation before the treatment), temperature is high more, and the interval that needs heat is then short more.

The invention provides a kind of method of the mammal interior therapeutic viral disease in needs treatments, this method comprises uses heater that the described mammiferous tissue that is infected by the virus is heated, and makes its temperature than at least 2 ℃ of the normal physiological fevers of this tissue.In a preferred implementation of the present invention, this method makes the tissue temperature of receiving treatment than about 2 ℃～about 13 ℃ of this tissue normal physiological fevers.The applicable types of organization of the method for the invention comprises the tissue of viral infection, and this tissue comprises the cell that can hide from such as organs such as lung, nasal meatus, trachea, alveolar and the epithelial virion of body part; Also comprise such as foot, hands, skin, sexual organ and a part thereof body part as penis and scrotum, external genital and other appropriateness organ structures.The organizing of viral infection also comprises from kidney, liver, heart and uterus and a part thereof as cervix uteri, clitoris, vaginal orifice (labium majus and nympha), perineum and the cell of organ such as infected skin on every side.

The invention provides the method that a kind of intracellular virus that suppresses to be infected by the virus duplicates in mammalian subject (patient) body, this method comprises that the described tissue that is infected by the virus is heated to is higher at least 2 ℃ but be no more than 13 ℃, preferred 2 ℃～5 ℃ than this tissue normal physiological body temperature, and continue 1 hour at least, preferred 1～4 hour, more preferably 1～2 hour, most preferably 1～1.5 hour.In a further preferred implementation of this method, the invention provides and in mammalian subject (patient) body, suppress to be infected by the virus to organize the method for viral replication in, this method comprises that this method comprises that the described tissue that is infected by the virus is heated to is higher at least 6 ℃ but be no more than 9 ℃ than this tissue normal physiological body temperature, and continued 45 minutes at most so that can in the induced tissue apoptosis not take place, preferred about 10 minutes～about 45 minutes.In another further preferred implementation, can be than the normal physiological body temperature of the tissue of receiving treatment high at least 10 ℃ but be no more than 13 ℃ of the heating-up temperature that the inventive method adopted, and continue to be lower than 10 minutes time, making is heated, and organize substantially can be not apoptosis-induced.It is generally acknowledged that this interval is enough to induce the albumen of thermal induction gene synthetic.

Respiratory tract is than the more frequent generation viral infection of other any organs.Consider that thereby these tissues and physical environment have a large amount of and lasting direct the contact to be exposed among microorganism such as the virus, this is predictable.According to viewpoint of the present invention, can think that the intensity that RNAi replys is relevant with the rising of temperature: temperature raises and has strengthened RNAi, and RNAi was suppressed relatively when same temperature was low.The temperature of respiratory tract cell is usually less than the temperature of other body parts, except the given body part, as skin and testis.Breathe and also can make respiratory tract part (upper respiratory tract and lower respiratory tract) temperature decline, be lower than core temperature.It is said this is why respiratory tract seems the reason more responsive to viral infection than other body parts.Compare with the cell of other body parts, because temperature is lower in the cell in upper respiratory tract and the Skin Cell, its antiviral rna i replys and has weakened, thereby the chance of generation viral infection has increased.

In a preferred embodiment of the present invention, the mammals patient who receives treatment is just suffering from viral infection.Because human normal physiological (core) temperature is about 37 ℃, of the present invention heat to treat to generally include make tissue be heated at least 39 ℃.But then more can suppress virus replication because temperature is high more, therefore more preferably higher temperature.On the other hand, human tissue temperature too high (as above 42 ℃) overlong time is as surpassing 1 hour, the enhancing of possible overslaugh RNAi even inducing cell death.Therefore inducing of heat shock protein (HSP) can be used as that the present invention heats to treat suitable enhancing RNAi and the sign that do not cause cell death.Therefore avoid when the present invention uses using too coarse, can not induce heating to treat of heat shock protein (as HSP70).For example, in the heat protocol of the present invention, human tissue can be heated to 37 ℃～42 ℃, preferred 39 ℃～42 ℃, and continues at least 1 hour interval; In another different heating scheme of the present invention, human tissue can be heated to 43 ℃～46 ℃, and continues to be no more than 1 hour interval, preferably is no more than about 15～45 minutes.The temperature of the inventive method institute treated tissue is usually less than the temperature to the steam or the hot liquid of this tissue heat supply.

Need its normal physiological body temperature of organizing of treatment can obviously be different from patient (subject) normal physiological body temperature, under this type of situation, can in time regulate heating-up temperature.For example, Ren Lei nasal meatus temperature is 33 ℃.In addition, the mapping of human airways heat studies show that, the mean temperature of respiratory tract is 32 ℃ in upper tracheal during eupnea under indoor air temperature, then is 35.5 ℃ of (McFadden et al.J.Appl.Physiol.1985 at secondary bronchus; 58 (2): 564-70).Therefore, these tissues are heated to than these when to organize the normal physiological body temperature such as the mankind be 37 ℃～38 ℃ higher temperature, should be enough to suppress the viral replication in of organizing that normal temperature is lower than core temperature.

The method of utilizing host cell RNAi mechanism to come the enhanced virus nucleolysis among the present invention and strengthening antiviral response is not limited to the virus of any particular type.In fact, to mRNA own or the genome or the responsive any virus of its part degraded of RNAi mediation, will be to heating induction of the present invention or enhanced RNAi sensitivity.

In an embodiment, the method for the invention is used for suppressing the virus replication that can enter mucosal sites and/or duplicate in epithelial cells.The example of this viroid comprises Respirovirus and herpesvirus.Respirovirus is to cause upper respiratory tract and/or lower respiratory infection to comprise the virus of interstitial pneumonia.Upper respiratory tract infection comprises common cold (rhinitis), influenza, laryngitis (vocal cords inflammation), pharyngitis (pharyngolaryngitis), sinusitis, tonsillitis, measles and croup (child).The virus that surpasses more than 200 kinds can cause upper respiratory tract infection.The virus of these types very easily infects and propagates by directly contacting, as shake hands, shared diet and kiss.They also can be propagated by C﹠S's face.Virus can propagate into upper respiratory tract from hands by contact eye, nose or mouth.

Respirovirus comprises that orthomyxoviridae family (Orthomyxoviridae) virus that belongs to other is as influenza virus.Influenza virus is a RNA viruses, can be as propagating in the crowd winter in the certain hour in every year.In all viral respiratory tract infection, the M ﹠ M of influenza is the highest, and especially the old people is all the more so.Spontaneous recovery and recovery from illness are also arranged.Paramyxoviridae (Paramyxoviridae) as parainfluenza virus (Parainfluenzavirus) and respiratory syncytial virus (respiratory syncytialvirus, RSV).The two is RNA viruses, be neonate and childhood childrens respiratory tract infection major incentive.Main infringement is a bronchiolitis, is necrotizing sometimes, and more rare is interstitial pneumonia.

Ebola virus belongs to Filoviridae (Filoviridae), can propagate by suspended particulates.There is the relevant Ebola virus antigen of cell in the macrophage of having found its airway epithelia of aerogenic bacteria infected animals, alveolar pneumonocyte and pulmonary and pulmonary lymph node, and the mucomembranous surface of nose, pars oralis pharyngis and air flue has extracellular antigen to exist.

Coronavirus is positive chain RNA virus and comprises partially human-respiratory virus (Meta-PneumoVirus) that it can cause the particularly respiratory tract infection and the sars coronavirus (Severe Acute Respiratory Syndrome virus) of infant.The main path of propagating coronavirus is by breathing and pollutant.

Picornaviridae comprises that enterovirus belongs to (enterovirus), rhinovirus and hepatovirus.Enterovirus is propagated by feces and suspended particulates approach, is the virulence factor of poliomyelitis (poliovirus), heating, hand-foot-mouth disease (Coxsackie virus), diarrhoea (enterovirus), common cold (rhinovirus) or hepatitis (hepatovirus).

Herpesvirus family comprises the known viruse more than 80 kinds, is divided into three major types: α, β and gamma herpes viruses.The most common α herpesvirus of quick copy among the mankind is representative with herpes simplex types 1 virus (HSV-1), herpes simplex types 2 virus (HSV-2) and varicella zoster virus (VZV) virus.HSV-1 and HSV-2 all can infect mouthful (mouthful bleb, lip bleb, bicker bleb) or a genitals (genital herpes).HSV-1 falls ill usually in the zone, oral cavity, and HSV-2 is common in genital area.HSV-1 causes often being called the herpes labialis of a mouthful bleb, lip kitchen or fever blster usually.These all are the opening ulcer of hyperinfection before the incrustation healing.HSV-2 mainly causes male and female sex organs herpes.Modal signal of genital herpes and symptom comprise recurrent herpes recurrens bunch, lump and the erythra of genital area.Although more rare than HSV-1, HSV-2 also can cause herpes labialis.

VZV or 3 type nerpes vinrus hominises can cause two kinds of diseases, i.e. chickenpox (varicella) and herpes zoster (herpes zoster).After the primary infection, VZV is in resting state at the spinal sensory nerve root.When infection activated once more, virus caused pain and erythra in the zone of infected sensory nerve support.These zones are called the dermatotome.Duplicating slowly the β herpesvirus is representative with cytomegalovirus (CMV) and nerpes vinrus hominis-6 and nerpes vinrus hominis-7.Main infects epithelial of CMV and endotheliocyte.It can cause immunocompetence host's pulmonary subclinical (sub-clinical) infects, make immunocompromised patient generation clinical infection.Pulmonary infection can cause focal or chronic interstitial pneumonia more, with or without hyaline membrane form, exudate, hemorrhage and fibrosis in the alveolar.

Human papillomavirus (HPVs) is the Papillomavirus member of human papillomavirus family.The HPV genome comprises double-stranded annular DNA, and it is contained in the dodecahedron capsid.The HPV that has discerned is above 70 kinds.The HPV of reproductive tract infects can cause cervical cancer, can cause juvenile form recidivity respiratory papillomatosis when propagating into neonatal respiratory tract.HPV infects and also can make on the skin and the interior long wart of reproductive tract, digestive tract and respiratory tract.

The viral example that the present invention can advantageously suppress to duplicate comprises orthomyxovirus, influenza virus, Paramyxo virus, parainfluenza virus, respiratory syncytial pneumovirus (RSV), Filovirus such as Ebola virus, coronavirus such as hMPV and SARS virus, picornavirus such as rhinovirus, CA and Coxsackie B virus, herpesvirus such as HSV-1, HSV-2, VZV, CMV and HPV.

In a preferred implementation, particularly tissue is positioned under the situation of respiratory system, described tissue is exposed in the hot dampness that can heat this tissue described tissue is heated.Like this, in the methods of the invention, the persistent period that heats to treat, than the long twice of therapy included in existing atmiatry such as the preamble Cochrane research, wherein the experimenter accepted 20～30 minutes treatment usually, accepts extra treatment with 1～2 hour interval alternatively then at least.As previously mentioned, known heat therapy does not show tangible effect to virus replication.The present invention's proof utilizes 43 ℃ hot dampness mixture simple therapy to be enough to induce intravital virus replication to suppress in 1.5 hours.Certainly a period of time as one day or many days or one week the back repetitive therapy.

Dampness refers to that relative humidity (RH) is at least 70%, preferred 85%, more preferably at least 90% as 95%, 96%, 98%, 99% or 100% physiology acceptable gas.Preferred gas comprises the combination of air, oxygen or these two kinds of gases, can add or not add CO ₂In principle, any in-house virus replication of experimenter can utilize heat therapy provided by the invention to be suppressed, as long as this tissue can heat described tissue is raise 2 ℃ at least than this tissue normal physiological body temperature.In a preferred implementation, be organized as the mucosal tissue that contacts with hot dampness and heat.Mucosa (mucoid) tissue is present in some organs and body cavity (as nose, mouth, lung), and justacrine mucus (thick fluid) is to prevent its desiccation.Compare with the tissue of other types, mucosal tissue is subject to infectious microorganism most and comprises viral infection, because these tissues lack the physical barriers of intact skin.For example, many microorganisms can be passed the epithelium of gastrointestinal tract, urogenital tract or respiratory tract.Because steam is humidification, can pass on to tissue by supplemental heat during from the water recovery of steam on the mucosal tissue surfaces, and in the process of heating to treat damp mass (mucus) from the mucosal tissue evaporation simultaneously linked groups's thermal loss the inventive method all manage to minimum.In a preferred embodiment, heated air is 100% and water saturation.

The temperature of used steam and dampness will depend on various factors in the inventive method, comprise the temperature required of the tissue heat to treat, gas method of application and the approach, and the temperature-sensitive sensitivity that is exposed to the tissue in the gas accepted.Therefore the moisture temperature that is transported to target tissue can be 40 ℃～50 ℃, preferred 42 ℃～48 ℃, and more preferably 42 ℃～46 ℃, most preferably 43 ℃～44 ℃.100% water saturated 43 ℃～44 ℃ warm gases suck and seemed in 1.5 hours to be particularly suitable for making the temperature of respiratory tissues to raise at least 2 ℃, prevent because of the inductive RNAi inhibition of too harsh temperatures treatment (as be heated to more than 42 ℃ significant period of time as 45 minutes) and/or cause the risk minimization of cell death thereby make when strengthening RNAi.But, though other types of the present invention heat to treat the gas that imports may the higher or lower temperature of needs according to the viral infection that will treat and viral tissue of being resided.

In one embodiment, method of the present invention has suppressed to be positioned at the virus replication of respiratory tract inner tissue.Respiratory tract comprises upper respiratory tract and lower respiratory tract.Upper respiratory tract (upper airway) comprises nose, ear, mouth, nasal sinuses and larynx.Lower respiratory tract comprises the internal structure of trachea, bronchus and lung.During breathing, gas is from nose or mouthful suction and following to trachea (trunnion).Trachea is divided into two bronchus in its bottom end and enters the each several part lung respectively.Mucous function mainly is to prevent that tissue from becoming dry in the bronchus, and catches and wrap and by grit it is not abraded or infect precision tissue in the lung.Trachea is divided into thinner branch after entering in the lung, is called bronchioles.The thinnest bronchioles branch links to each other with alveolar, and alveolar is minimum, and many lobes air bag is arranged, and is made up of the simple squamous epithelium cell.The wall of alveolar as thin as a wafer can the same thin blood capillary generation gas exchange with the blood circulation tube wall.Alveolar must keep moistening ability operate as normal.

Although most of respiratory tract infection betides upper airway, various microbial mediums also can be operated lung.In upper airway, viral infection is main.In a preferred embodiment, method of the present invention is used for the opposing of the subject breathes road inner virus infection of needs treatment.For this reason, the infected tissue of respiratory tract (comprising trachea, bronchus, bronchioles) contacts a period of time of at least 1 hour with hot dampness such as air or oxygen.

Suppress in the method for respiratory tract viral replication in the present invention, the dampness of heating can be applied to the experimenter easily by sucking, and suction can be finished by autonomous or mechanically ventilated.Can use any device known in the art or the apparatus that are suitable under uniform temperature control, providing hot dampness (normally air or oxygen).These comprise invasive device such as tracheal intubation.Certainly non-invasive device preferably.Suppressing the concrete used device of respiratory tract viral replication in the inventive method is to be generally used for the respiratory tract rewarming device that hypothermia sucks rewarming.Example is referring to Morrison et al.1979J.Appl.Physiol.1979,46 (6): 1061 or the RES-Q-AIR non-invasive rewarming system fromRESQ Products Inc.at Sooke, B.C., generally speaking Canada at www.hypothermia-ca.com. sucks the dampness outlet after the rewarming device comprises water-bath, humidifying unit and heat exchanger, temperature controller display unit, gas access and heating.The experimenter can suck gas by mouth-and-nose piece or face shield.Flow velocity can change, and depends on experimenter and other conditions.In a preferred embodiment, the experimenter is with 10～80L/min, preferred 15～50L/min, more preferably the flow velocity of 20～35L/min sucks the dampness of heating.

In an embodiment, the experimenter sucks the dampness of heating with the ventilation rate that raises.Ventilation rate during experimenter's rest is usually about 10L/min even lower.Under such speed, the heat tissue especially darker tissue (lung) in position may be not enough to reach the temperature that needs.In a preferred implementation, the experimenter is at the Hyperpneic dampness that sucks heating simultaneously.Hyperpnea hyperventilation is a kind of like this states of more air admission pulmonary alveoli.Sucking the dampness that heats with method of the present invention under Hyperpneic situation can make respiratory tract obtain maximum heat exchange.Heat can infiltrate the darker tissue in position (lung).The experimenter may be required autonomous hyperpnea hyperventilation, but may cause dizzy like this.Method can be made controlled (as CO in subject as an alternative ₂Auxiliary) the hyperpnea hyperventilation condition.For example, this device can comprise a recirculation circuit, and the gas of exhalation can be recirculated through over-heat-exchanger.In a preferred implementation of the present invention, experimenter's first-selection does not add CO ₂Heated moisture be drawn into upper respiratory tract, a period of time can add CO as after 10～30 minutes in gas ₂(as by the recirculation of breath or from gas bomb), auxiliary experimenter's hyperpnea hyperventilation, and make heat farthest give (preheating) tissue from gas transfer.The CO that is sucked ₂Pressure (pCO ₂) be preferably 5～7.5kPa, more preferably 6～7kPa.The experimenter trains its ventilation rate of back to improve.Use the training equipment to train bicycle or treadmill to have the experimenter of helping and improve its ventilation rate as domestic.

In a preferred implementation, method of the present invention comprises utilizes 100% water saturation or H ₂O presses (pH ₂O) 6.5kPa at least, more preferably the steam of 7.5kPa carries out heating to treat of respiratory tract at least.Can make the The Thermal Capacity of Gaseous maximization like this and heat delivery be arrived tissue, make the thermal loss of evaporation drop to minimum simultaneously by condensing.With water saturated gas can be to spray mist or the steam that forms.Mist contains very little common 1～5 micron different liquids granule of diameter, with moisture vapor gas different fully.The inventive method preferably adopts the gas of moisture vapor.The most effective for the steam that makes suction, preferably the experimenter sucks (on every side) cold air as few as possible after sucking heat.Preferably before sleeping, suck the dampness that heats.

In an embodiment, can utilize method treatment herpes labialis (herpes simplex) of the present invention: with the dampness that heats the patient's who needs treatment infected tissue (being lip/oral region) is heated to than described and organizes the high at least 2 ℃ temperature of normal physiological body temperature and continue a period of time of at least 1 hour.Use the suction that the face shield that is enough to cover infected area is housed as described herein to review device and be easy to reach this point.

The present invention also provides apparatus of the present invention as described herein to supply hot dampness so that suppress the purposes of virus replication in vivo to tissue or body part on the other hand.This device can produce 37 ℃～50 ℃ according to the viral therapy that will carry out, relative humidity is the highest can be in 100% humidified gas (as air).More preferably, this device provides the steam of moisture vapor.

In a preferred implementation, the invention provides the device of the airway epithelial tissue that is used to heat the experimenter who suffers from viral infection, make it to be heated to than described and organize the high at least 2 ℃ temperature of normal physiological body temperature and continue a period of time of at least 1 hour.The preferred device that air or gas recirculation circuit are housed that uses, thus allow Hyperventilation to take place, make simultaneously between steam and the airway epithelial tissue and obtain maximum exchange heat.Mode as an alternative, device of the present invention is equipped with CO ₂Steel cylinder in the running can be to the gas such as air or the O that suck ₂Add controlled CO ₂, make the experimenter to sucking CO in the gas ₂Level raises to produce and replys and forced respiration.

In a specific embodiment of the present invention, the invention provides the method that suppresses herpes virus replication in mammalian subject such as the human tissue, wherein said experimenter is by herpesvirus infection.According to religious doctrine of the present invention, infected tissue is heated to the temperature higher at least 2 ℃ than its normal temperature (as 39 ℃～42 ℃) and continues a period of time of at least 1 hour, the virus replication in the infected tissue is inhibited.This point is easy to reach by (part) heating infected tissue, for example uses heat pad or patch to be positioned on the infected tissue or the next door.Preferably these heat pads or patch contain gel rubber material, contact closely with infected area thereby make it be easy to form definite shape.The gel mat or the patch that comprise this gellike can maintain suitable temperature (as 40 ℃～43 ℃) with the thermostatic control heater.In addition, also can use heat release sheet such as the ThermaCare Air-Activated Heat Wraps (can be from Procter﹠amp; Gamble obtains).

The present invention also further provides the element of heating such as the purposes that pad is used to heat infected tissue on the other hand, and this element makes infected tissue be heated to than the high at least 2 ℃ temperature of its normal temperature and continues a period of time of at least 1 hour.Preferably equipment therefor is equipped with the thermostatic control heater, in the implantable pad of this heater.

Preferably after the signal of viral infection and symptom occur to the greatest extent early the ground antiviral heat to treat.If virus replication is inhibited in early days metainfective, the probability that this virus is successfully removed by body immune system has just raise.For respiratory tract infection, nose is upset, throat is itched is typical first signal that infects, and is beginning sneeze and flowing water sample nasal mucus in a few hours then.Other symptoms of viral infection (as herpes) comprise twinge, pruritus, the burning sensation or rubescent of infection site skin.

Heat to treat with regard to beginning antiviral as early as possible whenever possible after further preferably being exposed to known or suspicious viral infection.If virus replication is inhibited in early days metainfective, the probability that this virus is successfully removed by body immune system has just raise, and infection may just stop at asymptomatic stage (subclinical phase) and can not further develop.Thereby treatment can act on the prophylactic treatment application.

Thereby thought of the present invention is based on strengthening and suppress virus replication by prolonging in the tissue RNAi, that is to say that ability that silent gene obtains by RNAi stops the back fully and keeps elevated levels for a long time in 6 hours but be no more than 96 hours (comparing with situation before the treatment) heating to treat.Therefore for chronic viral infection, preferably with repetitive therapy at interval clocklike.

In the specific embodiment of the present invention, the invention provides the method for treatment cervical atypical hyperplasia, this method comprises utilizes heater of the present invention as herein described to make the regional heating of a Cervical part.Cervical atypical hyperplasia is endocervical abnormal cell growth.Compare with normal morphology cell around it when some cervical cells and to show and to think misgrowth when immature.Immature cervical cell division is also fast than expection, and nucleus shows the microscopic change of specific type.According to the science name of used different dysplasia situations, cervical atypical hyperplasia is also referred to as the damage of Intradermal squamous cell (SIL) or Cervical intraepithelial neoplasia (CIN).The cervical atypical hyperplasia also common virus with a kind of human papillomavirus by name (HPV) is relevant.The HPV that exists surpasses 70 kinds, and surpassing has more than 1/3rd and can spread through sex intercourse.Some strains are wart consequently, comprises genital wart; Other strains then can be carcinogenic.Especially HPV-16 and HPV-18 participate in cervical atypical hyperplasia, and infected cell under the free load of expressing of HPV DNA, may make progress lentamente for malignant tumor (Melsheimer et al.Clin.Cancer Res.2004,10:3059-3063).Cervical atypical hyperplasia can be diagnosed with conventional vagina cervical smear, can treat when cervical atypical hyperplasia is diagnosed in early days to prevent it to make progress into cancer.The vagina cervical smear is when test under microscope, if abnormal cervical cells is less than 1/3rd of specimen, then this situation is called " slightly " cervical atypical hyperplasia (low SIL or CIN 1).Cervical cells accounts for the major part of specimen if note abnormalities, and then this situation is called " moderate " or " severe " cervical atypical hyperplasia (High grade SIL or CIN 2 or CIN 3).According to the position of damage, size with and grade malignancy height different, the treatment of cervical atypical hyperplasia also has nothing in common with each other.Existing treatment comprises with cryotherapy or laser therapy and destroys this infringement, uses loop electrosurgical excision procedure (LEEP) or cone biopsy to remove then, and wherein the tissue of a taper is removed by cone biopsy from cervical dilation.The invention provides a kind of method that HPV duplicates in the cervix cells that suppresses now, this method makes infected tissue be heated to temperature also to continue a period of time of at least 1 hour than its normal temperature high at least 2 ℃ (as 39 ℃～42 ℃), thereby can suppress virus replication.This point is easy to reach by the local heat infected tissue, for example uses other existing methods of thermostatic control heated probe or this area.By every day, the next day or weekly the twice pair of cervix uteri affected area treat two weeks, three weeks or week more how, HPV infects load and significantly descends, the progress that changes to malignant tumor stops even having reversed.This is for preferred low SIL of preceding malignant stages or CIN 1 Cervical treatment particular importance.In these stages, cell growth still depends on the existence of virus usually, and at the growth of malignant stages tumor cell dependovirus not.Heat therapy of the present invention can with the known treatment methods coupling of cervical atypical hyperplasia.Local cooling is method ((de Wit et al.Br.J.Cancer, 1999,80 (9): 1387-1391) that treatment cancer known in the art comprises cervical atypical hyperplasia.But tumor cell is more responsive to thermoinducible apoptosis during this anticancer therapy basis, during especially with cell cellular toxicity medicament or radiotherapy coupling.The anticancer target that heats to treat is to apply sufficiently high temperature (as more than 42 ℃) to promote death of neoplastic cells.On the contrary, the present invention is absorbed in the RNAi mechanism that suppresses virus replication in the cell to strengthen that heats to treat of non-tumor cell, preceding cancer cell, therefore really or potentially avoids developing into carcinoma stage.And, induce (tumor) cell to need temperature more than 42 ℃ usually, and the preferred temperature that suppresses virus replication is 39 ℃～42 ℃, more preferably 39 ℃～40 ℃.Those of skill in the art know too high temperature possibility inducing cell death naturally, therefore should be avoided in the application of the present invention and use.

Thought of the present invention is based on the RNAi enhancing suppresses virus replication in the tissue by prolonging, and wherein RNAi is a kind of infected host cell antiviral defense mechanism that makes the viral gene silence.But body internal heating treatment of the present invention is not limited to strengthen the antiviral gene silence.If when host cell imports dsRNA with dna homolog, need endogenous or exogenous target gene that the gene silencing of RNAi mediation takes place, also can use this heating to treat easily.Do not influence other genes when its target is found out and destroyed to gene RNAi, the RNAi effect has high selectivity.Medical field infers that extensively the clinical practice of RNAi may be inexhaustible: all are potential target spots to the contributive gene of disease (disease) arbitrarily, from the viral gene to oncogene, to the gene that causes heart disease, Alzheimer's disease, diabetes or the like.For the RNAi effect of the dsRNA that strengthens original position transfered cell (can be, with and/or utilize virus or non-nonviral delivery vehicle), can consider of the present invention heating to treat by injection, technique for gene engineering.

The present invention provides the method that strengthens the gene silencing of RNAi mediation in a kind of tissue in vivo simultaneously, and this method rises by provide heat that described in-house RNAi is stablized to described tissue.In a preferred implementation, tissue is heated to the temperature higher at least 2 ℃ than its normal physiological body temperature and also continues at least 1～4 hours, and preferred 1～2 hour, more preferably 1～1.5 hour.Method of the present invention can be advantageously used in strengthening in vivo the silence of disease gene.

The present invention also provides the device that is used to suppress patient (experimenter) respiratory tissues viral replication in, and this device comprises:

The gas access of this device receiver gases,

Be used to heat the heater of described gas,

The humidifier that is used for the described gas of humidification,

The gas flow guiding device will be from the gas channeling heater and the humidifier of gas access, directional later exhaust outlet then, and the gas release behind gas outlet's handle heating and the humidification is come out,

Make the ventilation rate lifter of experimenter's ventilation rate rising, and

Temperature controller, it links to each other with described heater and controls the temperature of subject breathes road tissue, and it is higher at least 2 ℃ and be no more than 9 ℃ temperature than this tissue normal physiological body temperature to make when using at least a portion of described tissue be heated to.

As mentioned above, the ventilation rate lifter can comprise CO ₂Adder discharges from gas outlet or the experimenter adds CO before using the training devices at described gas ₂This device also can comprise the oxygen adder, is used for described gas and adds oxygen before gas outlet discharges.Gas outlet can have mouth-and-nose piece or face shield.

The present invention also provides the device of a kind of experimenter's of inhibition rectal tract, female genital tract, cervix uteri or vagina tissue viral replication in, and this device comprises:

The interspersed element that comprises outer wall is used for interting experimenter's rectal tract, female genital tract, cervix uteri or vagina,

Secondary heater is used to heat the tissue of described interspersed component ambient, and

Second temperature controller, it links to each other with described secondary heater and controls temperature of tissue surrounding and makes in use that described to organize at least a portion to be heated to higher at least 2 ℃ and be no more than 9 ℃ temperature than this tissue normal physiological body temperature.

It is acral that the present invention also is used for the treatment of health on the other hand, also provides to suppress the acral device of organizing viral replication in of experimenter, and this device comprises:

Admit element, be used to hold the acral of experimenter, wherein admit element to comprise inwall, and held the acral of experimenter when using at least in part,

The 3rd heater is used to heat the tissue of admitting element to hold, and

The 3rd temperature controller, it links to each other with described the 3rd heater and controls the temperature of the acral tissue of described experimenter, makes that described when using to organize at least a portion to be heated to higher at least 2 ℃ and be no more than 9 ℃ temperature than this tissue normal physiological body temperature.

In above-mentioned different device, secondary heater and the 3rd heater can be similar on shape and function, and one of them is done to describe applicable to another.Similarly, other parts also can be equal to as second temperature controller and the 3rd temperature controller.Heater comprise the liquid heater that is used for heating liquid and with liquid at liquid heater and interspersed element or admit the liquid guide flow device of water conservancy diversion between the element.Interspersed element and admittance element can comprise conduit separately, and described liquid is promptly promoted to flow through this conduit and heat outer wall or inwall respectively by pump installation.

The inwall of the outer wall of interspersed element and admittance element can comprise expansible and/or deformable material, preferably has elasticity.This expansible or deformable material can be expanded to substantially and will contact with organizing fully for the treatment of of the inventive method.Those skilled in the art know that naturally the expansion of described retractable material is subjected to the liquid of pump installation driving and/or the influence that gas flow is regulated.

Outer wall or inwall also can comprise the bulge towards tissue.Interspersed element or admittance element can have the electromagnetic shaker that makes its vibrations, because the thermo-contact between can improving and organize like this.

The temperature controller of each embodiment of device also can further comprise time controller, is used for controlling the effective time time limit that described tissue is heated according to the treatment that will carry out.

With reference now to accompanying drawing, describe particular aspects of the present invention in detail, wherein:

Fig. 1 is an embodiment sketch map of the device of inhibition patient respiratory road virus replication.

Fig. 2 is the sketch map of second embodiment of the device of inhibition patient's rectal tract or female genital tract such as cervix uteri or vagina tissue viral replication in, and wherein part is a sectional view.

Fig. 3 is for suppressing acral the 3rd the embodiment sketch map organizing the device of viral replication in of patient, and wherein part is a sectional view.

Fig. 1 has shown an embodiment of the device that suppresses subject breathes road virus replication, and this device comprises the gas access 2 of receiver gases.In the embodiment of Fig. 1, gas access 2 still also can link to each other gas access 2 from the surrounding receiver gases with gas container, and described container contains specific gas (being preferably oxygen) or specific gas mixture.The air-flow that enters the gas access resembles the arrow that the usefulness through install of air flow subsequently follows and represents.The air that receives is directed to heater 3 through gas flow guiding device 5, and here gas obtains heating.Heater 3 links to each other with the humidifier 4 that makes air wetting through gas flow guiding device 5.Between gas access 2 and heater 3, gas flow guiding device 5 with comprise CO ₂The ventilation rate lifter 6 of gas cell 8 links to each other.CO ₂Gas cell 8 can be used for adding CO to the air that flows to the experimenter ₂Thereby experimenter's ventilation rate is raise in use.Raise experimenter's ventilation rate except changing gas composition, ventilation rate lifter 6 can comprise that the experimenter trains equipment, when using these equipments breathing rate is risen.

The gas that heater 3 makes it to heat to guarantee process before gas flows to humidifier can obtain suitable humidity.Its temperature of air that flows into humidifier can be the temperature that need be sent to tissue, also can be higher temperature.Air being derived the gas flow guiding device 5 of heater and/or humidifier can be adjusted, so that make gas remain on required temperature or allow its dissipated heat to reach needed temperature.The gas flow guiding device extends to gas outlet 11.The air-flow that comes out from gas outlet 11 as shown by arrows.

This device also further comprises temperature controller 9, its also temperature of control heater 3 that links to each other with heater 3.Temperature controller 9 comprises time controller 10, is used to control the time bar that temperature controller 9 activates heater 3.Temperature controller also can link to each other with gas flow guiding device 5 last parts before the outlet 11, flows into experimenter's temperature before thereby can monitor gas.When if the temperature of gas when humidifier 4 supplies is higher than the temperature that offers the experimenter, like this for guaranteeing that gas has fully been cooled off with regard to particular importance.

Gas outlet 11 comprises face shield 13, and wherein face shield 13 has elastic webbing 12, can make face shield 13 suitably be fixed on the experimenter on the face.During use the experimenter will suck the heating and humidification after air and CO ₂Mixture makes the temperature of respiratory tissues be increased to specific temperature and keeps the regular hour.The in-house virus replication in subject breathes road will be suppressed like this.

Fig. 2 has shown that inhibition experimenter's rectal tract or female genital tract comprise second embodiment of the device of cervix uteri or vagina tissue viral replication in.This device comprises interspersed element (21), is used for interspersed experimenter's rectal tract or female genital tract.The element (21) that interts comprises scalable and rubber-like outer wall (22).Formed hollow core 30 with conduit 25 in the outer wall 22 of interspersed element 21.During use, liquid flows into and through conduit 25, flows out through the hollow core 30 and the space of outer wall 22 then.Telescopic outer wall 22 makes the shape of interspersed element 21 be adjusted to the shape of surrounding tissue in use.The elastic characteristic of outer wall makes its expansion, thereby size also can be adjusted.Outer wall also can contain the bulge (not shown), can provide bigger contact surface between interspersed element 21 and surrounding tissue, and does not make interspersed element 21 lengthenings.

Embodiment shown in Fig. 2 also comprises secondary heater 23.Secondary heater 23 comprises hot body heater 26 and pump installation 27, and the liquid after the heating is through pump installation 27 promotions and through liquid guide flow device 28 and enter interspersed element 21.Secondary heater 23 links to each other with interspersed element 21 by liquid guide flow device 28, thereby the liquid after the heating is flow through from interspersed element 21.Some comprises that whole interspersed element 21 shows with sectional view sketch map.The flow direction of liquid in the arrow indication device among the figure.Liquid after liquid guide flow device 28 will heat is from secondary heater 23 guiding catheters 25.Liquid after the heating returns secondary heater 23 through interspersed element 21 and by the loop feature of liquid guide flow device 28 then.Conduit 25 inside are provided with liquid flow controller (not shown) to guarantee liquid circulation fully in conduit 25.

The device of second embodiment also comprises second temperature controller 24, and it links to each other with secondary heater 23 and controls secondary heater 23.Second temperature controller 24 comprises second time controller 29, is used to control the time bar that second temperature controller 24 activates secondary heater 23.

The element 21 that interts during use is put into the appropriate location of experimenter's rectum road or female genital tract.Flow of liquid after the heating is crossed when interting element 21, makes the temperature that outer wall 22 is heated to be needed.Tissue around the element 21 that interts makes by this way is heated the specific time, thereby this in-house virus replication is suppressed.

This device also comprises the electromagnetic shaker that makes interspersed element 21 vibrations.This mode makes to intert has better thermo-contact between element 21 and the surrounding tissue.Fig. 3 shows that this device is used to suppress acral the 3rd embodiment organizing viral replication in of experimenter's health.This device comprises admits element 41, is used to hold the acral of experimenter.Health is acral can be hands, foot, scrotum and/or penis.Acral the putting into of health admitted element 41 during use, admits element 41 to hold the acral of experimenter at least in part.Admit element 41 to comprise outer sleeve 51, sleeve is provided with opening 50 and enters sleeve inner.Deformable and rubber-like inwall 42 are positioned at outer sleeve 51, form the conduit 45 that liquid can flow through between the two.Thereby conduit 45 inside are provided with liquid flow controller (not shown) and circulate fully in admitting element 41 also around acral circulation fully to guarantee liquid.

Deformable inwall 42 may be adjusted in use acral shape or the profile of the health of admitting because it has elasticity and inflatable, so that its size can be adjusted to adapt to is littler acral.Inwall can comprise bulge inwardly, can make that to admit element 41 better to hold the health of being admitted acral or make contact better between them.

The device of the third embodiment also comprises supply heating liquid mechanism same as shown in Figure 2.With similar index number similar portions is described.Liquid after heater 23 will heat pumps into and pumps admittance element 41 through liquid guide flow device 28.Show that with sectional view the arrow of this part has shown the flow direction of liquid among the figure.

Experimenter's acral putting into by opening 50 admitted element 41 during use.Liquid after heater will heat pumps into through second conduit 45 and admits element 41, thereby makes inwall 42 heating.Admit element 41 to make acral being heated one specific period on every side by this way, thereby suppress described in-house virus replication.This device also can comprise and be used to make the electromagnetic shaker of admitting element 41 vibrations, can promote to admit the thermo-contact of element 41 and surrounding tissue like this.

Liquid in second kind of enforcement and the third embodiment can be to have appropriate viscosity, thermal capacity and toxic any suitable kind of liquid.Water or light mineral oil are suitable liquid.

Can also between the contact wall (as interting the outer wall of element or the inwall of admittance element) of tissue and device, add heat-conducting medium, thereby further improve thermo-contact.After thermo-contact between interspersed element or admittance element and the adjacent tissue improves, also improved usefulness of the present invention.Heat-conducting medium also can improve the comfort level of use, can be gel, saliva, water, lubricant etc.

Claims

1. the method for a treatment viral disease in the mammal of needs treatments, this method comprises uses heater to heat the be infected by the virus cell of tissue of described mammal, makes described tissue be heated to temperature than at least 2 ℃ of this tissue normal physiological fevers.

2. according to the described method of claim 1, wherein said heating-up temperature is than described 2 ℃～13 ℃ of the normal physiological fervescence of organizing.

3. according to claim 1 or 2 described methods, wherein said viral infection tissue is selected from lung, nasal meatus, trachea, bronchioles, alveolar, and such as foot, hands, skin, sexual organ and a part thereof as penis and scrotum, external genital, uterus, cervix uteri, clitoris, vaginal orifice (labium majus and/or nympha), perineum and the epithelial cell of the body part the infected skin on every side.

4. the method for the histiocyte viral replication in that in mammals patient body, suppresses to be infected by the virus, this method comprise make the described tissue that is infected by the virus be heated to than this tissue normal physiological body temperature high at least 2 ℃～9 ℃, preferred 2 ℃～5 ℃, and continue 1 hour at least, preferred 1～4 hour, more preferably 1～2 hour, most preferably 1～1.5 hour.

5. one kind is suppressed to be infected by the virus to organize the method for viral replication in mammals patient body, this method comprises that the described tissue that is infected by the virus is heated to is higher at least 6 ℃ but be no more than 9 ℃ than this tissue normal physiological body temperature, and continued 45 minutes at most so that can in the induced tissue apoptosis not take place, preferred about 10 minutes～about 45 minutes.

6. according to each described method in the claim 1 to 5, wherein said mammal is human.

7. according to the described method of claim 6, wherein said heating-up temperature is 39 ℃～42 ℃, and implements with at least 60 minutes interval.

8. according to the described method of claim 6, wherein said heating-up temperature is 43 ℃～46 ℃, and implements preferred interval about 10 minutes～about 45 minutes with the interval less than 60 minutes.

9. according to the described method of aforementioned each claim, wherein heat cell and implement in the mode of heated moisture or heating element heater, described dampness relative humidity is at least 70%, can contain CO ₂

10. one kind is suppressed the device that viral replication in is organized in the patient respiratory road, and this device comprises:

The gas access (2) of this device receiver gases;

Be used to heat the heater (3) of described gas;

The humidifier (4) that is used for the described gas of humidification;

Gas flow guiding device (5) will be from the gas channeling heater (3) and the humidifier (4) of gas access (2), directional later exhaust outlet (11) then, and the gas release behind gas outlet's handle heating and the humidification is come out;

Comprise CO ₂The ventilation rate lifter (6) of adder (8) added CO at described gas before gas outlet discharges ₂, patient's ventilation rate is raise, and

Temperature controller (9), it links to each other with described heater (3) and controls the temperature of patient respiratory road tissue, and it is higher at least 2 ℃ and be no more than 13 ℃ temperature than this tissue normal physiological body temperature to make when using at least a portion of described tissue be heated to.

11. one kind is suppressed the device that viral replication in is organized in the patient respiratory road, this device comprises:

The gas access (2) of this device receiver gases;

Be used to heat the heater (3) of described gas;

The humidifier (4) that is used for the described gas of humidification;

Ventilation rate lifter (6), it comprises the training equipment that is used by the patient,

12. according to claim 10 or 11 described devices, wherein said device also comprises the oxygen adder, is used for described gas and adds oxygen before gas outlet (11) discharges.

13. according to each described device of claim 10 to 12, wherein said gas outlet (11) comprises mouth-and-nose piece or face shield (13).

14. according to each described device of claim 10 to 13, wherein said temperature controller (9) comprises time controller (10), is used to control the time bar that described tissue is heated.

15. a device that suppresses patient's rectal tract, female genital tract, cervix uteri or vagina tissue viral replication in, this device comprises:

Intert element (21), be used for interting experimenter's rectal tract, female genital tract, cervix uteri or vagina, the element (21) that interts comprises outer wall (22);

Secondary heater (23), be used to heat described interspersed element (21) tissue on every side, and second temperature controller (24), it links to each other with described secondary heater (23) and controls temperature of tissue surrounding and makes in use that described to organize at least a portion to be heated to higher at least 2 ℃ and until 13 ℃ temperature than this tissue normal physiological body temperature.

16. according to the described device of claim 15, wherein said secondary heater (23) comprises the hot body heater (26) that is used for heating liquid and with the liquid guide flow device (28) of liquid water conservancy diversion between liquid heater (26) and interspersed element (21), described interspersed element (21) comprises conduit (25), and described liquid is promptly promoted to flow through this conduit by pump installation (27) and heats outer wall (22).

17. according to claim 15 or 16 described devices, wherein said outer wall (22) comprises expansible and/or deformable material, preferred rubber-like material.

18. according to each described device of claim 15 to 17, wherein said outer wall (22) comprises bulge.

19. according to each described device of claim 15 to 18, wherein said device comprises the electromagnetic shaker that makes described interspersed element (21) vibrations.

20. according to each described device of claim 15 to 19, wherein said second temperature controller (24) comprises that second time controller (29) is used to control the time bar that described tissue is heated.

21. one kind is suppressed the acral device of organizing viral replication in of patient, this device comprises:

Admit element (41), be used to hold the acral of experimenter, wherein admit element (41) to comprise inwall (42), and held the acral of patient when using at least in part;

The 3rd heater (43) is used for the tissue that heating admits element (41) to hold, and

The 3rd temperature controller (44), it links to each other with described the 3rd heater (43) and controls the temperature of the acral tissue of described patient, makes that described when using to organize at least a portion to be heated to higher at least 2 ℃ and until 13 ℃ temperature than this tissue normal physiological body temperature.

22. according to the described device of claim 21, wherein said the 3rd heater (43) comprises second liquid heater (46) that is used for heating liquid and with the second liquid guide flow device (48) of liquid water conservancy diversion between the 3rd liquid heater (43) and interspersed element (41), described interspersed element (41) comprises second conduit (45), and described liquid is promptly promoted to flow through this conduit by second pump installation (47) and heats inwall (42).

23. according to claim 21 or 22 described devices, wherein said inwall (42) comprises expansible and/or deformable material, preferably has elasticity.

24. according to each described device of claim 21 to 23, wherein said inwall (42) comprises second bulge.

25. according to each described device of claim 21 to 24, wherein said device comprises second electromagnetic shaker that makes described admittance element (41) vibrations.

26. according to each described device of claim 21 to 25, wherein said the 3rd temperature controller (44) comprises that the 3rd time controller (49) is used to control the time bar that described tissue is heated.

27. suppress the purposes of virus replication in vivo according to each described device heating infected tissue of claim 10 to 26 or body part.

28. according to the described purposes of claim 27, wherein said heating is used with dampness, and provides with 37 ℃～50 ℃ temperature, relative humidity reaches as high as 100%.

29. according to the described purposes of claim 27, wherein said heating is applied to infected tissue or body part with heating element heater such as heat pad or elongated warming parts.