CN103687599A - The use of chloroquine, chlorpromazine, derivatives thereof, or mixtures thereof in preparing medications for treating and/or preventing pulmonary infection and injury - Google Patents
The use of chloroquine, chlorpromazine, derivatives thereof, or mixtures thereof in preparing medications for treating and/or preventing pulmonary infection and injury Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
Abstract
The present invention relates to the use of chloroquine for the treatment and chlorpromazine for the prevention of pulmonary infection and injury. In particularly, the present invention relates to the use of chloroquine, chlorpromazine, derivatives thereof, mixtures thereof, or medicinal compositions containing the same for the preparation of medications for treating and/or preventing pulmonary infection and/or injury in mammals, including humans, caused by influenza viruses.
Description
Chloroquine is treated and chlorpromazine prevents the purposes technical field of Lung infection and damage
The present invention relates to the purposes of chloroquine or chlorpromazine or derivatives thereof or their mixture in mammal caused by preparing treatment and/or flu-prevention virus includes the Lung infection of people and/or the medicine of injury of lungs.Background technology
Influenza virus, abbreviation influenza virus, point first, second, the third three types are spherical in shape or thread, and the 120nm of diameter 80, three types virus has similar biochemistry and biological property, is a kind of RNA virus for causing the mankind and animal to suffer from influenza.On taxology, influenza virus belongs to Orthomyxoviridae family, and it can cause acute upper respiratory infection, and rapidly be propagated by air, often have and be periodically very popular all over the world.Influenza virus can cause more serious symptom, such as pneumonia or cardiopulmonary exhaustion in the patient of the weaker old man of immunity and child and some immune disorders.
Influenza A virus is common influenza virus, is easiest to morph, it is different according to H with N antigens, many hypotypes are divided into again, H can be divided into 15 hypotypes（H1 H15), N has 9 hypotypes（N1〜N9).Wherein only H1N1, H2N2, H3N2 main infection mankind, the natural reservoir (of bird flu viruses) of other many hypotypes is a variety of birds and animal.The hypotype of influenza A virus is then known as avian influenza virus (Avian Influenza Virus, AIV), wherein being H5, H7 and H9 hypotype strain to birds harm maximum.
Widely, with birds carrier at most, wild fowl is generally band poison or subclinical infection to nature to avian influenza virus host range, and poultry is the most susceptible with turkey, and chicken takes second place, and duck, goose can also infect.Generally, avian influenza virus will not infect the animal beyond birds and pig.But 18 H5N1 human avian influenza cases of infection of generation are reported in Hong Kong in 1997 first, wherein 6 death, cause global extensive concern.After 1997, the event of avian flu virus infection people successively there occurs several times again in the world.With highly pathogenic H5N1, H7N7, H9N2, etc. avian influenza virus, once morphing and the transmission capacity with person to person, human world bird flu can be caused popular.The infection sources of human avian influenza is mainly the chicken for having infected avian influenza virus, duck, goose, particularly chicken.Route of transmission is mainly contact transmission or air borne.
So far, number of the infected is most in global bird flu patient, and case fatality rate highest is H5N1
Type bird flu, the death rate is up to 60%.People infection H5N1 type avian influenza virus after clinical characters be：Incubation period is longer, most patients are with hyperpyrexia onset, with cold like symptoms and lower respiratory tract symptom, sometimes upper airway symptoms are had, the conjunctivitis as caused by H7 type influenza viruses seldom occur, diarrhoea, vomiting, stomachache, costalgia, bleeding gums, nosebleed occurs in some patientss early stage, compared with common cold, watery diarrhea is more common, as infection time extends, and respiratory distress, the explosion sound being short of breath during with air-breathing are common.How much indefinite amount of expectoration is, is sometimes courage and uprightness.There is clinical pneumonia in nearly all patient；X lines, which change, includes diffusivity, multiple or oozing out of being dispersed in；Tissue space is oozed out；Partial fusion or leaflet fusion are with air bronchogram.The median time generally occurred within there are some researches show the exception of radiological examination 7 d (3 17d) after heating.
Clinical and pathological examination points out patient with severe symptoms's lesion main in respiratory system.There is consolidation in the lung of the visible patient with severe symptoms of pathological examination, be often accompanied by bleeding, ooze out, the pathological change such as abscess.Visible oar fluidity or cellulosic ooze out in alveolar space, are formed with different degrees of hyaline membrane, point out have diffused lung injury.It is now recognized that people's infection H5N1 type bird flu patient with severe symptoms's lung injury basic lesions are similar with the lung basic lesion of other kinds of influenza, SARS and H1N1 influenza virus, it is the diffusivity lung injury that weight is not waited.
Have yet so far and be directed to the effective medicine of H5N1 type avian influenza virus, and because the aberration rate of influenza virus is high, drug resistance is also being raised, therefore there are still the demand of the treatment of influenza medicine to new type.
Chloroquine（Chloroquine) it is mainly used in treating malaria acute attack, malaria control symptom.Recurrence can not be prevented, but it is more lasting because acting on, therefore recurrence can be postponed, prevention and the blocking propagation of malaria can not be made.There is radical cure effect to pernicious malaria, it may also be used for treatment hepatic amebiasis, clonorchiasis, paragonimiasis, CTD etc..It is another to can be used for treatment light sensitivity illness, as day expects Erythema.The pharmacological action of chloroquine is：Chloroquine acts on erythrocytic stage schizont, and through 48 ~ 72 hours, schizont was killed in blood.Acted on through chloroquine, the karyorrhexis of plasmodium, vacuole, malarial pigment lumped occurs in cell oar.
Chlorpromazine（Chlorpromazine) application is generally its phosphate, is white or creamy white crystals powder；Have micro- smelly, taste is extremely bitter；Have and draw moist；Meet light gradient color；The aqueous solution reacts acid.Chlorpromazine pharmacological action be central dopaminergic receptor blocking agent, told with calmness, antipsychotic, town, reduce body temperature and basic metabolism, alpha-adrenergic receptor and m- cholinergics by
The effects such as body blocking, antihistaminicum, influence endocrine, are clinically used for controlling the symptom such as schizophrenia or the restless, nervous of other mental diseases, illusion, vain hope；Treat and vomitted caused by a variety of causes；Also it is used for hypothermic anesthesia and artificial hibernation；Shared with antalgesic, the severe pain for the treatment of cancer end-stage patients.
Chloroquine and chlorpromazine and its derivative respectively or are used in combination for treating and/or flu-prevention has not been reported at present.The content of the invention
Therefore, the technical scheme is that the purposes of chloroquine or chlorpromazine or derivatives thereof or their mixture in mammal caused by preparing treatment and/or flu-prevention virus includes the Lung infection of people and/or the medicine of injury of lungs.
Purposes of the technical scheme further to the pharmaceutical composition comprising chloroquine or chlorpromazine or their derivative or their mixture in mammal caused by preparing treatment and/or flu-prevention virus includes the Lung infection of people and/or the medicine of injury of lungs.
In one embodiment of the invention, the derivative of the chloroquine is selected from hydroxychloroquine, hydroxychloroquine sulfate, two chloroquine phosphoric acid；The derivative of the chlorpromazine is selected from acetylpromazinimaleas, perphenazine, triperazine.
In another embodiment of the present invention, the influenza virus is influenza A virus, preferably A type Hl, H3, H5, H7 or H9 hypotypes strain, more preferably A type H5 hypotypes strain, more preferably A type H5N1 influenza viruses, most preferably A type H5N1 influenza virus As/Jilin/9/2004 (H5N1) strain.
In another embodiment of the present invention, chloroquine of the described pharmaceutical composition comprising therapeutically effective amount or chlorpromazine or derivatives thereof or their mixture, and one or more pharmaceutically acceptable carriers, the carrier includes but is not limited to diluent, excipient, filler, adhesive, wetting agent, disintegrant, surfactant, absorption carrier.
In another embodiment of the present invention, described pharmaceutical composition can also play the active constituents of medicine of the treatment effective dose of synergy comprising one or more and the chloroquine or chlorpromazine or derivatives thereof or their mixture.
In another embodiment of the present invention, described pharmaceutical composition can be made into any pharmaceutically acceptable formulation, and the formulation includes but is not limited to injection, spray, nasal drop, inhalant or oral agents.
Include the method for the Lung infection and/or injury of lungs of people the invention further relates to mammal caused by a kind for the treatment of and/or flu-prevention virus, it includes giving chloroquine or chlorpromazine of the bacterium of influenza virus infection or derivatives thereof or their mixture.
Chloroquine or chlorpromazine or derivatives thereof or their mixture of the invention of further disclosing includes the Lung infection and/or injury of lungs of people for mammal caused by treatment and/or flu-prevention virus.
In the present invention, the chloroquine, chlorpromazine and its derivative, can be used alone or in combination includes the Lung infection and/or injury of lungs of people for mammal caused by influenza virus.
The present invention utilizes H5N1 types avian influenza virus attack mouse to prove that chloroquine or chlorpromazine play a significant role during avian influenza virus A/Jilin/9/2005 (H5N1) strain infection causes the damage of chmice acute pathologic, death, and the intervention for chloroquine or chlorpromazine plays a significant role in the damage caused by prevention avian influenza virus A/Jilin/9/2005 (H5N1) strain infection.Therefore, the serious consequence caused by H5N1 type avian flu virus infections can be prevented or slow down to the present invention by demonstrating chloroquine or chlorpromazine for the first time.
Simultaneously, those skilled in the art know, when confirming that chloroquine or chlorpromazine play important prevention and/or therapeutic action during pathology damage, death etc. caused by avian flu virus infection, its related derivatives or their mixture can also play same or similar effect.Those skilled in the art know, and the atom or atomic group that derivative refers in parent compound molecule are replaced formed compound by other atoms or atomic group.
Similarly, the pharmaceutical composition comprising chloroquine of the present invention or chlorpromazine or derivatives thereof or their mixture can be used for preventing and/or treating H5N1 type avian influenza virus, particularly A/Jilin/9/2005 (H5N1) strain.The active component of described pharmaceutical composition is chloroquine or chlorpromazine or derivatives thereof or their mixture, while can also include other can playing the active component of synergy with described chloroquine or chlorpromazine or derivatives thereof or their mixture.Brief description of the drawings
Fig. 1：Wild type BALB/c mouse infects virus control or TCID5.For 106H5N1 type avian influenza virus, after infection 6 hours, 1 day, 2 days, 3 days, 4 days and 5 days respectively, solvent control or chloroquine is injected intraperitoneally.Record survival condition in its 8 days, the mortality curve of drafting.Every group of 10 mouse.
Fig. 2:Wild type BALB/c mouse infects virus control or TCID5.For 106H5N1 type avian influenza virus, before infection 2 hours and 0.5 hour respectively, twice intraperitoneal injection solvent pair
According to or chloroquine.Record survival condition in its 8 days, the mortality curve of drafting.Every group of 10 small Fig. 3：Wild type BALB/c mouse infects virus control or TCID5QFor 106H5N1 type avian influenza virus, before infection 2 hours and 0.5 hour respectively, twice intraperitoneal injection solvent control or chlorpromazine.Record survival condition in its 8 days, the mortality curve of drafting.Every group of 10 mouse.
Fig. 4:Wild type BALB/c mouse infects virus control or TCID5QFor 106H5N1 type avian influenza virus, after infection 6 hours, 1 day, 2 days, 3 days, 4 days and 5 days respectively, solvent control or chlorpromazine is injected intraperitoneally.Record survival condition in its 8 days, the mortality curve of drafting.Every group of 10 mouse.
Fig. 5：Wild type BALB/c mouse infects virus control or TCID5QFor 106H5N1 type avian influenza virus, after infection 6 hours, 1 day, 2 days, 3 days, 4 days and 5 days respectively, solvent control or chloroquine is injected intraperitoneally.After infection 4 days, mouse lung tissue is taken to carry out lung tissue wet-dry ratio detection figure.Every group of 4 mouse.
Fig. 6:Wild type BALB/c mouse infects virus control or TCID5QFor 106H5N1 type avian influenza virus, before infection 2 hours and 0.5 hour respectively, twice intraperitoneal injection solvent control or chloroquine.After infection 4 days, mouse lung tissue is taken to carry out lung tissue wet-dry ratio detection figure.Every group of 4 mouse.
Figure wild type BALB/c mouse infects virus control or TCID5QFor 106H5N1 type avian influenza virus, before infection 2 hours and 0.5 hour respectively, twice intraperitoneal injection solvent control or chlorpromazine.After infection 4 days, mouse lung tissue is taken to carry out lung tissue wet-dry ratio detection figure.Every group of 4 mouse.
Fig. 8:Wild type BALB/c mouse infects virus control or TCID5QFor 106H5N1 type avian influenza virus, after infection 6 hours, 1 day, 2 days, 3 days, 4 days and 5 days respectively, solvent control or chloroquine is injected intraperitoneally.After infection 4 days, mouse lung tissue is taken to carry out pathologic detection.Every group of 4 mouse.Wherein A is represented：PBS+ allantoic fluids are compareed；B is represented：Chloroquine（Treatment）+ allantoic fluid is compareed；C is represented：PBS+H5N1 avian influenza virus；D is represented：Chloroquine（Treatment）+ H5N1 avian influenza virus；E is represented：Pathologic section inflammatory cell counting statistics result.
Fig. 9:Wild type BALB/c mouse infects virus control or TCID5QFor 106H5N1 type avian influenza virus, before infection 2 hours and 0.5 hour respectively, twice intraperitoneal injection solvent pair
According to or chloroquine.After infection 4 days, mouse lung tissue is taken to carry out pathologic detection.Every group of 4 mouse.Wherein A is represented：PBS+ allantoic fluids are compareed；B is represented：Chloroquine（Treatment）+ allantoic fluid is compareed；C is represented：PBS+H5N1 avian influenza virus；D is represented：Chloroquine（Prevention）+ H5N1 avian influenza virus；E is represented：Pathologic section inflammatory cell counting statistics result.
Figure 10:Wild type BALB/c mouse infects virus control or TCID5QFor 106H5N1 type avian influenza virus, before infection 2 hours and 0.5 hour respectively, twice intraperitoneal injection solvent control or chlorpromazine.After infection 4 days, mouse lung tissue is taken to carry out pathologic detection.Every group of 4 mouse.Wherein A is represented：PBS+H5N1 avian influenza virus；B is represented：Chlorpromazine (prevention）+ H5N1 avian influenza virus.
Figure 11:Wild type BALB/c mouse infects virus control or TCID5QFor 106H5N1 type avian influenza virus, after infection 6 hours, 1 day, 2 days, 3 days, 4 days and 5 days respectively, solvent control or chlorpromazine is injected intraperitoneally.After infection 4 days, mouse lung tissue is taken to carry out pathologic detection.Every group of 4 mouse.Wherein A is represented：PBS+H5N1 avian influenza virus；B is represented：Chlorpromazine（Treatment）+ H5N1 avian influenza virus.
Figure 12:Wild type BALB/c mouse infects virus control or TCID5QFor 106H5N1 type avian influenza virus, after infection 6 hours, 1 day, 2 days, 3 days, 4 days and 5 days respectively, solvent control or chloroquine is injected intraperitoneally.0 hour after infection, mouse lung tissue is taken within 3 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours and 96 hours to be used for the detection of western blot.Every group of 4 mouse.
Figure 13:Wild type BALB/c mouse infects virus control or TCID5QFor 106H5N1 type avian influenza virus, after infection 6 hours, 1 day, 2 days, 3 days, 4 days and 5 days respectively, solvent control or chloroquine is injected intraperitoneally.0 hour after infection, mouse lung tissue is taken within 3 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours and 96 hours to be used to extract RNA and carry out the detection of Ml and M2 gene expression doses.Every group of 4 mouse.Wherein A is represented：H5N1 types avian influenza virus Ml gene expression doses in mouse lung tissue；B is represented：H5N1 types avian influenza virus M2 gene expression doses in mouse lung tissue.
Figure 14:Wild type BALB/c mouse infects virus control or TCID5QFor 106H5N1 type avian influenza virus, after infection 6 hours, 1 day, 2 days, 3 days, 4 days and 5 days respectively, solvent control or chloroquine is injected intraperitoneally.0 hour after infection, 3 hours, 6 hours, 12 hours, 24 hours, 36 hours, mouse lung tissue is taken within 48 hours, 72 hours and 96 hours to be used to extract RNA and carry out the gene expression dose of interleukin-6, Interleukin -1β and tumor necrosis factor-alpha
Detection.Every group of 4 mouse.Wherein A is represented：Interleukin -1β gene expression dose in mouse lung tissue；Β is represented：Interleukin-6 gene expression dose in mouse lung tissue；C is represented：TNF-α gene expression in mouse lung tissue.Embodiment
The present invention will be further illustrated by following non-limiting examples below, it is as well known to those skilled in the art, without departing from the spirit of the invention, many modifications can be made to the present invention, such modification also falls into the scope of the present invention.
Following experimental methods are conventional method unless otherwise instructed, and used experiment material unless otherwise instructed, can be obtained easily from commercial company.Embodiment
Embodiment 1:Chloroquine, chlorpromazine reduction H5N1 types avian flu virus infection cause mouse death rate
Experiment material：
1) major experimental instrument：BSL-3 laboratory, three-grade biological safety cabinet, animal breeding cabinet, mice rearing cage, small animal surgical apparatus, asepsis injector, pipettor, pipette etc..
2) major experimental reagent：Chloroquine（C6628, purchased from Sigma-Aldrich companies）, chlorpromazine (C8138, purchased from Sigma-Aldrich companies）, solvent control be PBS, 1% (W/V) Nembutal sodium solution, viral dilution liquid, disinfectant（2.5% tincture of iodine and 75% alcohol）Deng.
3) it is viral：H5N1 avian influenza virus A/Jilin/9/2004 (H5Nl)
4) experimental animal：
SPF grades of wild type (WT) BALB/c mouses（4 week old）：It is purchased from Nat'l Pharmaceutical ＆ Biological Products Control Institute.
Experimental method：
1) it is grouped：Virus control+solvent control group, virus control+medicine group, virus+solvent control group, virus+medicine group；
2) chloroquine (50mg/kg), chlorpromazine is injected intraperitoneally in mouse peritoneal injection solvent control or medicine, every mouse every time（15mg/kg), prevention co-injection 2 times, 2h and 0.5h before respectively infecting;Co-injection 6 times is treated, 6 hours, 1 day, 2 days, 3 days, 4 after respectively infecting
It and 5 days；
3) the fixed mouse of safety, is injected intraperitoneally 1% (W/V) Nembutal sodium solution with lmL asepsis injectors and anaesthetizes；
4) keep anesthetized mice head to tilt backwards posture upwards, make its nasal cavity upward.Disinfect neck in alcohol, skin of neck is cut off with scissors, separate tracheae, be 10 with syringe injection titre6 TCID50H5N1 type avian influenza virus, 10 mouse of every group of infection；
5) this position of holding mouse 5 minutes, makes virus be uniformly distributed in lung tissue.Mouse is placed in mouse cage, after its recovery is clear-headed, water and food is given；
6) observed after infecting, the mouse that death occurs in 24 hours is nonspecific death, refuse to count when carrying out mortality statistics；
7) Continuous Observation 8 days, record every group of dead mouse situation daily；
8) with the software statistics mouse death rate situations of GraphPad Prism 5.
Experimental result：
1) wild type BALB/c mouse is after the control of abdominal cavity injection solvent or chloroquine, two kinds of medicines of chlorpromazine, and infection virus titer is 106 TCID5.H5N1 type avian influenza virus after mortality results, as shown in Figure 1, Figure 2, Figure 3, Figure 4.
2) this result explanation, chloroquine plays a significant role during treatment and chlorpromazine cause dead mouse in prevention H5N1 type avian flu virus infections, and chloroquine plays a significant role in treatment and chlorpromazine in the damage caused by prevention H5N1 type avian flu virus infections；Chloroquine nothing during prevention and chlorpromazine cause dead mouse in treatment H5N1 type avian flu virus infections is clearly acted on.The chloroquine of embodiment 2, chlorpromazine alleviate the pulmonary edema of mouse after H5N1 type avian flu virus infections
Experiment material：
1) major experimental instrument：BSL-3 laboratory, three-grade biological safety cabinet, animal breeding cabinet, mice rearing cage, small animal surgical apparatus, asepsis injector, pipettor, pipette etc..
2) major experimental reagent：Chloroquine（C6628, purchased from Sigma-Aldrich companies）, chlorpromazine (C8138, purchased from Sigma-Aldrich companies）, solvent control be PBS, 1% (W/V) Nembutal sodium solution, viral dilution liquid, disinfectant（2.5% tincture of iodine and 75% alcohol）Deng.
3) it is viral：H5N1 avian influenza virus A/Jilin/9/2004 (H5Nl)
4) experimental animal：SPF grades of wild type (WT) BALB/C mices（4 week old）：It is purchased from Nat'l Pharmaceutical ＆ Biological Products Control Institute.
Experimental method：
1) it is grouped：Virus control+solvent control group, virus control+medicine group, virus+solvent control group, virus+medicine group；
2) chloroquine (50mg/kg), chlorpromazine is injected intraperitoneally in mouse peritoneal injection solvent control or medicine, every mouse every time（15mg/kg), prevention co-injection 2 times, 2h and 0.5h before respectively infecting;Co-injection 6 times is treated, 6 hours, 1 day, 2 days, 3 days, 4 days and 5 days after respectively infecting；
3) the fixed mouse of safety, is injected intraperitoneally 1% (W/V) Nembutal sodium solution with lmL asepsis injectors and anaesthetizes；
4) keep anesthetized mice head to tilt backwards posture upwards, make its nasal cavity upward.Disinfect neck in alcohol, skin of neck is cut off with scissors, separate tracheae, be 10 with syringe injection titre6 TCID5.H5N1 type avian influenza virus, 4 mouse of every group of infection；
5) this position of holding mouse 5 minutes, makes virus be uniformly distributed in lung tissue.Mouse is placed in mouse cage, after its recovery is clear-headed, water and food is given；
6) observed after infecting, the mouse that death occurs in 24 hours is nonspecific death, refuse to count when carrying out mortality statistics；
7) infect after virus the 4th day or the 5th day, make dead mouse with the method for the excessive anesthetic of intraperitoneal injection；
8) mouse is fixed on small animal surgical platform, removes skin of chest and bone, the complete lungs of mouse are taken out, remove surface blood and unnecessary connective tissue, weigh and record lungs weight in wet base by exposure thoracic cavity；
9) lungs, which are placed in 55 °C of high temperature microstructure driers, does roasting, is taken out after 24 hours, treats that temperature is down to weighing and record that room temperature carries out lungs dry weight；
10) mouse lung weight in wet base/dry weight ratio (Wet/Dry Ratio) is calculated, statistical analysis is carried out.Experimental result：
1) wild type BALB/c mouse is after the control of abdominal cavity injection solvent or chloroquine, two kinds of medicines of chlorpromazine, and infection virus titer is 106Wet-dry ratio result after TCID50 H5N1 type avian influenza virus, as shown in Fig. 5, Fig. 6, Fig. 7.
2) this result illustrates, chloroquine plays a significant role during treatment and chlorpromazine cause mouse pulmonary edema in prevention H5N1 type avian flu virus infections.
Pathology damage
The present embodiment experiment material and experimental method equivalent integers 2 are essentially identical, experimental method difference is that this example determines pathologic damage results, specifically, experimental method difference is that the operation by experiment mice excess anesthesia after lethal is that mouse is fixed on into small animal surgical platform, skin of chest and bone are removed, exposure thoracic cavity takes out mouse lung together with heart simultaneously, surface blood is washed away with sterile PBS, room temperature in formaldehyde fixer is placed in and fixes 48h;The processing such as the sample after fixation is embedded by Pathology Lab, cut into slices, HE dyeing；Pathological section is placed in micro- Microscopic observation, and records.
Experimental result：
1) wild type BALB/c mouse is after the control of abdominal cavity injection solvent or chloroquine, two kinds of medicines of chlorpromazine, and infection virus titer is 106Pulmonary lesions situation and pulmonary inflammatory cell infiltration statistical result after TCID50 H5N1 type avian influenza virus are as shown in Figure 8, Figure 9, Figure 10 and Figure 11.
2) in Fig. 8（X200 times, HE dyeing）Pathological photograph is shown：Infect after H5N1 type avian influenza virus, serious pathology damage occur in the wild type C57 BL/6 mouse lung tissues that 4 week old of PBS control are injected intraperitoneally.Lung tissue normal configuration is destroyed, and Fei Zu Zhi Pattern reasons are disorderly, is oozed out with bleeding, inflammatory and the pathology damage such as a large amount of red blood cell, inflammatory cell infiltrations.Infect identical titer viral intraperitoneal injection chloroquine treatment（Co-injection 6 times is treated, 6 hours, 1 day, 2 days, 3 days, 4 days and 5 days after respectively infecting）Mouse lung tissue have no notable pathology damage, without significant bleeding, ooze out or the pathological change such as inflammatory cell infiltration, Fei Zu Zhi Pattern clear clear, structural integrity；Fig. 9 result display intraperitoneal injection chloroquine is prevented（Prevent co-injection 2 times, 2h and 0.5h before respectively infecting) mouse lung tissue pathology damage situation be not significantly different compared with PBS solvent groups.As a result illustrate, chloroquine treatment can significantly improve the chmice acute pathologic degree of injury of infection H5N1 influenza viruses, and chloroquine prevention is then without positive effect.
3) in Figure 10（X200 times, HE dyeing）Pathological photograph is shown：Infect H5N1 types
After avian influenza virus, there is serious pathology damage in the wild type C57 BL/6 mouse lung tissues that 4 week old of PBS control are injected intraperitoneally.Lung tissue normal configuration is destroyed, and Fei Zu Zhi Pattern reasons are disorderly, is oozed out with bleeding, inflammatory and the pathology damage such as a large amount of red blood cell, inflammatory cell infiltrations.Identical titer viral intraperitoneal injection chlorpromazine is infected to be prevented（Prevent co-injection 2 times, 2h and 0.5h before respectively infecting) mouse lung tissue have no notable pathology damage, without significant bleeding, ooze out or the pathological change such as inflammatory cell infiltration, Fei Zu Zhi Pattern clear clear, structural integrity；Figure 11 result prompting intraperitoneal injection Post-treatment of Chlorpromazine（Co-injection 6 times is treated, 6 hours, 1 day, 2 days, 3 days, 4 days and 5 days after respectively infecting）Mouse lung tissue pathology damage situation be not significantly different compared with PBS solvent groups.As a result illustrate, chlorpromazine prevention can significantly improve the chmice acute pathologic degree of injury of infection H5N1 influenza viruses, and the treatment of the quinoline of chlorine third is then without positive effect.The chloroquine of embodiment 4 treats the autophagy degree for reducing the lung tissue of mouse after H5N1 type avian flu virus infections
Experiment material：
1) major experimental instrument：BSL-3 laboratory, three-grade biological safety cabinet, animal breeding cabinet, mice rearing cage, small animal surgical apparatus, asepsis injector, pipettor, pipette etc..
2) major experimental reagent：Chloroquine（C6628, purchased from Sigma-Aldrich companies）, β-actin and LC-3 protein antibodies（It is purchased from Sigma-Aldrich companies）, solvent control be PBS, 1% (W/V) Nembutal sodium solution, viral dilution liquid, disinfectant（2.5% tincture of iodine and 75% alcohol）Deng.
3) it is viral：H5N1 avian influenza virus A/Jilin/9/2004 (H5Nl)
4) experimental animal：SPF grades of wild type (WT) BALB/C mices（4 week old）：It is purchased from Nat'l Pharmaceutical ＆ Biological Products Control Institute.
Experimental method：
1) it is grouped：Virus+solvent control group, virus+medicine group；
2) chloroquine (50mg/kg) is injected intraperitoneally in mouse peritoneal injection solvent control or medicine, every mouse every time, and injection is divided into 6 times totally, 6 hours, 1 day, 2 days, 3 days, 4 days and 5 days after respectively infecting；
3) the fixed mouse of safety, 1% (W/V) penta bar is injected intraperitoneally with lmL asepsis injectors
Than the anesthesia of appropriate sodium solution；
4) keep anesthetized mice head to tilt backwards posture upwards, make its nasal cavity upward.Disinfect neck in alcohol, skin of neck is cut off with scissors, separate tracheae, be 10 with syringe injection titre6 TCID50H5N1 type avian influenza virus, 10 mouse of every group of infection；
5) this position of holding mouse 5 minutes, makes virus be uniformly distributed in lung tissue.Mouse is placed in mouse cage, after its recovery is clear-headed, water and food is given；
6) observed after infecting, the mouse that death occurs in 24 hours is nonspecific death, refuse to count when carrying out mortality statistics；
7) 0 hour after infection after infection virus, 3 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, take within 72 hours and 96 hours mouse lung tissue to be used for the detection of western blot, the transformation situation of beta-actin and LC-3 I proteins to LC-3 II albumen is detected respectively.Every group of 4 mouse.
Experimental result
Figure 12 result shows that the mouse of chloroquine treatment group is compared to solvent control group, and the degree that lung's LC-3 I proteins change to LC-3 II albumen after infection H5N1 type avian influenza virus has the reduction of highly significant.Those skilled in the art know, because the degree that LC-3 I proteins change to LC-3 II albumen is a recognised standard of reflection autophagy, therefore this experimental result can prove that chloroquine treatment can significantly reduce the mouse lung tissue autophagy degree as caused by H5N1 type avian influenza virus.
As a result point out, the mechanism of action of mouse injury of lungs may be by reducing what lung tissue autophagy degree was realized caused by chloroquine treatment alleviation H5N1 type avian influenza virus.The treatment of the chloroquine of embodiment 5 does not influence H5N1 types avian influenza virus in the duplication of mouse lung tissue
Experiment material：
1) major experimental instrument：BSL-3 laboratory, three-grade biological safety cabinet, animal breeding cabinet, mice rearing cage, small animal surgical apparatus, asepsis injector, pipettor, pipette etc..
2) major experimental reagent：Chloroquine（C6628, purchased from Sigma-Aldrich companies）, H5N1 type avian influenza virus Ml and M2 gene primers（Invitrogene companies）, Trizol, 1% (W/V) Nembutal sodium solution, viral dilution liquid, sterile PBS, chloroform, isopropanol, reverse transcription PCR
Kit（Invitrogen companies）, real-time quantitative PCR kit（Roche), solvent control is PBS, 1% (W/V) Nembutal sodium solution, viral dilution liquid, disinfectant（2.5% tincture of iodine and 75% alcohol）Deng.
3) it is viral：H5N1 avian influenza virus A/Jilin/9/2004 (H5Nl)
4) experimental animal：SPF grades of wild type (WT) BALB/C mices（4 week old）：It is purchased from Nat'l Pharmaceutical ＆ Biological Products Control Institute.
Experimental method：
1) it is grouped：Virus+solvent control group, virus+medicine group；
2) chloroquine (50mg/kg) is injected intraperitoneally in mouse peritoneal injection solvent control or medicine, every mouse every time, and injection is divided into 6 times totally, 6 hours, 1 day, 2 days, 3 days, 4 days and 5 days after respectively infecting；
3) the fixed mouse of safety, is injected intraperitoneally 1% (W/V) Nembutal sodium solution with lmL asepsis injectors and anaesthetizes；
4) keep anesthetized mice head to tilt backwards posture upwards, make its nasal cavity upward.Disinfect neck in alcohol, skin of neck is cut off with scissors, separate tracheae, be 10 with syringe injection titre6 TCID50H5N1 type avian influenza virus, 10 mouse of every group of infection；
5) this position of holding mouse 5 minutes, makes virus be uniformly distributed in lung tissue.Mouse is placed in mouse cage, after its recovery is clear-headed, water and food is given；
6) observed after infecting, the mouse that death occurs in 24 hours is nonspecific death, refuse to count when carrying out mortality statistics；
7) 0 hour after infection after infection virus, 3 hours, 6 hours, 12 hours, 24 hours, take mouse lung tissue that mouse is fixed on into small animal surgical platform within 36 hours, 48 hours, 72 hours and 96 hours, remove skin of chest and bone, exposure thoracic cavity, the complete lungs of mouse are taken out, freezen protective in liquid nitrogen is immediately placed in；
8) lung tissue of freezen protective is taken out, adds 1.5 milliliters of Trizol, and grind 20 seconds using even oar device maximum (top) speed；
9) lung tissue RNA is extracted, the change of H5N1 type avian influenza virus Ml and M2 gene expression amounts in lung tissue is determined by reverse transcription PCR and real-time quantitative PCR；
10) data analysis is carried out using Graphpad Prism5 mappings.
Experimental result
Figure 13 A and B result shows, the mouse of chloroquine treatment group compared to solvent control group,
Simultaneously there was no significant difference for the expression quantity of lung H5N1 type avian influenza virus Ml and M2 genes after infection H5N1 type avian influenza virus.As a result illustrate that using chloroquine treatment duplication of the H5N1 type avian influenza virus in mouse lung tissue can't be influenceed.
As a result point out, the mechanism of action of mouse lung degree of injury is not by influenceing virus replication to realize caused by chloroquine treatment alleviation H5N1 type avian influenza virus.The treatment of the chloroquine of embodiment 6 reduces the elevated-levels of interleukin l- β and interleukin-6 gene expression amount in mouse lung tissue caused by H5N1 type avian influenza virus, but has no effect on the change of TNF-α gene expression quantity
The present embodiment experiment material and experimental method equivalent integers 5 are identical, except the primer in experiment material is mouse IL-1β, interleukin-6 and TNF-α gene primer
(Invitrogene companies)
Experimental result
Figure 14 A results show that the mouse of chloroquine treatment group is compared to solvent control group, and lung's interleukin l- beta gene expressions amount is decreased significantly for 12 hours, 24 hours and 36 hours after infection H5N1 type avian influenza virus；Figure 14 B results show that lung's interleukin-6 gene expression amount is decreased significantly for 24 hours after infection H5N1 type avian influenza virus；Figure 14 C results show that lung tumors necrosis factor-alpha gene expression amount is then without significant difference. * Ρ<0.05, * * Ρ<0.01.
As a result show, chloroquine treatment can significantly reduce the gene expression amount of mouse anticusp inflammation factor interleukin l- β and interleukin-6 viral initial stage in infection, and this result and lung tissue's pathological examination result match（Figure 11), illustrate that chloroquine treatment significantly reduces mouse lung tissue inflammation lesion degree, played an important role in mouse injury of lungs caused by treatment H5N1 type avian influenza virus.
Claims (11)
- Claims:1st, the purposes of chloroquine or chlorpromazine or derivatives thereof or their mixture in mammal caused by preparing treatment and/or flu-prevention virus includes the Lung infection of people and/or the medicine of injury of lungs.2nd, purposes according to claim 1, wherein the derivative of the chloroquine is selected from hydroxychloroquine, hydroxychloroquine sulfate, two chloroquine phosphoric acid；The derivative of the chlorpromazine is selected from acetylpromazinimaleas, perphenazine, triperazine.3rd, purposes according to claim 1, wherein described influenza virus is influenza A virus, preferably A type Hl, H3, H5, H7 or H9 hypotypes strain, more preferably A type H5 hypotypes strain, more preferably A type H5N1 influenza viruses, most preferably A type H5N1 influenza virus As/H5N1 plants of Jilin/9/2004.4th, purposes of a kind of pharmaceutical composition comprising chloroquine or chlorpromazine or derivatives thereof or their mixture in mammal caused by preparing treatment and/or flu-prevention virus includes the Lung infection of people and/or the medicine of injury of lungs.5th, purposes according to claim 4, wherein the derivative of the chloroquine is selected from hydroxychloroquine, hydroxychloroquine sulfate, two chloroquine phosphoric acid；The derivative of the chlorpromazine is selected from acetylpromazinimaleas, perphenazine, triperazine.6th, purposes according to claim 4, wherein described influenza virus is influenza A virus, preferably A type Hl, H3, H5, H7 or H9 hypotypes strain, more preferably A type H5 hypotypes strain, more preferably A type H5N1 influenza viruses, most preferably A type H5N1 influenza virus As/Jilin/9/2004 plants.7th, the chloroquine of the purposes according to claim 4-6 any one, wherein described pharmaceutical composition comprising therapeutically effective amount or chlorpromazine or derivatives thereof or their mixture, and one or more pharmaceutically acceptable carriers. 8th, purposes according to claim 7, it is characterised in that described pharmaceutical composition can also play the active constituents of medicine of the treatment effective dose of synergy comprising one or more and the chloroquine or chlorpromazine or derivatives thereof or their mixture.9th, any pharmaceutically acceptable formulation can be made in the purposes according to claim 4-8 any one, wherein described pharmaceutical composition.10th, purposes according to claim 9, wherein the pharmaceutically acceptable formulation is injection, spray, nasal drop, inhalant or oral agents.11st, a kind for the treatment of and/or the caused mammal of flu-prevention virus include the method for the Lung infection and/or injury of lungs of people, and it includes giving chloroquine or chlorpromazine of the bacterium of influenza virus infection or derivatives thereof or their mixture.12nd, chloroquine or chlorpromazine or derivatives thereof or their mixture are used to treat and/or the caused mammal of flu-prevention virus includes the Lung infection and/or injury of lungs of people.
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| CN201110300697.0 | 2011-09-29 | ||
| CN201280035308.9A CN103687599A (en) | 2011-09-29 | 2012-09-29 | The use of chloroquine, chlorpromazine, derivatives thereof, or mixtures thereof in preparing medications for treating and/or preventing pulmonary infection and injury |
| PCT/CN2012/082480 WO2013044871A1 (en) | 2011-09-29 | 2012-09-29 | The use of chloroquine, chlorpromazine, derivatives thereof, or mixtures thereof in preparing medications for treating and/or preventing pulmonary infection and injury |
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| CN110917196B (en) * | 2020-02-05 | 2020-06-05 | 广州康健医学科技有限公司 | Chloroquine antibacterial disinfectant and application thereof |
| AU2021231743A1 (en) * | 2020-03-02 | 2022-09-22 | 60 Degrees Pharmaceuticals Llc | Methods for the treatment and prevention of lung infections by administration of tafenoquine |
| US11007187B1 (en) * | 2020-03-25 | 2021-05-18 | Therapeutica Borealis Oy | Medicine for Covid-19 and treatment |
| US11638722B2 (en) | 2020-03-25 | 2023-05-02 | Therapeutica Borealis Oy C/O Avance Attorneys Ltd. | Medicine for Covid-19 and treatment |
| US11278602B2 (en) | 2020-03-25 | 2022-03-22 | Therapeutica Borealis Oy | Medicine for Covid-19 and treatment |
| CN111419787A (en) * | 2020-04-16 | 2020-07-17 | 广州康健医学科技有限公司 | Chloroquine spray and preparation method thereof |
| CN113855674A (en) * | 2021-11-05 | 2021-12-31 | 中国科学院动物研究所 | Application of chloroquine |
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