JP2008503291A - Antiviral fever treatment - Google Patents

Abstract

  A method of treating a viral infection in vivo in a subject in need of treatment of a viral infection by applying heat to the affected body tissue, a moist gas heated or heated to the affected body tissue infected with the virus A device for supplying a liquid and a device capable of applying heat to a virus-infected body part are provided.

Description

  The present invention relates to the medical field. More specifically, the present invention provides a method of treating a viral infection that includes applying heat to an organ or body part that includes a constant viral load, the ability to apply heat to the organ or body part described above. And a method of using such a device. Specifically, the present invention relates to organs such as skin and body organs, as well as the respiratory system (lung), female reproductive tract (eg cervix), body limbs such as limbs, and penis, scrotum. Applicable to the eradication or treatment of viral infections of body parts such as male gender parts such as vulva and genital area.

  Viruses are obligate intracellular parasites that require host cell biochemical mechanisms for replication and propagation. Viral genetic material is typically enclosed in a protein capsid, which may be surrounded by a lipid envelope.

  Viruses vary greatly in structure and genetic complexity, with some having an RNA genome that encodes only a few genes, and some having a DNA genome that encodes about 200 genes. Viruses bind to host cells through specific receptors. Following entry into the host cell, the virus removes the envelope and releases and expresses the nucleic acid to produce viral proteins. The viral genome is replicated, new progeny virus particles (virions) are assembled and released, and these processes progress to infect neighboring cells. Virus entry into cells generally occurs at mucosal sites. Replication typically occurs on the epithelial surface, but in the case of certain viral infections it can also be caused by viremia, i.e. viral particles enter the general circulation and propagate through it to other tissues. Infect.

  Eukaryotes have developed numerous defense mechanisms for antimicrobials based on the recognition of conserved molecular patterns shared by large microbial communities, including viruses. Double stranded RNA (dsRNA) is representative of one such molecular pattern. In mammalian cells, the defense response elicited by dsRNA is induction of interferon, a type of protein, which alleviates viral transmission by inhibiting viral gene expression and causing cell death in infected cells. can do. Another antiviral response elicited by dsRNA is what is called RNA interference (RNAi) in animals and post-transcriptional gene silencing (PTGS) or RNA silencing in plants (Fire et al., Nature, 1998). 391, 806-811; Ding, Curr. Opin.Biotechnology, 2000, 11, 152-156; and Hutvanger and Zamore, Curr.Opin.Gen.Dev, 2002, 12th. No., pages 225-232). The main feature of RNAi is remarkable sequence specificity. That is, an infected organism reacts with dsRNA by selectively degrading mRNA having a sequence homology with the dsRNA inducer. Therefore, when RNAi is used, not only viral gene expression but also host cell gene expression can be specifically prevented upon introduction of homologous dsRNA. The central starting molecule in RNA silencing is a (long) dsRNA molecule, which is broken down into 21-23 nucleotide fragments by a nuclease targeting dsRNA called DICER. Subsequently, these short interfering RNAs (siRNAs) target homologous cognate RNAs for degradation mediated by the RNA initiation silencing complex (RISC), resulting in small amounts of cytoplasmic target RNA. When this target RNA is either the viral genome, antigenome or mRNA, RNAi-induced RNA degradation specifically inhibits or completely prevents viral replication. Conversely, if the target RNA is of cellular origin, RNAi can prevent cognate gene expression after translation.

  To overcome host RNA silencing, many plant viruses have been found to encode RNA silencing suppressors (RSS). The published patent applications WO 98/44097, WO 01/38512 and WO 02/056767 include an RNA silencing suppressor derived from a plant virus and the suppressor of this suppressor. The usage in plants is described. WO 02/053011 describes RSS derived from plant viruses and the use of this RSS in animal cells, while Li et al., Science, 296, pp. 1319-1321, 2002, Describes RSS derived from insect viruses and the activity of this RSS in plant and insect cells. The use of RSS derived from vertebrate viruses and the use of this RSS in animal cells is described in WO 04/035796. In addition, a study by Li et al. (Proc. Natl. Acad. Sci. USA, 2004, No. 101, pp. 1350-1355) shows that NSI protein and E3L protein encoded by mammalian viruses influenza and vaccinia are respectively , Indicating that antiviral RNA silencing in Drosophila cells could be suppressed, which strongly demonstrates the role of RNAi as a natural antiviral response not only in plant cells but also in eukaryotic cells other than plants. I support it.

  Yet another host defense against viruses is fever. Fever takes advantage of the fact that many invading organisms allow a narrower temperature range than body tissues and are therefore more susceptible to temperature rise, i.e., can be killed by overheating before harming human tissues It is generally considered to be. Fever also stimulates the immune system by increasing the production of antibodies and interferons.

  Several studies have shown that viral replication in vitro can be suppressed by increasing temperature. For example, Sweet et al. (Br. J. Exp. Path., 1978, 59, pp. 373-380) show that influenza A virus grown in ferret nasal turbinate organ cultures is inactivated at fever temperature. It describes what to do. The discovery of Sweet et al. Was supported by the results of studies on virus-infected ferrets. In some animals, fever induced by viral infections was suppressed by shaving ferrets or treatment with antipyretic drugs. It was observed that the mean virus titer with nasal washes decreased more slowly in animals with lower body temperature compared to fever control animals (Husseini et al. (1982), J. of Infectious Diseases, vol. 145). 520-524). Thus, a correlation has been observed between body temperature and the virus titer of influenza A virus. Conti et al. (Antimicr. Agents and Chemoth. 1999, 43, 822-829) described the effect of short-term (20 minutes 45 ° C.) hyperthermia (HT) on replication of human rhinovirus in HeLa cells. Studying about HT was observed to inhibit viral replication in vitro by more than 90% when applied at certain stages of the viral replication cycle.

Virus replication, including rhinovirus and coxsackie virus, occurs mainly in epithelial cells that thinly cover the upper respiratory tract. Vapor inhalation is a well-known home remedy for infection of the upper respiratory tract. This method typically involves holding the head under a towel over a bowl of hot water over a period of 5 to 20 minutes. A nasal congestion remover or other aromatic compound may be added to the hot water. The fragrance oil can gently irritate the mucous membrane of the respiratory tract and promote the secretion of mucus and saliva to relieve sore throat and stuffy nose. An apparatus for these applications is known under the name rhinotherm ™. The invention described in the published patent application WO 03/97143 provides an alternative device for blowing a negatively ionized heated air stream into the nasal cavity to alleviate a common cold. Disclosure.
Fire et al., Nature, 1998, 391, 806-811. Ding, Curr. Opin. Biotechnology, 2000, No. 11, pp. 152-156 Hutvanger and Zamore, Curr. Opin. Gen. Dev, 2002, No. 12, pp. 225-232 International Publication No. 98/44097 Pamphlet WO 01/38512 pamphlet International Publication No. 02/057467 Pamphlet International Publication No. 02/055731 Pamphlet Li et al., Science, 296, pp. 1319-1321, 2002 International Publication No. 04/035796 Pamphlet Li et al., Proc. Natl. Acad. Sci. USA, 2004, No. 101, 1350-1355. Sweet et al., Br. J. et al. Exp. Path. 1978, 59, 373-380) Husseini et al. (1982), J. Am. of Infectious Diseases, 145, 520-524 Conti et al., Antimicr. Agents and Chemoth. 1999, 43, 822-829. International Publication No. 03/97143 Pamphlet Singh M.M. , Heated, humidified for the common cold (Cochrane Review), The Cochrane Library, 2nd edition, 2004. McFadden et al. Appl. Physiol. 1985, Vol. 58, No. 2, pp. 564-70 Morrison et al., 1979 J. MoI. Appl. Physiol. 1979, Vol. 46, No. 6, p. 1061 www. hyperthermia-ca. com Melsheimer et al., Clin. Cancer Res. 2004, No. 10, pp. 3059-3063 de Wit et al., Br. J. et al. Cancer, 1999, Vol. 80, No. 9, pp. 1387-1391

  Vapor inhalation is widely used to relieve some of the common cold symptoms, but the evidence that vapor inhalation has some beneficial effect on the disease process is very limited . According to one study of the use of heated and humidified air for a common cold (including one or more treatments for 20 to 30 minutes), there is evidence that symptoms are alleviated, but nose It was concluded that there was no objective improvement in outcome measures such as virus shedding or virus titer in washing (Singh M., Heated, for the air for the common cold (Cochrane Review), The Cochrane Library, Second printing, 2004). Thus, the inhibitory effect of hyperthermia on viral replication in vitro has been demonstrated convincingly, but the therapeutic value of fever for eradicating viral infections in vivo is Has not yet been elucidated.

  The inventors surprisingly found that at elevated temperatures, i.e. above body temperature during normal heating, the activity of RNAi in the animal host cell population is enhanced over similar animal host cell populations in normal body temperature. Observed to be. Based on this finding, we have shown that the thermal treatment of virally infected organs or body parts may have an inhibitory effect on viral replication in vivo that may be sufficient to eradicate or treat viral infections. I guess it has. A sufficient level of inhibition of virus replication heats the organ or body part to a temperature that is at least 2 ° C. above the normal physiological temperature for a period of time sufficient to induce protein synthesis from the heat-induced gene. I need that. These conditions entail a long-term increase in RNAi in the tissue, indicating that the ability to silence the gene via RNAi is up to about 96 hours or more, typically from about 6 hours to about 96. Implying staying elevated over time. Typically, the higher the temperature, the shorter the time required for heating, but this high temperature is not so high (as compared to the pre-treatment situation) that it is detrimental to the viability of the tissue exposed to the heating temperature. On the condition.

  According to the present invention, there is provided a method of treating a viral disease in a mammal in need of treatment of the viral disease, wherein the method comprises physiologically treating the cells of the mammalian virus-infected tissue with a heating device during normal heating of the tissue. Heating to a heating temperature that is at least 2 ° C. higher than the body temperature heating temperature. In a preferred form, the method is performed at a temperature that is 2 ° C. to about 13 ° C. above the normal temperature of the tissue being treated. The types of tissues to which the method of the present invention can be applied include organs and body parts such as lung epithelial cells, nasal passages, trachea and alveoli, etc., as well as feet, hands, skin, penis and scrotum, and vulva. And, as appropriate, virus-infected tissues including cells that harbor virus particles from body parts such as genitals and genital parts such as genital structures. Also within the area of the virus-infected tissue are the uterus, such as the kidney, liver, heart, and cervix, clitoris, genitalia (both large and small labia), perineum and surrounding infected skin. Including parts, cells from organs such as the uterus are also included.

  In accordance with the present invention, there is provided a method of inhibiting viral replication in vivo in a virus-infected cell of a subject mammalian tissue, said method comprising: A temperature above at least 2 ° C but not above 13 ° C, preferably at least 2 ° C to above about 5 ° C, for at least 1 hour, preferably 1 hour to 4 hours, more preferably 1 hour to Heating for a duration of 2 hours, most preferably 1 hour to 1.5 hours. In a further preferred form of the method of the invention, a method is provided in vivo for inhibiting viral replication in a virus-infected tissue of a subject mammal, said method comprising the physiological treatment of the tissue during normal heat. Heating to a temperature above the temperature by at least 6 ° C but not exceeding 9 ° C for up to 45 minutes, preferably from about 10 minutes to about 45 minutes, so as not to induce tissue cell death. . In an even more preferred form of the method of the invention, the heating temperature used may be at a temperature that is at least 10 ° C. above the normal physiological temperature of the tissue being treated, but does not exceed 13 ° C. The temperature may be applied for a duration of less than 10 minutes so that cell death is not substantially induced in the heated tissue. This time is believed to be sufficient to induce protein synthesis from the heat-induced gene.

  Viral infections occur more frequently in the respiratory tract than in any other organ. This can be expected considering the close and uninterrupted direct contact these tissues have with the physical environment and thus exposure to microorganisms such as viruses. According to the concept of the present invention, the magnitude of the antiviral RNAi reaction is believed to correlate with an increase in temperature, i.e., an elevated temperature enhances RNAi, while RNAi is suppressed as the temperature decreases. The temperature of the cells of the respiratory tract is usually lower than other body parts, except for the temperature of limited body parts such as the skin and testis. Breathing also causes local cooling to a temperature below the deep body temperature of the respiratory tract (upper and lower respiratory tract). This seems to be the reason why the respiratory tract appears to be more sensitive to viral infections than other body parts. Since the cell temperature is relatively low in cells of the upper respiratory tract and skin, the antiviral RNAi reaction is lowered and the probability that a viral infection is established is higher than cells in other body parts.

  In a preferred embodiment of the invention, the mammalian subject being treated is a human suffering from a viral infection. The physiological (deep) temperature during normal warming is about 37 ° C., and the thermal treatment of the present invention typically involves heating the tissue to a temperature of at least 39 ° C. However, higher temperatures are preferred because they more efficiently inhibit virus replication. On the other hand, if the human tissue becomes too hot (for example, more than 42 ° C.) for an excessively long time such as more than about 1 hour, it may prevent the enhancement of RNAi or induce cell death. Induction of heat shock proteins by heat treatment (in vivo) is well known in the art. Thus, induction of heat shock protein (HSP) can be employed as an indicator for heat treatment according to the present invention to appropriately enhance RNAi without causing cell death. Thus, excessively intense heat treatment that does not induce heat shock proteins (eg, HSP70) should be avoided when applying the present invention. For example, in the heating protocol of the present invention, the human tissue is heated to a temperature in the range of 37 ° C. to 42 ° C., preferably up to 39 ° C. to 42 ° C. for a time of at least 1 hour, or a different heating protocol of the present invention. Then, the human tissue can be heated to a temperature in the range of 43 ° C. to 46 ° C. for a time not exceeding 1 hour, preferably not exceeding about 15 minutes to 45 minutes. The temperature of the tissue treated by the method of the present invention is typically lower than the temperature of the heated gas or heated liquid that provides heat to the tissue.

  In some cases, the physiological temperature of the tissue to be treated during normal heating deviates significantly from the normal body temperature of the subject during normal heating. In these cases, the heating temperature can be adjusted accordingly. For example, the temperature of the human nasal passage is 33 ° C. In addition, heat mapping studies of the human respiratory tract have shown that during indoor air breathing, the average temperature of the respiratory tract ranges from 32 ° C in the upper trachea to 35.5 ° C in the subregional bronchus. (McFadden et al., J. Appl. Physiol., 1985, Vol. 58, No. 2, pages 564-70). Therefore, in the case of a human subject, in the method of the present invention, if these tissues are heated to a temperature that is higher than the physiological temperature during normal heating of such tissues, for example, 37 ° C. or 38 ° C., It will be sufficient to achieve inhibition of viral replication in body temperature tissues.

  The methods of the present invention that enhance the antiviral response of a host cell by enhancing viral nucleic acid degradation via the host cell's RNAi mechanism are not limited to any particular type of virus. Indeed, any virus that is susceptible to RNAi-mediated degradation of the viral mRNA or genome or portion thereof is sensitive to heat-induced or heat-enhanced RNAi according to the present invention.

  In one embodiment, a method as described herein is used to inhibit viral replication that can enter a mucosal site and / or replicate in epithelial cells. Examples of such viruses are respiratory viruses and herpes viruses. Respiratory viruses cause infections in the upper and / or lower respiratory tract, including interstitial pneumonia. Upper respiratory tract infections include common cold (rhinitis), influenza, laryngitis (laryngeal inflammation), pharyngitis (throat pain), sinusitis, tonsillitis, measles and croup (children) is there. There are over 200 viruses that can cause infection of the upper respiratory tract. These types of viruses are highly infectious and are transmitted by direct contact such as shaking hands, food sharing and kissing. It can also propagate through coughing and sneezing. Viruses can spread from the hand to the upper respiratory tract by touching the eyes, nose or mouth.

  Respiratory viruses include the Orthomyxoviridae family, especially the influenza virus. Influenza viruses are RNA viruses that can be transmitted through populations at a given time of the year, such as winter. Influenza has the highest morbidity and mortality among all viral respiratory infections, especially for the elderly. There is generally a natural recovery and dissipation. Paramyxoviridae, such as parainfluenza virus and respiratory multinucleated virus (RSV), are both RNA viruses that are an important cause of respiratory infections in infants and children. The main lesion is bronchiolitis, in some cases necrotic, and less frequently interstitial pneumonia.

  Ebola virus belongs to the family Filoviridae and can be transmitted by aerosol. Infected animals show cell-related Ebola virus antigens present in airway epithelium, alveolar cells, and macrophages of lung and lung lymph nodes, and extracellular antigens are present on the nasal mucosal surface, oropharynx and airways. It has been found that it was.

  Coronaviruses are positive (+) strand RNA viruses, including human metapneumoviruses that can cause respiratory infections in children, and severe acute respiratory syndrome viruses. The main route of infection of coronavirus is via respiration or vectors.

  The Picornaviridae family consists of the Enteroviruses, Rhinoviruses and Hepatoviruses. Picornaviruses are transmitted by the fecal and aerosol routes, and are associated with leukomyelitis (poliovirus), fever, and hand-foot-and-mouth disease (coxsackie virus), diarrhea (enterovirus), common cold (rhinovirus) or hepatitis (hepatovirus). It is a pathogen.

  The herpesviridae consists of over 80 known viruses and is divided into three classes: alphaherpesviruses, betaherpesviruses and gammaherpesviruses. The most common in humans is alphaherpesvirus, which is usually fast replicating, herpes simplex virus type-1 (HSV-1) and type-2 (HSV-2), and varicella-zoster virus (VZV). ). Both HSV-1 and HSV-2 may infect the mouth (mouth herpes, lip blisters, mouth blisters), or the genitals (genital herpes). Normally, HSV-1 occurs in the mouth area and HSV-2 occurs in the genital area. HSV-1 is usually the cause of cold sores, commonly known as cold sore or cold blister. These herpes are very highly infectious and heal after they become scabs. HSV-2 is primarily responsible for male and female genital herpes. The most common signs and symptoms of genital herpes include recurrent concentrated outbreaks of genital blisters, rashes and rashes. HSV-2 may cause cold sores but is less frequent than HSV-1.

  VZV or human herpesvirus type-3 can cause two diseases, namely varicella and herpes zoster. After primary infection, VZV lurks at the root of sensory nerves in the spinal cord. When the infection is reactivated, pain and rash occur at the site supplied by the affected sensory nerve. These sites are known as skin segments. Slow replicating beta-herpesviruses are represented by cytomegalovirus (CMV) and human herpesvirus-6 and -7. CMV mainly infects epithelial cells and endothelial cells. CMV results in asymptomatic infections in the lungs of immunocompetent hosts and clinical infections in immunocompromised patients. Lung infections result in focal or diffuse interstitial pneumonia, which may or may not be accompanied by hyaline film formation, intraalveolar exudation, hemorrhage and fibrosis.

  Human papillomavirus (HPV) is a constituent species of the genus papillomavirus of the Papoviridae family. The HPV genome consists of double-stranded circular DNA contained within an icosahedral capsid. More than 70 HPVs are recognized. HPV infection of the genital tract can lead to the development of cervical cancer, and transmission to the neonatal respiratory tract can result in juvenile recurrent respiratory papillomatosis. HPV infection also causes warts in the skin and the genital, digestive and respiratory tracts.

  Illustrative of viruses whose replication is advantageously suppressed using the methods of the present invention include phyllosides such as orthomyxovirus, influenza virus, paramyxovirus, parainfluenza virus, respiratory multinuclear virus (RSV), and Ebola virus. There are viruses, coronaviruses such as hMPV and SARS viruses, picornaviruses such as rhinovirus, coxsackie A and B viruses, herpesviruses such as HSV-1, HSV-2, VZV, CMV and HPV.

  In a preferred embodiment, the tissue is heated by exposing the tissue to a heated and humidified gas capable of heating the tissue, particularly where the tissue is located in the respiratory system. Thus, in the methods of the present invention, the duration of heat treatment is at least twice as long as known vapor inhalation treatments, such as those included in the Cochrane study above, and the subject typically Receive treatment for 20 to 30 minutes, optionally followed by additional treatment at time intervals of 1 to 2 hours. As noted, known heat treatment protocols do not have a significant effect on virus replication. The present invention now demonstrates that a single hour and a half heat treatment with a heated and humidified 43 ° C. air mixture is sufficient to induce inhibition of virus replication in vivo. To do. It goes without saying that this treatment may be repeated after some time, such as a day or days, or a week.

Humidified gases are those physiologically having a relative humidity (RH) of at least 90%, such as at least 70%, preferably at least 85%, more preferably 95%, 96%, 98%, 99% or 100%. Refers to an acceptable gas. A preferred gas is air, oxygen, or a combination of these two gases, with or without the addition of CO ₂ . In principle, the use of thermotherapy according to the present invention allows the tissue to be heated so that the tissue temperature can be raised to at least 2 ° C. above the normal physiological temperature during normal heating. Viral replication can be inhibited. In a preferred embodiment, the tissue heated via contact with the heated and humidified gas is mucosal tissue. Mucosal (or mucinous) tissue covers several organs and body cavities (nose, mouth, lungs, etc.) thinly and secretes mucus (viscous fluid) to prevent drying. Compared to other tissue types, mucosal tissue is susceptible to infection by infectious microorganisms, including viruses, because it lacks intact skin that forms a physical barrier. For example, many microorganisms can contact across the epithelium of the gastrointestinal tract, genitourinary tract, or respiratory tract. Since the heated gas is humidified, condensation of the water vapor from the heated gas on the surface of the mucosal tissue helps heat transfer to the tissue, and moisture from the surface of the mucosal tissue during thermotherapy (mucus) ) And the associated heat loss from the tissue is believed to be minimized in the method of the present invention. In a preferred embodiment, the heated gas is 100% saturated with water.

  The temperature of the heated and humidified gas used in the methods of the present invention depends on the desired temperature of the tissue undergoing thermotherapy, the mode and route of administration of the gas, and the heat of the tissue (s) exposed to the gas. Needless to say, it depends on various factors including sensitivity. Thus, the temperature of the humidified gas delivered to the target tissue may be between 40 ° C and 50 ° C, preferably between 42 ° C and 48 ° C, more preferably between 42 ° C and 46 ° C, most preferably 43 ° C. It may be ˜44 ° C. Inhalation of warm air 100% saturated with water at 43 ° -44 ° C. over 1.5 hours is triggered by excessively vigorous temperature treatment (eg heating above 42 ° C. for a considerable time such as over 45 minutes) Appear to be particularly suitable for raising the temperature of the respiratory tract tissue by at least 2 ° C. so that RNAi is enhanced while at the same time minimizing the risk of disturbing RNAi suppression and / or causing cell death It is. However, other types of heat treatment according to the present invention may require the temperature of the introduced gas to be higher or lower depending on the viral infection to be treated and the tissue in which the virus is present.

  In one example, the method of the invention inhibits viral replication in tissues located inside the respiratory tract. The respiratory tract consists of an upper part and a lower part. The upper respiratory tract (upper airway) consists of the nose, ears, mouth, nasal cavity and throat. The lower respiratory tract consists of structures inside the trachea, bronchi, and lungs. During breathing, air is sucked in through the nose or mouth and descends the trachea (throat flute). The trachea divides into two bronchi at the bottom, one by one to each lung. Bronchial mucus prevents the tissue from drying out and helps to trap and cover the dust particles so that the dust particles do not injure or infect the fine lung tissue. The bronchi break into smaller branches called bronchioles in the lungs. The thinnest bronchiole branches into alveoli, which are air sacs divided into a number of small bags composed of simple squamous cells. Since the alveolar walls are thin, air can be exchanged with capillaries having equally thin walls of the circulatory system. In order to work correctly, the alveoli must always be moist.

  Although most respiratory infections occur in the upper respiratory tract, various types of microorganisms also damage the lungs. Viral infections predominate in the upper respiratory tract. In a preferred embodiment, the methods of the invention are used to eradicate viral infections in the respiratory tract of a subject in need of treatment for a viral infection. For this purpose, the infected tissue of the respiratory tract (including trachea, bronchi, bronchiole and / or alveoli) is contacted with a heated and humidified gas such as air or oxygen for at least 1 hour.

  In the method of the present invention, a heated and humidified gas can be conveniently applied to a subject by inhalation that can be performed via spontaneous or mechanical ventilation to inhibit viral replication in the respiratory tract. Be administered. Any type of device or function known in the art suitable for supplying a person with a hot moist gas (usually air or oxygen) at a controlled temperature can be used. These devices include invasive devices such as endotracheal tubes. However, it goes without saying that a non-invasive device is preferred. Particularly useful in the methods of the invention that inhibit viral replication in the respiratory tract are respiratory rewarming devices typically used for inhalation rewarming from hyperthermia. For example, Morrison et al., 1979 J. et al. Appl. Physiol. 1979, 46, 6, 1061, or RESQ Products Inc. of Sooke, British Columbia, Canada. See RES-Q-AIR non-invasive rewarming system by (www.hyperthermia-ca.com). Generally speaking, an inhalation rewarming device includes a water bath, a humidification unit and a heat exchanger, a temperature control and display unit, a gas suction port, and a heated and humidified gas outlet. The subject can inhale gas through a mouth-nose pad or a facial mask. The flow rate may vary depending on the subject and other conditions. In a preferred embodiment, the subject inhales a humidified gas heated at a flow rate of 10 L / min to 80 L / min, preferably 15 L / min to 50 L / min, more preferably 20 L / min to 35 L / min. .

In one embodiment, the subject inhales heated and humidified gas at an increased ventilation. The ventilation volume of the subject at rest is typically about 10 L / min, and may be slower. At this ventilation, tissue heating, especially in deep (lung) tissue, may be insufficient to reach the desired temperature. In a preferred embodiment, the subject inhales a heated and humidified gas while hyperventilating. Hyperventilation is a condition where an increased amount of air flows into the alveoli. Inhalation of heated and humidified gas in a hyperventilated situation in the method of the present invention maximizes heat exchange by breathing. Heat can penetrate to deeply located (lung) tissue. The subject is required to spontaneously hyperventilate even if it may cause dizziness. Alternatively, a controlled hyperventilation situation may be created in the subject (eg, with CO ₂ assistance). For example, the device may include a recirculation loop that allows the exhaled gas to be recirculated through the heat exchanger. In a preferred embodiment of the invention, the subject first heats the upper respiratory tube by inhaling a heated and humidified gas to which no CO ₂ has been added. After some time, for example after 10-30 minutes, CO ₂ is added to the gas (eg, via recirculation of exhaled air or from a gas cylinder) to assist in subject hyperventilation Heat transfer from the gas to the (preheated) tissue can be maximized. The sucked CO ₂ pressure (pCO ₂ ) is preferably 5 kPa to 7.5 kPa, and more preferably 6 kPa to 7 kPa. The ventilation amount of the subject may be increased by causing the subject to exercise. Exercise equipment such as home training bicycles or roller bands can help the subject to increase ventilation.

In a preferred embodiment, the method of the invention comprises a heated gas that is 100% saturated with water or a heated gas that has an H ₂ O pressure (pH ₂ O) of at least 6.5 kPa, more preferably at least 7.5 kPa. Includes thermotherapy of respiratory tract using This maximizes the heat capacity of the gas, delivers heat to the tissue via condensation and minimizes heat loss due to evaporation. The gas saturated with water may be in the form of a spray or vapor. A spray is distinguished from a gas containing water vapor by the presence of distinct liquid particles of small diameter, typically 1 to 5 microns in diameter. Preferably, a gas containing water vapor is used in the method of the present invention. In order to maximize the effect of the inhaled heated gas, it is preferable to minimize the subject inhaling cold (ambient) air following the thermal inhalation procedure. Preferably, the heated and humidified air is inhaled before going to bed.

  In one embodiment, cold sores (herpes simplex) is produced using a method of the present invention using a gas that is heated and humidified from an infected tissue (ie, lip / mouth area) of a subject in need of treatment. Can be treated by heating to a temperature that is at least 2 ° C. above the normal temperature of for at least one hour. This can be easily achieved with an inhalation rewarming device as described herein equipped with a facial mask that is large enough to cover the infected area.

  In yet another aspect of the present invention, there is provided the use of a device of the present invention as described herein for supplying a heated and humidified gas to a tissue or body part to inhibit viral replication in vivo. provide. This device is capable of generating a humidified gas (eg air) at a temperature of 37 ° C. to 50 ° C. and a relative humidity of up to 100% depending on the virus treatment being performed. More preferably, the apparatus supplies a heated gas containing water vapor.

In a preferred embodiment, the respiratory tract epithelial tissue of a subject suffering from a viral infection is heated to a temperature that is at least 2 ° C. above the normal physiological temperature of the tissue for a period of at least 1 hour. The apparatus used is provided. Preferably, the device equipped with an air or gas recirculation loop allows hyperventilation to occur, thereby maximizing heat exchange between the heated gas and the epithelial tissue of the respiratory tract. Use. Alternatively, the device of the present invention allows for controlled addition of CO ₂ to inhaled air or a gas such as O _{2 in operation} , thus increasing the inhaled gas. It is equipped with a simple CO ₂ cylinder that reacts to the amount of CO ₂ and causes hyperventilation in the subject.

  Certain embodiments of the present invention provide a method of inhibiting herpesvirus replication in a mammalian tissue, such as a human infected with a herpesvirus. According to the teachings of the present invention, viral replication in diseased tissue can be inhibited by heating such tissue to a temperature that is at least 2 ° C. above the normal temperature (eg, 39 ° C. to 42 ° C.) for at least 1 hour. . This is easily accomplished by (locally) heating the affected tissue, for example by the use of a heated pad or bandage placed in contact with or in close proximity to the affected tissue. Preferably, these pads or bandages comprise a gel material that is readily formed into a shape capable of intimate contact with the virus affected area. The adhesive bandage containing such a gel pad or gel can be maintained at an appropriate temperature (for example, 40 ° C. to 43 ° C.) with a thermostat-controlled heater. The heater conditioned with this thermostat can be incorporated into the gel pad or bandage. Alternatively, an exothermic patch such as a ThermoCare air activated heat wrap (sold by Procter & Gamble) may be used.

  In yet another aspect of the invention, the subject's virus-infected tissue is heated such as a pad that heats the tissue to a temperature that is at least 2 ° C. above the normal physiological temperature of the tissue for a period of at least 1 hour. Provides usage of the elements. Preferably, a device equipped with a thermostat-controlled heater that can be incorporated into the pad is used.

  Antiviral fever treatment as described herein is preferably initiated as early as possible following the initial signs and symptoms of viral infection. If virus replication is suppressed at an early stage following infection, the probability of the virus being successfully eradicated by the body's immune system increases. In the case of respiratory infections, nasal inflammation or tingling throat is typically the first sign of infection, followed by sneezing and a watery runny nose within a few hours. Symptoms of other viral (eg, herpes) infections include skin irritation, itching, burning, or redness at the site of infection.

  Furthermore, antiviral fever treatment as described herein is preferably initiated as soon as possible after exposure to the infection by the virus is known or suspected. If virus replication is suppressed at an early stage following infection, the probability of the virus being successfully eradicated by the body's immune system increases, and infection does not progress from the asymptomatic stage. Thus, the treatment can be applied as a prophylactic treatment.

  The concept of the present invention is based on the inhibition of viral replication through increased RNAi over time in tissues, and the ability to silence genes through RNAi is 6 hours after the heat treatment body has stopped. It usually means staying in an elevated state for less than 96 hours (compared to the pre-treatment situation). Thus, for the treatment of chronic viral infections, the treatment is preferably repeated at regular intervals.

  In certain embodiments of the present invention, a method of treating cervical dysplasia is provided, the method using a heating device of the present invention as described herein to heat the cervical area. Steps to add. Cervical dysplasia is abnormal cell growth in the cervix. Cell growth is considered abnormal when some cervical cells appear to be undeveloped compared to neighboring cells of normal appearance. Undeveloped cervical cells also divide faster than expected and the nucleus of the cell exhibits a specific form of microscopic change. Depending on the nomenclature used for different dysplastic conditions, cervical dysplasia is also referred to as squamous intraepithelial lesion (SIL) or cervical intraepithelial neoplasia (CIN). Cervical dysplasia is a serious health problem because it can progress to cervical cancer. Cervical dysplasia has also been implicated in a very common virus called human papillomavirus (HPV). There are over 70 HPV strains, of which more than a third can be sexually transmitted. Some strains can cause warts, including genital warts, and others can cause cancer. Specifically, HPV-16 and HPV-18 are involved in cervical dysplasia, and virus-infected cells may slowly progress to malignant tumors under the load of episomal expression of HPV DNA (Melsheimer). Et al., Clin. Cancer Res., 2004, 10, 3059-3063). Cervical dysplasia can be diagnosed with standard papill smears and, if diagnosed early, can be treated to prevent cervical dysplasia from becoming cancerous. A microscopic examination of a pape smear indicates that abnormal cervical cells are involved in the lower third of the specimen, and this condition is described as “mild” cervical dysplasia (low grade SIL or CIN1) To do. If abnormal cervical cells are found in the majority of the specimen, this condition is described as “moderate” or “severe” cervical dysplasia (high grade SIL, or CIN2 or CIN3) . Treatment of cervical dysplasia depends on the patient, depending on the location and size of the lesion and whether it is low or high grade. Known treatments include lesion destruction by cryotherapy or laser treatment, and removal of the lesion by looped electrocautery resection (LEEP) or conical test resection that removes a conical tissue piece from the cervical opening. Contains. The present invention now inhibits HPV replication in cervical cells by heating the affected area to a temperature at least 2 ° C. above its normal temperature (eg, 39 ° C. to 42 ° C.) for at least 1 hour. Provide a method. This method is readily accomplished by locally heating the affected area, for example by use of a heated probe conditioned with a thermostat or other methods known in the art. Stop progression to malignancy or possibly retrograde by treating the affected area of the cervix daily, or every other day or twice a week for 2 weeks, 3 weeks or longer To significantly reduce the load of HPV infection. It is particularly important to treat the cervix before reaching the malignant stage, preferably while in low grade SIL or CIN1. At these stages, cell growth is usually still dependent on the presence of the virus, but at the malignant stage, tumor cell growth can be independent of the virus. The heat treatment according to the present invention may be combined with known treatments for cervical dysplasia. For the treatment of cancer, including cervical cancer, local hyperthermia is known in the art (de Wit et al., Br. J. Cancer, 1999, 80, 9, 1387). ~ 1391). However, this anti-cancer treatment is based on the observation that tumor cells are relatively sensitive to heat-induced cell death, especially when combined with cytotoxic drugs or radiation. The purpose of anti-cancer hyperthermia is to apply a sufficiently high temperature (eg, greater than 42 ° C.) to promote tumor cell death. In contrast, the present invention involves the thermal treatment of non-tumor cells prior to becoming malignant and inhibits viral replication, potentially inhibiting even if it cannot actually be avoided to reach the malignant stage. Strengthen the RNAi mechanism in the cell. Furthermore, although temperatures above 42 ° C are typically required to induce (tumor) cell death, preferred temperatures for inhibiting viral replication are 39 ° C to 42 ° C, more preferably 39 ° C to 40 ° C. ° C. Of course, those skilled in the art will appreciate that excessively high temperatures that can induce cell death should be avoided in the application of the present invention.

  The concept of the present invention is based on the inhibition of viral replication through enhancing RNAi, ie, the antiviral defense mechanism of infected host cells that deceive viral gene silencing. However, the application of in vivo heat treatment according to the present invention is not necessarily limited to enhancing antiviral gene silencing. This heat treatment is also advantageously used when RNAi-mediated silencing of an endogenous or exogenous gene of interest is desired upon introduction of a dsRNA homologous to the gene into a host cell. RNAi sequences can be extremely selective because RNAi sequences seek out and destroy targets without affecting other genes. In the medical community, it is widely considered that there are a myriad of clinical applications of RNAi. In other words, any gene (disease gene) whose expression contributes to a disease, from a viral gene to an oncogene, to a gene that affects heart disease, Alzheimer's disease, diabetes, and many more diseases. , A potential target. In order to enhance the RNAi effect of dsRNA introduced into cells “in situ” (either by injection, genetic engineering techniques and / or using viral or non-viral transporters) The thermal treatment according to the invention can also be envisaged.

  Here, the present invention provides a method for enhancing RNAi-mediated gene silencing in a tissue in vivo, which stably increases RNAi in the tissue by applying heat to the tissue. Includes steps. In a preferred embodiment, the tissue is at least 2 ° C above the normal physiological temperature of the tissue for 1 hour to 4 hours, preferably 1 hour to 2 hours, more preferably 1 hour to 1.5 hours. Heated for the duration of. The methods of the present invention are advantageously used to enhance in vivo silencing of disease genes.

According to the present invention, there is also provided an apparatus for inhibiting virus replication in a subject's respiratory tract tissue,
A gas inlet for receiving gas in the device;
A heating device for heating the gas;
A humidifier for humidifying the gas;
Gas guiding means for guiding the gas from a gas inlet to a heating device and a humidifying device and then to a gas outlet for releasing the heated and humidified gas;
A ventilation enhancement device that increases the ventilation of the subject;
The subject is connected to the heating device, and when used, the subject is heated so that at least a part of the tissue is heated to a temperature that is at least 2 ° C. higher than the physiological temperature during normal heating of the tissue and not higher than 9 ° C. A temperature controller that controls the temperature of the respiratory tract tissue;
Is included.

As described above, the ventilation enhancement device may include CO ₂ addition means for introducing CO ₂ into the gas before the gas is released from the gas outlet, or exercise equipment used by the subject. The apparatus may further include an oxygen addition device that introduces oxygen into the gas before the gas is released from the gas outlet. The gas outlet may be provided with a mouth-nose pad or a face mask.

According to the present invention, there is further provided an apparatus for inhibiting viral replication in a subject's rectal tract, female genital tract, cervix or vaginal tissue, the apparatus comprising:
An insertion element that includes an outer wall and is inserted into the subject's rectal tube, female reproductive tract, cervix or vagina;
A second heating device for heating the tissue surrounding the insertion element when in use;
Connected to the second heating device, and in use, at least a portion of the tissue is heated to a temperature that is at least 2 ° C to 9 ° C above the normal physiological temperature of the tissue. A second temperature controller for controlling the temperature;
Is included.

The present invention can also be used to treat the outer limbs of the body, and according to yet another aspect of the present invention there is provided an apparatus for inhibiting viral replication in the tissues of the subject's outer limbs. This device is
A receiving element for containing the subject's outer limb that includes an inner wall and at least partially surrounds the subject's outer limb when in use;
A third heating device for heating the tissue surrounded by the containing element;
Connected to the third heating device, and when used, at least a portion of the tissue is heated to a temperature that is at least 2 ° C. to 9 ° C. higher than the physiological temperature during normal heating of the tissue. A third temperature controller for controlling the temperature of the tissue of the outer limb;
Is included.

  In the various devices described above, the second heating device and the third heating device may be similar in form and operation, and what is described for one applies to the other. Similarly, other members such as the second temperature controller and the third temperature controller may be equivalent. The heating device may include a liquid heating unit that heats the liquid, and a liquid guide unit that guides the liquid between the liquid heating unit and the insertion element or the storage element. The insertion element and the containment element can each comprise a tube through which the liquid warmed to heat the outer or inner wall, respectively, is pumped by the pump means.

  The outer wall of the insertion element and the inner wall of the receiving element may comprise an inflatable or flexible material, which material is preferably elastic. Such expandable or flexible materials can be expanded so that substantially complete contact with the surface of the tissue to be treated by the method of the present invention is achieved. Of course, those skilled in the art will appreciate that the expansion of the flexible material can be accomplished by adjusting the flow of liquid and / or gas with a pump.

  The outer and inner walls may also include protrusions that extend toward the tissue. The insertion element and the containment element may be provided with a vibrating device that vibrates these elements as improving thermal contact with the tissue.

  The temperature controller of each embodiment of the device may further include a time controller that controls the time to heat the tissue over an effective time depending on the treatment being performed.

  Several aspects of the invention are described in detail below with reference to the accompanying drawings.

FIG. 1 shows an embodiment of a device that inhibits virus replication in the tissue of the subject's respiratory tract, which includes a gas inlet 2 for receiving gas. In the embodiment of FIG. 1, air is received from the environment by the gas inlet 2, but the gas inlet 2 is connected to a gas container containing a specific gas (preferably oxygen) or a specific mixture of gases. Is also possible. The airflow flowing into the gas inlet 2 is indicated by a side arrow, and the subsequent flow of air flowing through the apparatus is also shown. The received air is guided by the gas guiding means 5 to the heating device 3 for heating the air. The heating device 3 is connected to a humidifying device 4 that humidifies air by a gas guiding means 5. Between the gas inlet 2 and the heating device 3, the gas guiding means 5 is connected to a ventilation enhancement device 6 including a CO ₂ gas unit 8. The CO ₂ gas unit 8 can be used to add CO ₂ to the air that is sent to the subject so that the subject's ventilation is increased during use. Instead of changing the gas component to increase the ventilation, the ventilation enhancement device 6 may include exercise equipment for the subject used to increase the respiration.

  The heating device 3 heats the gas before it reaches the humidifier to ensure that proper moisture can be achieved in the air passing through the humidifier. The air entering the humidifier may be at the temperature required for delivery to the tissue or at a higher temperature. The gas guiding means 5 for the air leaving the heating device and / or the humidification device may be configured to keep the gas at the required temperature or to dissipate heat to reach the desired temperature. May be possible. The gas guiding means extends to the gas outlet 11. The airflow leaving the gas outlet 11 is indicated by an arrow.

  The apparatus further includes a temperature controller 9 connected to the heating device 3 for controlling the heating device 3. The temperature controller 9 includes a time controller 10 that controls the time for which the temperature controller 9 starts the heating device 3. The temperature controller may also be connected to the last part of the gas guiding means 5 before the outlet 11, so that the temperature of the gas before the gas reaches the subject can be monitored. This can be particularly important to ensure that the gas is sufficiently cooled when supplied to the humidifier 4 at a temperature higher than the temperature at which the gas is to be supplied to the subject.

The gas outlet 11 includes a face mask 13 having an elastic retaining band 12 so that the gas outlet 11 can be kept at a predetermined position on the face of the subject. In use, the subject breathes in a heated and humidified mixture of air and CO ₂ such that the temperature of the respiratory tract tissue rises to a specific temperature over a specific time. In this way, virus replication in the respiratory tract tissue of the subject is inhibited.

  FIG. 2 shows a second embodiment of a device that inhibits viral replication in the subject's rectal tract or in the tissues of the female genital tract, including the cervix or vagina. The device includes an insertion element 21 that, when used, is inserted into the subject's rectal or female genital tract. The insertion element 21 includes an outer wall 22 that is flexible and elastic. Inside the outer wall 22 of the insertion element 21, there is a hollow core 30 having a feed pipe 25 formed therein. In use, liquid flows through this tube 25 and then exits through the space between the hollow core 30 and the outer wall 22. The flexible outer wall 22 allows the shape of the insertion element 21 to be adjusted during use to match the shape of the surrounding tissue. Since the outer wall is allowed to expand due to the elastic nature of the outer wall, the dimensions of the outer wall can also be adjusted. The outer wall can also have protrusions (not shown) that can provide a wider contact surface between the insertion element 21 and the surrounding tissue without extending the insertion element 21.

  The embodiment shown in FIG. 2 further includes a second heating device 23. The second heating device 23 includes a liquid heating means 26 and a pump means 27 that sends the heated liquid through the liquid guide means 28 into the insertion element 21. The second heating device 23 is connected to the insertion element 21 by liquid guiding means 28 so that heated liquid can flow into and out of the insertion element 21. The part of the figure including the entire insertion element 21 is shown in cross-section. The arrows in the figure indicate the flow of liquid in the apparatus. The liquid guiding means 28 transfers the heated liquid from the second heating device 23 to the feed pipe 25. The heated liquid then flows through the insertion element 21 and returns to the second heating device 23 through the return part of the liquid guiding means 28. Inside the pipe 25, liquid flow control means (not shown) are configured to ensure complete circulation of the liquid through the pipe 25.

  The apparatus of the second embodiment also includes a second temperature controller 24 that is connected to the second heating device 23 and controls the second heating device 23. The second temperature controller 24 includes a second time controller 29 that controls the time during which the second temperature controller 24 activates the second heating device 23.

  In use, the insertion element 21 is placed in the subject's rectal or female genital tract. The heated liquid flow through the insertion element 21 heats the outer wall 22 to the desired temperature. In this way, the insertion element 21 heats the surrounding surrounding tissue for a specific time so that virus replication in the tissue is inhibited.

  The device may also include a vibration device that vibrates the insertion element 21. In this way, a further sufficient thermal contact between the insertion element 21 and the surrounding tissue is achieved. FIG. 3 shows a third embodiment of an apparatus for inhibiting virus replication in tissues of the outer limbs of a subject's body. This device includes a housing element 41 for housing the outer limb of a subject. The outer limb of the body part may be the hand, foot, scrotum and / or penis. In use, the outer limb of the body part is housed in a housing element 41 that at least partially surrounds the outer limb. The containment element 41 includes an outer sleeve 51 that defines an opening 50 that allows access to the interior. A flexible and elastic inner wall 42 is arranged inside the outer sleeve 51 so as to form a second feeding tube 45 through which liquid can flow. Inside the second delivery tube 45, liquid flow control means (not shown) are configured to ensure a complete circulation of the liquid through the containment element 41 and therefore around the outer limb. .

  In use, the flexible inner wall 42 is adjusted to the shape or contour of the contained body outer limb, and the inner wall 42 is flexible so that it can be inflated to reduce the relatively small outer limb. The size of the inner wall can be adjusted to accommodate. The inner wall may include inward projections that allow sufficient grasping or sufficient contact between the containment element 41 and the tissue of the contained body outer limb.

  The apparatus of this third embodiment further includes a mechanism for supplying the same heated liquid as described with respect to FIG. Similar reference numbers are used to indicate similar elements. The heating device 23 pumps the heated liquid to and from the storage element 41 via the liquid guiding means 28. The arrow in the part of the figure shown in cross section indicates the flow of liquid.

  When in use, the outer limb of the subject is placed in the housing element 41 through the opening 50. When the heating device pumps the heated liquid through the second pipe 45 of the storage element 41, the inner wall 42 of the storage element 41 generates heat. In this way, the containment element 41 heats the tissue of the enclosed outer limb for a specified time so that virus replication in the tissue is inhibited. The device can also include a vibrating device that vibrates the containment element 41 as improving thermal contact between the containment element 41 and the surrounding tissue.

  The liquid used in the second and third embodiments may be of any suitable type having suitable viscosity, heat capacity and toxicity. Water or light oil is suitable.

  Thermal contact can be further improved by providing a heat transfer medium between the tissue and the contacting wall of the device (eg, the outer wall of the insertion element or the inner wall of the containment element). By improving the thermal contact between the insertion or containment element and the adjacent tissue, the efficiency of the present invention can be increased. This heat transfer medium can also improve comfort during use and may be a gel, saliva, water, lubricant, and the like.

1 is a schematic diagram of an embodiment of an apparatus for inhibiting virus replication in a respiratory tract tissue of a subject. FIG. FIG. 4 is a schematic diagram partially showing in section a device of a second embodiment that inhibits viral replication in the subject's rectal tube or in the female reproductive tract tissue such as the cervix or vagina. It is a schematic diagram which shows partially the apparatus of 3rd Embodiment which inhibits the replication of the virus in the structure | tissue of the test subject's outer limb in a cross section.

Claims (29)

  A method of treating a viral disease in a mammal in need of treatment of a viral disease, wherein cells of the mammalian virus-infected tissue are at least 2 more than the heating temperature of the physiological body temperature during normal heating of the tissue by a heating device. A method comprising the step of heating to a heating temperature higher by ℃.   The method according to claim 1, wherein the heating temperature is in a range of 2 ° C. to 13 ° C. higher than the heating temperature of the physiological body temperature during the normal heating of the tissue.   The virus-infected tissues include lung epithelial cells, nasal passages, trachea, bronchioles, alveoli, and feet, hands, skin, penis and scrotum, vulva, uterus, cervix, clitoris, vulva (large labia) 3. A method according to claim 1 or claim 2 selected from body parts such as genitals and parts of genitals such as (and / or labia), perineum and surrounding infected skin.   A method for inhibiting virus replication in a virus-infected cell of a mammalian tissue in a subject in vivo, wherein the virus-infected tissue is at least 2 ° C to 9 ° C above the physiological temperature during normal heating of the tissue Heat to a temperature, preferably at least 2 ° C. to about 5 ° C., for at least 1 hour, preferably 1 hour to 4 hours, more preferably 1 hour to 2 hours, most preferably 1 hour to 1.5 hours. A method with steps.   A method of inhibiting viral replication in vivo in a virus-infected tissue of a subject mammal, wherein said tissue is at least 6 ° C. above the normal physiological temperature of said tissue but not above 9 ° C. A method comprising heating to a temperature that does not exceed 45 minutes, preferably from about 10 minutes to about 45 minutes, so that cell death of the tissue is not induced.   6. The method according to any one of claims 1 to 5, wherein the mammal is a human.   The method of claim 6, wherein the temperature of heating ranges from 39 ° C. to 42 ° C. over a period of at least 60 minutes.   The process according to claim 6, wherein the temperature of the heating is applied over a period of from 43C to 46C for less than 60 minutes, preferably from about 10 minutes to 45 minutes. The heat to the cell is supplied in the form of a heated and humidified gas, optionally in the form of a heated element, with a relative humidity of at least 70% and optionally CO _2. 9. The method according to any one of items 8. A device that inhibits virus replication in the tissue of the respiratory tract of a subject,
A gas inlet (2) for receiving gas in the device;
A heating device (3) for heating the gas;
A humidifier (4) for humidifying the gas;
Gas guiding means for guiding the gas from the gas inlet (2) to the heating device (3) and the humidifying device (4) and then to the gas outlet (11) for releasing the heated and humidified gas. 5) and
In order to increase the ventilation amount of the subject, the ventilation enhancement device (6) includes CO ₂ addition means (8) for introducing CO ₂ into the gas before the gas is released from the gas outlet (11). When,
It is connected to the heating device (3) so that at the time of use, at least a part of the tissue is heated to a temperature that exceeds the physiological temperature of the tissue during normal heating by at least 2 ° C. and does not exceed 13 ° C. A temperature controller (9) for controlling the temperature of the tissue of the respiratory tract of the subject;
With a device. A device that inhibits viral replication in the tissue of the subject's respiratory tract,
A gas inlet (2) for receiving gas in the device;
A heating device (3) for heating the gas;
A humidifier (4) for humidifying the gas;
Gas guiding means for guiding the gas from the gas inlet (2) to the heating device (3) and the humidifying device (4) and then to the gas outlet (11) for releasing the heated and humidified gas. 5) and
A ventilation enhancement device (6) including exercise equipment used by the subject;
It is connected to the heating device (3) so that at the time of use, at least a part of the tissue is heated to a temperature that exceeds the physiological temperature of the tissue during normal heating by at least 2 ° C. and does not exceed 13 ° C. A temperature controller (9) for controlling the temperature of the tissue of the respiratory tract of the subject;
With a device.   The apparatus according to claim 10 or 11, further comprising an oxygen addition device for introducing oxygen into the gas before the gas is released from the gas outlet (11).   13. Apparatus according to any one of claims 10 to 12, wherein the gas outlet (11) comprises a mouth-nose pad or a face mask (13).   14. A device according to any one of claims 10 to 13, wherein the temperature controller (9) comprises a time controller (10) for controlling the time to heat the tissue. A device that inhibits viral replication in a subject's rectal tube, female reproductive tract, cervix or vaginal tissue,
An insertion element (21) comprising an outer wall (22) and inserted into the subject's rectal tube, female reproductive tract, cervix or vagina;
A second heating device (23) for heating the tissue surrounding the insertion element (21) in use;
Connected to the second heating device (23), so that at the time of use, at least a part of the tissue is heated to a temperature that is at least 2 ° C to 13 ° C above the physiological temperature during normal heating of the tissue. A second temperature controller (24) for controlling the temperature of the surrounding tissue;
With a device.   The second heating device (23) includes a liquid heating means (26) for heating a liquid, and a liquid guide means (26) for guiding the liquid between the liquid heating means (26) and the insertion element (21). 28) and the insertion element (21) comprises a tube (25) through which the liquid is pumped by pump means (27) to heat the outer wall (22). The apparatus of claim 15.   17. Device according to claim 15 or 16, wherein the outer wall (22) comprises an inflatable and / or flexible material, preferably elastic.   18. A device according to any one of claims 15 to 17, wherein the outer wall (22) comprises a protrusion.   19. A device according to any one of claims 15 to 18, comprising a vibration device for vibrating the insertion element (21).   20. The second temperature controller (24) according to any one of claims 15 to 19, comprising a second time controller (29) for controlling the time to heat the tissue. apparatus. A device that inhibits virus replication in the tissues of the outer limb of a subject,
An accommodating element (41) for containing the outer limb of the subject, including an inner wall (42) and at least partially surrounding the outer limb of the subject when in use;
A third heating device (43) for heating the tissue surrounded by the containment element (41);
Connected to the third heating device (43) so that, when in use, at least a portion of the tissue is heated to a temperature that is at least 2 ° C to 13 ° C above the normal physiological temperature of the tissue. A third temperature controller (44) for controlling the temperature of the tissue of the outer limb of the subject;
With a device.   The third heating device (43) guides the liquid between the third heating device (43) and the storage element (41) by second liquid heating means (46) for heating the liquid. Second liquid guiding means (48), wherein the receiving element is in use when the liquid is pumped by the second pump means (47) for heating the inner wall (42). The apparatus of claim 21, comprising a second tube (45) through.   23. A device according to claim 21 or claim 22, wherein the inner wall (42) comprises an inflatable and / or flexible material, preferably elastic.   24. Apparatus according to any one of claims 21 to 23, wherein the inner wall (42) includes a second protrusion.   25. Device according to any one of claims 21 to 24, comprising a second vibration device for vibrating the receiving element (41).   26. The third temperature controller (44) according to any one of claims 21 to 25, wherein the third temperature controller (44) comprises a third time controller (49) for controlling the time to heat the tissue. apparatus.   27. Use of the device according to any one of claims 10 to 26, wherein the virus-infected tissue or body part is heated to inhibit viral replication in vivo.   28. The usage according to claim 27, wherein the heat is applied as a humidified gas and is supplied at a temperature of 37 [deg.] C to 50 [deg.] C and a relative humidity of up to 100%.   28. The method of claim 27, wherein the heat is applied to a virus-infected tissue or body part by a heating element such as a heated pad or an elongated warmed member.

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