CN107617101A - Drug regimen and its application containing zoledronic acid and interleukin 2 - Google Patents
Drug regimen and its application containing zoledronic acid and interleukin 2 Download PDFInfo
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- CN107617101A CN107617101A CN201610560001.0A CN201610560001A CN107617101A CN 107617101 A CN107617101 A CN 107617101A CN 201610560001 A CN201610560001 A CN 201610560001A CN 107617101 A CN107617101 A CN 107617101A
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- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 229940079593 drug Drugs 0.000 title claims abstract description 38
- 229960004276 zoledronic acid Drugs 0.000 title claims abstract description 33
- 108010002350 Interleukin-2 Proteins 0.000 title claims description 23
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- 238000011282 treatment Methods 0.000 claims abstract description 44
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
- 102000015696 Interleukins Human genes 0.000 claims abstract description 16
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- 230000036457 multidrug resistance Effects 0.000 claims description 25
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
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- 238000002360 preparation method Methods 0.000 claims description 12
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Abstract
The invention provides containing zoledronic acid and interleukins drug regimen and application thereof.Specifically, the invention provides a kind of drug regimen, and pharmaceutical composition and medicine box comprising the drug regimen and treatment chemotherapeutic agent combination lungy.Present invention also offers said medicine combination, the application of pharmaceutical composition and medicine box in tuberculosis is treated.
Description
Technical field
The present invention relates to drug field, relates more specifically to the drug regimen containing zoledronic acid and interleukin 2, and
Application of the drug regimen in resistant tuberculosis treatment.
Background technology
Tuberculosis is that the respiratory infectious disease of human health is seriously endangered as caused by mycobacterium tuberculosis.Tuberculosis is by me
State is classified as one of serious infectious diseases, and China is one of high burden country of 22, whole world tuberculosis.World Health Organization's estimation, at present
Chinese tuberculosis year number of the infected is about 1,000,000, accounts for the 11% of global number of the infected, ranks the second in the world.Meanwhile China
It is one of popular serious country of 27, whole world multi-drug resistance tuberculosis, global annual new hair multi-drug resistance tuberculosis example about 440,000, I
Multi-drug resistance tuberculosis example about 100,000 (latest data from the issue of Chinese Center for Disease Control) is newly sent out every year by state, accounts for the whole world
23%.Tuberculosis be Chinese countryside drive into poverty by medical crises, one of the principal disease backed into poverty by medical crises, serious China's economy and the society of restricting
Development.It is lungy occurred frequently, heavy economy and mental burden are not only brought to patient home, also directly affects the society in China
Can stablize and sustained economic development.
Resistant tuberculosis, refer to that the mycobacterium tuberculosis in tuberculosis patient body is (i.e. different to an a kind of line antituberculotic
Cigarette hydrazine, rifampin, ethambutol, pyrazinamide and streptomysin) produce resistance.Multi-drug resistance tuberculosis then refers at least to different cigarette
Hydrazine and rifampin-resistance.Because the lethal effect of isoniazid and rifampicin against Mycobacterium bacterium is most strong, therefore, multi-drug resistance tuberculosis is one
The even more serious drug resistance of tuberculosis type of kind.Shown according to World Health Organization's latest survey, in new patient, 100 tuberculosis
At least 1 is multi-drug resistance tuberculosis people in patient；And in the people that cures the disease again, at least seven is multi-drug resistant in 100 tuberculosis patients
Tuberculosis patient.According to the 4th national tuberculosis epidemiology investigation display in China, nearly 1/3 tuberculosis patient in China is resistance patient,
More than 1/10 patient is multi-drug resistant tuberculosis.Estimate accordingly, the annual new caused multi-drug resistance tuberculosis people in China will be more than 100,000.
The treatment of multi-drug resistance tuberculosis is extremely difficult at present, and reason includes：(1) diagnosis of complex, current common tuberculosis patient,
Diagnosis can be made within general 2~3 days；Multi-drug resistance tuberculosis diagnosis is completely dependent on laboratory, it is necessary to 2~March.(2) treatment cycle
Long, common tuberculosis patient treatment cycle is generally June.Multi-drug resistance tuberculosis people treatment cycle 18~24 months, or even 36 months, it is general
3~6 times of logical tuberculosis patient.(3) treatment cost is high, and multi-drug resistance tuberculosis people treats total cost by more than common tuberculosis patient
200 times.Moreover, multi-drug resistance tuberculosis people can use without medicine substantially at present, as a consequence it is hardly possible to be cured completely.
At present in tuberculotherapy, short term chemotherapy scheme under direct supervision, i.e. isoniazid, rifampin, second are relied primarily on
Amine butanol and 4 kinds of pyrazinamide treated with combined medication 2 months, reuse isoniazid and rifampin continuously treatment 4 months.This side
Method at least needs the course for the treatment of of 6 months, and treatment cycle is longer.Anti- scarring agent is most of active multiple in can a few days ago killing for treatment
The bacterium of system, but slow-growing or dormancy tubercle bacillus will long-term existence.Substantial amounts of drug administration for a long time, it will lead
Pathogenic people loses patience, so as to interrupt or shorten treatment.High relapse rate will be caused by interrupting treatment, and remaining bacterium will be to initial
The medicine for the treatment of produces resistance, produces antibody-resistant bacterium.
Therefore, there is an urgent need to develop the pharmaceutical composition of new treatment tuberculosis, especially multi-drug resistance tuberculosis for this area.
The content of the invention
It is an object of the invention to provide a kind of drug regimen containing zoledronic acid and interleukin 2.
It is another object of the present invention to provide application of the drug regimen in resistant tuberculosis treatment.
In the first aspect of the present invention, there is provided a kind of drug regimen, described drug regimen contain：
Active component (a) zoledronic acid or derivatives thereof；
Active component (b) interleukins.
In another preference, described interleukins includes IL-2, IL-33, IL-15, and/or IL-12.
In another preference, described drug regimen is used for the therapeutic effect for improving tuberculotherapy medicine.
In another preference, the ratio (mg of described active component (a) and active component (b):Mg it is) 1:0.01 to
1:0.0005, preferably 1:0.001 to 1:0.005.
In another preference, the total content of described active component (a) and active component (b) for drug regimen 1~
99wt%, it is more preferably 5~90wt%.
In the second aspect of the present invention, there is provided one kind is used to treat tuberculosis composition, described medicine group
Compound contains：
Active component (a) zoledronic acid or derivatives thereof；
Active component (b) interleukins；
Active component (c) tuberculotherapy medicine；And
(d) pharmaceutically acceptable carrier.
In another preference, described tuberculotherapy medicine is clinical treatment chemotherapeutic agent lungy.
In another preference, described tuberculotherapy medicine is chemotherapeutic agent.
In another preference, described tuberculotherapy medicine include capreomycin, MOXIFLOXACIN and ethambutol,
Isoniazid, streptomysin, rifampin, pyrazinamide, lavo-ofloxacin, amikacin, kanamycins, protionamide, to amino
Salicylic acid, seromycin or its combination.
In another preference, described tuberculotherapy medicine is the combination of 2-4 kind folk prescription medicines.
In another preference, described tuberculotherapy medicine is the combination of capreomycin, MOXIFLOXACIN, ethambutol
In another preference, described tuberculosis includes resistant tuberculosis, preferably multi-drug resistance tuberculosis.
In another preference, the ratio (mg of described active component (a), active component (b) and active component (c):
mg:Mg it is) 1:0.01:1000 to 1:0.0005:10, preferably 1:0.001:500 to 1:0.005:50.
In another preference, the total content of described active component (a), active component (b) and active component (c) is group
1~99wt% of compound, it is more preferably 5~90wt%.
In another preference, the formulation of described pharmaceutical composition is peroral dosage form or injection.
In another preference, described pharmaceutical composition can also contain other drugs active component, including treatment
Active component lungy.
In the third aspect of the present invention, there is provided a kind of purposes of drug regimen as described in the first aspect of the invention, institute
The drug regimen stated is used to prepare a preparation or a medicine box, and the preparation or medicine box are used for (i) treatment pulmonary tuberculosis, and/or (ii)
Tuberculotherapy medicine is improved to tuberculosis patient therapeutic effect.
In another preference, described preparation includes pharmaceutical composition.
In another preference, the preparation is administered simultaneously with tuberculotherapy medicine or successively applied.
In another preference, the formulation of the preparation includes oral formulations or injection.
In another preference, described medicine box is as described in fifth aspect present invention.
In the fourth aspect of the present invention, there is provided a kind of purposes of pharmaceutical composition as described in respect of the second aspect of the invention,
Described pharmaceutical composition is used for the one or more purposes being selected from the group：
(i) it is used to prepare to treat phthisical medicine,
(ii) it is used to prepare the medicine that induction produces V γ 2V δ 2T cells, and/or
(iii) it is used to prepare the medicine that induction produces treating tuberculosis effector.
In another preference, described treating tuberculosis effector is selected from the group：
Gamma interferon (IFN-γ), TNF (TNF-α), perforin (perforin), particle cytolysin
(granulysin), granzyme (granzyme) or its combination.
In another preference, described treating tuberculosis effector is included by V γ 2V δ 2T cells, CD4, T cell and CD8
Treating tuberculosis effector caused by T cell.
In another preference, described treatment pulmonary tuberculosis includes pathology damage caused by mitigating pulmonary tuberculosis, and reduces lung
The number of bacteria in portion.
In the fifth aspect of the present invention, there is provided a kind of medicine box, the medicine box contain：
(i) the first container, and loaded on active component (a) zoledronic acid in first container or derivatives thereof, or contain
The medicine of active composition (a)；
(ii) second container, and loaded on active component (b) interleukins in the second container, or containing it is active into
Divide the medicine of (b)；And
(iii) the 3rd container, and loaded on active component (c) the tuberculotherapy medicine in the 3rd container, or contain
The medicine of active component (c)；And
(iv) specification, recorded in the specification be given in combination active component (a), active component (b) and activity into
Divide the explanation of (c) so as to treating cancer.
In another preference, the medicine in the first described container and second container is the folk prescription containing active component (a)
Preparation and the single preparations of ephedrine containing active component (b).
In another preference, the medicine in the 3rd described container is the compound preparation containing active component (c).
In another preference, the formulation of the medicine is peroral dosage form or injection.
In another preference, the medicine box is used to treat tuberculosis.
In another preference, described active component (a), active component (b) and active component (c) while or successively apply
With.
In the sixth aspect of the present invention, there is provided one kind treats method lungy, and described method includes step：
(i) active component (a) zoledronic acid or derivatives thereof is applied to the mammal needed；Active component (b) is white thin
Born of the same parents' interleukin；With active component (c) tuberculotherapy medicine.
In another preference, described administration includes being administered simultaneously or successively applied.
In another preference, described mammal includes people.
In another preference, the application dosage of described zoledronic acid or derivatives thereof is 1-10mg/ times, preferably 2-
6mg/ times.
In another preference, described interleukins application dosage is the unit (0.8-2million of 0.8-2 million
IU), preferably units of 1-1.5 million.
In another preference, the frequency of administration of the active component is 1 times/day.
In another preference, the time of application of the active component is 2-14 days, preferably 3-7 days, most preferably 5 days.
In another preference, treated by the conventional application dosage and frequency of administration of active component.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, so as to form new or preferable technical scheme.As space is limited, exist
This no longer tires out one by one states.
Brief description of the drawings
Fig. 1 shows V γ 2V δ 2T cells in each experimental group PBLC (PBMC) and bronchoalveolar lavage fluid (BAL)
Ratio change.Wherein, Figure 1A shows that V γ 2V δ 2T cells are in multi-drug resistant tuberculosis branch bar in periphery lymphocyte (PBMC)
Bacterium attacks the 7th day and the 13rd day ratio for (i.e. for the first time before and after treatment) accounting for CD3+T cells after poison.Figure 1B shows bronchoalveolar lavage fluid
(BAL) V γ 2V δ 2T cells are accounting for the ratio of CD3+T cells before and after treatment for the first time in.
Fig. 2 shows different treatment time points, and feature effector (gamma interferon can be produced in peripheral blood
(IFN-γ), perforin (perforin), TNF (TNF-α)) V γ 2V δ 2T cells number.
Fig. 3 shows different treatment time points, and feature effector (gamma interferon can be produced in peripheral blood
(IFN-γ), perforin (perforin), TNF (TNF-α)) CD4 T cells and CD8 T cells number.Its
In, Fig. 3 A show the number of CD4 T cells, and Fig. 3 B show the number of CD8 T cells.
Fig. 4 shows the colony count in each experimental group machin lung homogenate.
Fig. 5 shows each group machin lung pathologies score.
Embodiment
The present inventor is surprised to find that zoledronic acid and interleukin-22 use in conjunction first by depth studying extensively
V γ 2V δ 2T cells can be substantially expanded, the V γ 2V δ 2T cells after amplification can effectively kill the entozoic mycobacterium tuberculosis of born of the same parents.
Experiment shows, treating tuberculosis chemicals and immunotherapy medicaments (zoledronic acid/interleukin-22, ZOL+IL-2), which can combine, to be used for
Multi-drug resistance tuberculosis is treated, therapeutic effect is notable.
Term
Zoledronic acid
Zoledronic acid (Zoledronic Acid, ZOL) is a kind of diphoponate for specifically acting on bone, it
The bone information caused by osteoclastic activity increase can be suppressed.The molecular weight of zoledronic acid is 290.11, and chemical formula is
C5H10N2O7P2·H2O, structural formula are as follows：
Interleukin-22
Interleukin-22 (Interleukin 2, IL-2) is that body is drenched during immune response by a kind of of T cell release
Ba Yinzi, the factor play a role between leucocyte (such as macrophage, monocyte, lymphocyte) etc., are immunity of organism
Core substance during response, particularly cellullar immunologic response.With antitumor, the work(such as antiviral and enhancing immunity of organisms
Energy.
Tuberculotherapy medicine
As used herein, described " tuberculotherapy medicine " refers to the medicine for tuberculotherapy clinically commonly used
Thing, especially chemotherapeutic agent.
In another preference, described tuberculotherapy medicine includes but is not limited to：
Capreomycin, MOXIFLOXACIN, ethambutol, isoniazid, streptomysin, rifampin, pyrazinamide, lavo-ofloxacin,
Amikacin, kanamycins, protionamide, PAS, seromycin or its combination.
In another preference, described tuberculotherapy medicine is the combination of 2-4 kind folk prescription medicines.
In another preference, described tuberculotherapy medicine is the combination of capreomycin, MOXIFLOXACIN, ethambutol
When being treated for resistant tuberculosis, applied to the pharmaceutical composition of the present invention and the tuberculotherapy medicine of medicine box
Thing should select treatment target not have the species of drug resistance to it.
V γ 2V δ 2T cells
Gamma delta T cells are that one kind can kill cancer cell, tumor stem cell, and and can identifies the immunocyte of cancer antigen, killing
Property is stronger.V γ 2V δ 2T cells account for the 60-95% of people's body-internal-circulation gamma delta T cells, are that can uniquely identify tuberculosis phosphoantigen
Gamma delta T cells, exist only in people and non-human primates, and the gamma delta T cells of this antigen-specific are not present in other animals.
Resistance Mycobacterium Tuberculosis
Resistant tuberculosis, refer to that the mycobacterium tuberculosis in tuberculosis patient body is (i.e. different to an a kind of line antituberculotic
Cigarette hydrazine, rifampin, ethambutol, pyrazinamide and streptomysin) produce resistance.Multi-drug resistance tuberculosis then refers at least to different cigarette
Hydrazine and rifampin-resistance.
Tulase attacks poison
Substance of medicines-resistant branched tubercle bacillus 1mL solution is included into 500CFU, after Animal Anesthesia, guided down using bronchoscope
Attack malicious mode, import animal inferior lobe of right lung infection animal.
Compound medicament composition and medicine box
The invention provides contain active component (a) zoledronic acid or derivatives thereof；(b) interleukins；(c) tuberculosis
Medicine；And the compound medicament composition of (d) pharmaceutically acceptable carrier.This kind of carrier includes (but being not limited to)：
Salt solution, buffer solution, glucose, water, glycerine, ethanol, pulvis, and combinations thereof.Pharmaceutical preparation should match with administering mode.This hair
Bright pharmaceutical composition can be made into injection form, such as with physiological saline or the aqueous solution containing glucose He other assistant agents
Prepared by conventional method.The pharmaceutical composition of such as tablet and capsule etc, it can be prepared by conventional method.Medicine
Compositions such as injection, solution, tablet and capsule preferably aseptically manufacture.The drug regimen of the present invention can also be made into
Pulvis is used for Neulized inhalation.A kind of preferable formulation is ejection preparation.In addition, pharmaceutical composition of the present invention can also be with other treatment
Agent is used together.
Present invention also offers a kind of medicine box available for treating cancer, the medicine box contains：
(i) the first container, and loaded on active component (a) zoledronic acid in first container or derivatives thereof, or contain
The medicine of active composition (a)；
(ii) second container, and loaded on active component (b) interleukins in the second container, or containing it is active into
Divide the medicine of (b)；And
(iii) the 3rd container, and loaded on active component (c) the tuberculotherapy medicine in the 3rd container, or contain
The medicine of active component (c)；And
(iv) specification, recorded in the specification be given in combination active component (a), active component (b) and activity into
Divide the explanation of (c) so as to treating cancer.
In the compound medicament composition or medicine box of the present invention, in another preference, described active component
(a), the ratio (mg of active component (b) and active component (c):mg:Mg it is) 1:0.01:1000 to 1:0.0005:10, preferably
For 1:0.001:500 to 1:0.005:50.
The pharmaceutical composition and medicine box of the present invention is applied to treatment tuberculosis, is preferably used for treating resistant tuberculosis, more
It is used to treat multi-drug resistance tuberculosis goodly.
Invention formulation can be with taken three times a day or four times, or with sustained release fashion daily once.Preferable side
Formula is to take medicine once daily, because being so easy to patient to adhere to, so as to significantly improve the compliance of patient's medication.
When taking, the accumulated dose that thumping majority case is typically applied daily should be less than (or a small number of cases are equal or slightly larger than)
The daily common dose of each single medicine, certainly, the effective dose of active component used can be with the patterns of administration and to be treated
Order of severity of disease etc. and be varied from.
Treatment method
Present invention also offers the side treated with the three kinds of active components or corresponding medicine of the present invention to tuberculosis
Method, it includes applying active component (a) zoledronic acid of effective dose or derivatives thereof to mammal；(b) interleukins；
(c) tuberculotherapy medicine, or apply the pharmaceutical composition containing the active component (a), (b) and (c).
When the present invention each active component be used for such use when, can (difference) and one or more it is pharmaceutically acceptable
Carrier or excipient mixing, such as solvent, diluent, and can be administered orally with following form：Tablet, pill, capsule,
Dispersible powder, particle or suspension (containing such as from about 0.05-5% suspending agents), syrup (containing such as from about 10-50% sugar) and
Elixir (contains about 20-50% ethanol), or with sterile injectable solution or form of suspension (containing about in isotonic medium
0.05-5% suspending agents) carry out parenteral routes.For example, these pharmaceutical preparations contain the about 0.01-99% mixed with carrier,
More preferably about 0.1%-90% (weight) active component.
Each active component or pharmaceutical composition of the present invention can be administered by conventional route, including (but simultaneously
It is not limited to)：Intramuscular, intraperitoneal, intravenous, subcutaneous, intracutaneous, oral or part administration.Preferable method of administration includes orally giving
Medicine, intramuscular administration or intravenous administration.
In terms of the position for being easy to be administered, preferable pharmaceutical composition is fluid composition, especially injection.
Main advantages of the present invention include：
(a) zoledronic acid, interleukin-22 and the combination for the treatment of tuberculosis chemicals can substantially expand V γ 2V δ 2T cells.
(b) zoledronic acid, interleukin-22 and treating tuberculosis chemicals combination treating tuberculosis effector can stimulate generation more
Treating tuberculosis effector.
(c) zoledronic acid, interleukin-22 and the combination for the treatment of tuberculosis chemicals can treat multi-drug resistance tuberculosis.
(d) drug regimen of zoledronic acid and interleukin-22 can improve clinical tuberculotherapy medicine and tuberculosis patient is controlled
Therapeutic effect.
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip
Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are calculated by weight.
Versatile material and method
Multi-drug resistance tuberculosis 1. (XDR-TB) model of rhesus monkey
Experimental animal：Using macaque (machin Cynomolgus Macaque), age 4-6 year or so, 3-5 kilograms of body weight
Between.Experiment sets 4 groups altogether, every group of 6 healthy macaques, totally 24.
First group：Multi-drug resistance tuberculosis animalChemicalsTreatment group.
Second group：Multi-drug resistance tuberculosis animalImmunization therapyGroup withChemicalsTherapeutic alliance group.
3rd group：Multi-drug resistance tuberculosis animalInterleukin-22 (IL-2)WithChemicalsTherapeutic alliance group.
4th group：Multi-drug resistance tuberculosis animalPhysiological salineControl group.
After Animal Anesthesia, malicious mode is attacked under being guided using bronchoscope, imports the multi-drug resistant tuberculosis of animal inferior lobe of right lung 1mL
Mycobacterial infections animal.
2. substance of medicines-resistant branched tubercle bacillus
Substance of medicines-resistant branched tubercle bacillus is the separated clinical strains M.tb-V79 of Wuhan City's tuberculosis prevention and treatment, the bacterial strain pair
Isoniazid, rifampin, the tolerance of Ofloxacin and streptomysin.It is quiet using C57bl/c mouse 10, female, 6-8 week old, tail
Arteries and veins injects V7912 × 107Cfu/ only, determines the mouse half death time (ST50)。ST50=22 days.
3. experimental drug thing
Chemotherapy is combined as：Capreomycin (CM.), MOXIFLOXACIN (Mfx.), ethambutol (E).
Immunotherapy medicaments：Zoledronic acid (Zoledronic), interleukin 2 (IL-2).
4. therapeutic scheme
One treatment cycle is 5 days, and treatment time point is on May -11 on the 7th, on May -17 on the 13rd, on July -28 on the 24th, 7
Month 30 days-August 3 days, September -8 days on the 4th, September -29 days on the 24th.
Chemotherapy：Capreomycin CM (intramuscular injection)+MOXIFLOXACIN Mfx (tablet)+to ethambutol E (mouths
Clothes).Oral drugs (Mfx, E) are injected using stomach tube, and CM uses intramuscular injection.Oral drugs are independent in each treatment cycle respectively
Using once, and CM injections then continuous injection 5 days in each treatment cycle, once a day.
Immunotherapy regimens：It is injected intravenously (intravenous), zoledronic acid (1mg/ is only) (human body 4mg/ times) is (every time
Injection time can not be less than 15 minutes)；The medicine can not be with other drugs joint injection.
Each treatment cycle zoledronic acid is injected 1 time/5 days.
After injecting zoledronic acid, while (subcutaneous) 1.2 million unit recombination human source IL-2 are subcutaneously injected
(1-1.2 million IU), interleukin is continuously injected 5 days, daily 1.
Interleukin-22 therapeutic scheme：(subcutaneous) 1.2 million unit recombination human source IL-2 are subcutaneously injected every time
(1-1.2 million IU IL-2), interleukin is continuously injected 5 days.
Saline control group：Injecting normal saline 2ml.
5. experimental period
On May 1st, 2014 carries out the multi-drug resistant tulase challenge viral dosage of experimental animal；On October 12nd, 2015 carries out animal
Anatomy experiment.Period carries out multiple immunological experiment.
Embodiment 1
Immunization therapy can effectively evoke the amplification of V γ 2V δ 2T cells in vivo
In order to verify that can zoledronic acid and proleulzin (ZOL+IL-2) evoke the amplification of V γ 2V δ 2T cells in vivo,
Respectively before first time immunization therapy and after treatment, the peripheral blood and bronchoalveolar lavage fluid of experimental animal are acquired.It is thin by streaming
The mode of born of the same parents' dyeing, analyze the ratio of the V γ 2V δ 2T cells in PBLC (PBMC) and bronchoalveolar lavage fluid (BAL)
Example change.
PBMC analysis results (attack after poison the 7th day) in each group V γ 2V δ 2T cells in PBMC as shown in Figure 1A, before treatment
It is more essentially the same.(attacked after first time treats after poison the 13rd day), second group of (ZOL+IL-2 and chemicals joint
Treatment group) in V γ 2V δ 2T cells account for the ratio highests of CD3+T cells, be significantly higher than other groups.
As shown in Figure 1B, V γ 2V δ 2T cells account for the ratio of CD3+T cells to BAL analysis results in bronchoalveolar lavage fluid (BAL)
Change is consistent with trend in PBMC.
The above results illustrate that immunotherapy medicaments ZOL+IL-2 can cause the notable expansion of V γ 2V δ 2T cells in vivo
Increase.
Embodiment 2
Immunization therapy can promote V γ 2V δ 2T cells to produce more treating tuberculosis effectors
In order to detect the treating tuberculosis immunocompetence of the V γ 2V δ 2T cells after amplification, analyze in each experimental group therapeutic process
Treating tuberculosis effector (gamma interferon (IFN-γ), TNF (TNF-α), perforin can be produced
(perforin) number of variations of V γ 2V δ 2T cells).
As a result as shown in Fig. 2 (group is chemotherapeutic agent and is immunized at second group (immunization therapy group, ZOL+IL-2)
The combination group of medicine) animal peripheral blood in, have can more produce gamma interferon (IFN-γ), perforin
(perforin), the V γ 2V δ 2T cells of TNF (TNF-α), especially after after tulase attacks poison the 60th day,
The V γ 2V δ 2T cells that the functional cell factor is produced in second group of animal are significantly higher than other groups.
Embodiment 3
Immunization therapy can also promote CD4, CD8 T cell to produce more treating tuberculosis effectors
In order to further study the treating tuberculosis effect of each experimental group, have detected in each experimental group peripheral blood CD4 T cells and
The quantity of CD8 T cells.
As a result as shown in figure 3, in the peripheral blood of second group of (immunization therapy group, ZOL+IL-2) animal, have more
Gamma interferon (IFN-γ), perforin (perforin), the CD4 T cells (figure of TNF (TNF-α) can be produced
3A) and CD8 T cells (Fig. 3 B).The result illustrate, immunization therapy ZOL+IL-2 can not only specific, activated V γ 2V δ 2T it is thin
Born of the same parents, and other T cells can be stimulated to produce the functional cell factor extensively.
Embodiment 4
Immunization therapy can effectively reduce the colony count of experimental animal lung
At the end of experiment, We conducted animal to become celestial.Culture and bacterium colony have been carried out to the homogenate of experimental animal lung tissue
Count.
As a result as shown in figure 4, second group of (immunization therapy group, ZOL+IL-2) experimental animal lung's colony count most
It is low, it is substantially less than other each groups.The result illustrates that immunization therapy significantly more efficient can drop than pure chemistry drug therapy
The action effect of number of bacteria in low host, i.e. immunization therapy is better than pure chemistry medication effect.
Embodiment 5
Immunization therapy can mitigate experimental animal lung pathology damage as caused by tuberculosis
Tubercle bacillus affection can cause the pathology damage of the infection site of host, and pathology damage degree and hair lungy
Exhibition process is related.In order to evaluate the action effect of each experimental therapy group, we compare the lung pathologies damage after zootomy
Degree, and degree of injury is quantified according to mark.Pathology scoring values are higher to illustrate that its pathology damage is heavier.
As a result as shown in figure 5, the pathology score in immunization therapy group (second group) animal is minimum, i.e. its pathology damage degree
It is minimum, substantially less than pure chemistry medication therapy groups (first group).The experimental result illustrates that immunization therapy can effectively mitigate place
Main lung pathologies damage, its therapeutic effect are better than pure chemistry medication therapy groups.
The result of above-described embodiment shows, in multi-drug resistance tuberculosis model, immunotherapy medicaments (zoledronic acid+IL-2)
It is effective therapeutic scheme with chemicals therapeutic alliance.The therapeutic scheme is starting just dramatically increase food crab at treatment initial stage
The amplification of V γ 2V δ 2T cells in monkey body, and produce the functional cell factor；In immunization therapy and chemicals therapeutic alliance group
Other types T cell such as CD4, CD8 positive T cells can also produce more treating tuberculosis functional cell factors.Zootomy
As a result show, the pathological change degree of zoledronic acid combined therapy group animal is most light, better than other treatment and control group；Bacterium colony meter
Number result shows that second group and the 3rd group of lung's clump count is minimum, is substantially less than other groups, illustrates that this two groups of therapeutic schemes kill
Bacterium most pronounced effects.
All it is incorporated as referring in this application in all documents that the present invention refers to, it is independent just as each document
It is incorporated as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can
To be made various changes or modifications to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited
Enclose.
Claims (10)
1. a kind of drug regimen, it is characterised in that described drug regimen contains：
Active component (a) zoledronic acid or derivatives thereof；
Active component (b) interleukins.
2. drug regimen as claimed in claim 1, it is characterised in that described interleukins includes IL-2, IL-33, IL-
15, and/or IL-12.
3. one kind is used to treat tuberculosis composition, it is characterised in that described pharmaceutical composition contains：
Active component (a) zoledronic acid or derivatives thereof；
Active component (b) interleukins；
Active component (c) tuberculotherapy medicine；And
(d) pharmaceutically acceptable carrier.
4. pharmaceutical composition as claimed in claim 3, it is characterised in that it is mould that described tuberculotherapy medicine includes curling
Element, MOXIFLOXACIN and ethambutol, isoniazid, streptomysin, rifampin, pyrazinamide, lavo-ofloxacin, amikacin, block that
Mycin, protionamide, PAS, seromycin or its combination.
5. pharmaceutical composition as claimed in claim 3, it is characterised in that described tuberculosis includes resistant tuberculosis, preferably
Ground is multi-drug resistance tuberculosis.
6. a kind of purposes of drug regimen as claimed in claim 1, it is characterised in that described drug regimen is used to prepare one
Preparation or a medicine box, the preparation or medicine box are used for (i) treatment pulmonary tuberculosis, and/or (ii) improves tuberculotherapy medicine to knot
Core patient's therapeutic effect.
7. purposes as claimed in claim 6, it is characterised in that the preparation is administered simultaneously with tuberculotherapy medicine or priority
Using.
8. a kind of purposes of pharmaceutical composition as claimed in claim 2, it is characterised in that described pharmaceutical composition is used to select
From one or more purposes of the following group：
(i) it is used to prepare to treat phthisical medicine,
(ii) it is used to prepare the medicine that induction produces V γ 2V δ 2T cells, and/or
(iii) it is used to prepare the medicine that induction produces treating tuberculosis effector.
9. a kind of medicine box, it is characterised in that the medicine box contains：
(i) the first container, and loaded on active component (a) zoledronic acid in first container or derivatives thereof, or contain work
The medicine of property composition (a)；
(ii) second container, and loaded on active component (b) interleukins in the second container, or contain active component
(b) medicine；And
(iii) the 3rd container, and loaded on active component (c) the tuberculotherapy medicine in the 3rd container, or containing active
The medicine of composition (c)；And
(iv) specification, recorded in the specification and active component (a), active component (b) and active component (c) is given in combination
So as to the explanation for the treatment of cancer.
10. medicine box as claimed in claim 9, it is characterised in that the medicine box is used to treat tuberculosis.
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| CN201610560001.0A CN107617101B (en) | 2016-07-15 | 2016-07-15 | Zoledronic acid-containing and interleukin-containing medium pharmaceutical combination of element 2 and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110448681A (en) * | 2019-08-26 | 2019-11-15 | 华中科技大学 | A kind of combination medicine for malignant tumour immunization therapy |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100009447A1 (en) * | 2008-07-10 | 2010-01-14 | Hyogo College Of Medicine | Vgamma9Vdelta2 T cell proliferation agent, method for producing activated Vgamma9Vdelta2 T cells, and uses thereof |
-
2016
- 2016-07-15 CN CN201610560001.0A patent/CN107617101B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100009447A1 (en) * | 2008-07-10 | 2010-01-14 | Hyogo College Of Medicine | Vgamma9Vdelta2 T cell proliferation agent, method for producing activated Vgamma9Vdelta2 T cells, and uses thereof |
Non-Patent Citations (3)
| Title |
|---|
| ARWA QAQISH: "Adoptively Transferred Vγ2Vδ2 T cells Protect against the Dissemination of M. tuberculosis in Macaques", 《UNIVERSITY OF ILLINOIS AT CHICAGO PROQUEST DISSERTATIONS PUBLISHING》 * |
| CRYSTAL Y. CHEN等: "Phosphoantigen/IL2 Expansion and Differentiation of Vc2Vd2 T Cells Increase Resistance to Tuberculosis in Nonhuman Primates", 《PLOS ONE》 * |
| V.FERLAZZO等: "《In Vitro Effects of Aminobisphosphonates on Vγ9Vδ2T Cell Activation and Differentiation》", 《INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110448681A (en) * | 2019-08-26 | 2019-11-15 | 华中科技大学 | A kind of combination medicine for malignant tumour immunization therapy |
| CN110448681B (en) * | 2019-08-26 | 2020-12-15 | 君维安(武汉)生命科技有限公司 | Combined medicine for malignant tumor immunotherapy |
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