CN102178679B - Application of pyrroloquinoline quinone to the bone marrow hemopoietic function after recovery of radiation - Google Patents
Application of pyrroloquinoline quinone to the bone marrow hemopoietic function after recovery of radiation Download PDFInfo
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Abstract
The invention discloses application of pyrroloquinoline quinone to the bone marrow hemopoietic function after recovery of radiation, in particular application of the pyrroloquinoline quinone (PQQ) or a pharmaceutically acceptable salt or ester of the pyrroloquinoline quinine or a medicinal composition containing either salt or ester to preparing drugs for treating bone marrow hemopoietic damage. The tested drug PQQ can be administrated with a certain promoting effect on the recovery of white blood cells, thus being beneficial to the elimination of damaged erythropoiesis factors and the recovery of reticulocytes ratio. A tested drug group and a positive drug group are higher than a contrast group in the number of bone marrow cells, and tend to increase in bone marrow DNA (deoxyribonucleic acid) content. As indicated, the PQQ can promote the recovery of bone marrow hemopoietic function.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to the application of PQQ.
Background technology
Radiation injury is the body tissue infringement that is caused by radiation exposure.The radiation injury degree is relevant with exposure dose, persistent period and irradiation speed.The health area of roentgenization and ray distribution in vivo also can influence the radiation injury effect.The acute radiation injury that heavy dose of ray causes can cause damage to a plurality of organs of organism, comprises hemopoietic system, brain and gastrointestinal tract etc.Brain syndrome causes when receiving very high dose (greater than 30Gy) irradiation greatly, usually threat to life.And bone marrow is the vital tissue of being responsible for human body hemopoietic, and is high for radiosensitivity.If the irradiation accumulated dose surpasses 6Gy, usually cause body dead because of hematopoietic disorder.
The medicine that is used for radiation injury at present has a variety of.Wide spectrum cytoprotective amifostine (amifostine claims WR-2721 again) is the medicine that the most effectively protects radioprotective during the cold war surplus U.S.'s Walter-Reed Army Research Institute synthetic 4400 in kind of the radioprotector.Injectivity calcium calcium trisodium pentetate (Ca-DTPA) and zinc calcium trisodium pentetate (Zn-DTPA) can combine with some radioactive substance, quicken the speed that these material permeance urines are discharged, thereby reduce internal contamination.Also can Antiradiation injury to the medicine of free radical and oxidative damage, research shows that antioxidases such as superoxide dismutase (SOD), MnSOD can both reduce by the index of the active oxygen in the radiation murine liver tissue homogenate and other peroxide injury.Grape procyanidins, bayberry polyphenol, Radix Puerariae flavone, sargassan, spirulina, Folium Ginkgo, Radix Rhodiolae etc. all have certain protective action to the oxidative damage of radioactive exposure personnel or animal.
Though year still can not be satisfied the requirement of clinical application to effectiveness, toxicity, feasibility, specificity and allowance fully surplus the research of antiradiation drug had gone through 40.The medicine of wide spectrum cytoprotective amifostine and injectivity calcium calcium trisodium pentetate (Ca-DTPA) and this type of zinc calcium trisodium pentetate (Zn-DTPA) is not suitable for nephrotic and bone marrow depression patient.And often derive from natural animal and plant to the medicine of free radical and oxidative damage, and complicated component, wayward for content and the quality of the radiation-resisting functional factor wherein, using dosage is difficult for the requirement that accurate difficulty satisfies clinical application and war preparedness medicine.
PQQ (Pyrroloquinoline quinone; PQQ), be after pyridine nucleotide and riboflavin nucleotide, the coenzyme of the third oxidation-reduction type of finding the end of the seventies in last century; Be multiple oxidoreductase (for example; GDH and ethanol dehydrogenase) prothetic group, be the strongest material of oxidation resistance in the body found up to now, play a significant role in vivo.Research shows; PQQ is except that as somatomedin and the nutrient substance, also has to promote nerve growth factor to generate, promote wound healing, prevent and treat heart disease, reduce myocardial infarction area, the neuroprotective system, strengthen toleration, the liver protecting, blood sugar lowering, increase mitochondrial function to ethanol, remove different physiological roles such as free radical, antioxidation.
There are some researches show that in recent years PQQ can reduce oxidation level through strengthening the cell oxidation resistance, thereby to irradiated cell (the Jiangsu University's journal (medicine) 2009,19 (4): 293-295) that shields.The PQQ rat skin acute injury that local irradiation causes to high energy electron has treatment and preventive effect (Jiangsu University's journal (medicine) 2008,18 (5): 403-406; Chinese invention patent CN101507724A).PQQ can remove gamma-radiation mice interior free yl, transfers mice whole body free radical scavenging system simultaneously, reduces free-radical contents (Chinese radiation hygiene 2009,18 (4): 403-404).
Summary of the invention
The object of the present invention is to provide PQQ or its pharmaceutically acceptable salt or ester or contain in them any the application of pharmaceutical composition in the destructive medicine of preparation treatment hemopoietic function of bone marrow.
Wherein, described marrow hemopoietic function is destroyed and is caused by acute radiation injury.The dosage that causes described acute radiation injury is 3～5Gy, is preferably 4Gy.
Wherein, described PQQ pharmaceutically acceptable salt can be and well known to a person skilled in the art any salt, is preferably potassium salt or sodium salt.
Among the present invention, described pharmaceutical composition also can comprise amifostine, nilestriol, superoxide dismutase, vitamin C, one or more in the vitamin E.
In one embodiment of the invention, described medicine is tablet, pill, capsule, powder, granule, solution, suspending agent or syrup.
In one embodiment of the invention, said amount of drug is counted 0.001-10mg/kg body weight every day by the PQQ active component.
The present invention is right through PQQ
60Two tests that influence of Co gamma-rays high dose radiation mice survival condition and bone marrow hematogenesis function are estimated.Positive drug is a nilestriol; Radiation device is military medicine academy institute of radio-medicine
60The Co radiation source.
Twice result of experiment can find out and receive test product PQQ can significantly improve survival rate and the time-to-live that receives the roentgenization mice that wherein 4mg/kg group effect is remarkable.Right
60In the experiment to the hematopoietic function influence under the Co radiation; Receive reagent thing PQQ certain promotion to be arranged for leukocytic recovery; Promote the elimination of damage erythroid hematopoiesis factor; Make the increase of medullary cell quantity and the tendency that increases the bone marrow dna content is arranged, show that it can be applied to the destructive medicine of preparation treatment hemopoietic function of bone marrow.Compare with the medicine of the radiation-induced loss of present existing treatment, it is little that PQQ has toxicity, and side reaction is few, and it is wide to be suitable for the crowd, and content and quality are easy to advantages such as control.
Description of drawings
The survival curve figure of Fig. 1 raying mice (Kaplan-Meier curve, * P ∠ 0.05, * * P ∠ 0.01, * * P ∠ 0.001vs matched group).
The specific embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.
Embodiment 1 PQQ PQQ is right
60The research of mice survival condition influence under the radiation of Co gamma-rays
1 test objective
Utilize mice
60Co gamma-ray irradiation model is observed the influence of PQQ to the mice survival condition.
2 experiment materials
2.1 given the test agent
Medicine name: PQQ, be called for short PQQ, can commercially availablely obtain, or can be according to (microorganism journal .2007,47 (6): 982-986.) disclosed method preparation.
2.2 positive control drug
Medicine name: nilestriol (Nilestriol) is bought from Radiation Medical Science Inst., Chinese Academy of Military Medical Science (CN nine Room.
Batch number: 20081007.
Character: white powder.
2.3 laboratory animal
Adult KM mice, Military Medical Science Institute's Experimental Animal Center breeding.The mice body weight is 16.0～18.0g.Laboratory animal credit number: SCXK-(army) 2002-001.Laboratory animal is at the animal center SPF of Military Medical Science Institute experiment indoor feeding, the laboratory quality certification number: SYXK (army)-2002-016.10 mices of every cage are raised to be the mice feed prepared specially, freely drink water.The indoor temperature of zoopery remains on about 25 ℃, and relative humidity remains on 40-70%, illumination every day 12 hours.
3 experimental techniques
3.1 illuminate condition
60The Co gamma-rays, absorbed dose rate 236.05cGy/min.Exposure mice survival rate test absorbed dose are 8.0Gy, the whole body once irradiating.
3.2 group technology
Five groups are established in the test of mice survival rate: test is provided with dose groups (4mg/kg) among irradiation control group, positive drug control group (nilestriol 10mg/kg), PQQ low dose group (2mg/kg), the PQQ, PQQ high dose group (8mg/kg group).Receive the situation of 8.0Gy roentgenization mice survival rate.Every group 20, male and female half and half.
3.3 medication
Each group is the oral administration gavage administration, and the administration time scheme sees the following form 1
Table 1 administration time calendar
3.4 observation index and date processing
Press such scheme irradiation and administration,
60After the Co8.0Gy dose irradiation, every day at the upper and lower noon is respectively observed mice 1 time, and record dead animal number and date of death, be 30d observing time.
Calculate CNN surviving fraction PF (=processed group dead animal mean survival time/irradiation control group dead animal mean survival time).Enumeration data is used X
2Check, measurement data is carried out statistical procedures with the T method of inspection.Draw mice survival curve (Kaplan-Meier curve), carry out statistical analysis with sequential card side (Log rank test) method.
4 experimental results
4.1PQQ to receiving influence according to the mice survival condition
Receive the situation of 8.0Gy roentgenization mice survival rate, in 30 days observation period, the irradiation control group animal only survives 2; Survival rate is 10%, and PQQ 2mg/kg group survival rate is 35%, and PQQ 4mg/kg group survival rate is 60%; Statistical significance is arranged, and animals survived quantity is more; The survival rate of positive drug group is 40%; But the survival rate of PQQ 8mg/kg group is merely 25%, sees table 2.
Table 2PQQ is to receiving the influence of 8.0Gy roentgenization mice survival rate
Annotate: compare " * " P＜0.05 with irradiation control group; " * * " P＜0.01; " * * * " P＜0.001
The survival curve figure of raying mice (Kaplan-Meier curve); See Fig. 1; The survival curve of PQQ administration group and positive control treated animal is significantly higher than the radiation matched group, and wherein the sequential X 2 test of dose groups has statistical significance among positive drug, PQQ low dose group and the PQQ.
Add up each treated animal natural law of on average surviving, see table 3.PQQ administration group 2mg/kg and the average survival of 4mg/kg group natural law are higher than irradiation control group, and wherein buck survival natural law is longer, and statistical significance is arranged.
The influence that table 3PQQ survives to the mice that receives the 8.0Gy roentgenization
Annotate: compare " * " P＜0.05 with irradiation control group; " * * " P＜0.01; " * * * " P＜0.001; Observing time is by 30d.
Statistics is respectively organized the dead animal natural law of on average surviving, and sees table 4, with irradiation control group relatively, PQQ group dead animal prolonged survival period, CNN surviving fraction PF is greater than 1.
The influence that table 4PQQ survives to the dead mice that receives the 8.0Gy roentgenization
Annotate: compare " * " P＜0.05 with irradiation control group; " * * " P＜0.01; " * * * " P＜0.001;
5 discussion and conclusion
The most of animal deads of radiation control animals, current deposit rate is merely 10%, and the survival rate of being tried the thing treated animal is 25%-60%, is higher than the radiation matched group; The survival rate of positive drug treated animal is 40%.On average the survive observation index such as average survival natural law of natural law and dead animal of comprehensive irradiation animal dis motility rate, animal survival curve, each processed group receive reagent PQQ that the survival condition of exposure animal is had stronger protective effect.
Conclusion: PQQ is right
60The death of Co8.0Gy irradiation induced mice has protective effect, and the protective effect when dosage is 4mg/kg is the strongest.
Embodiment 2 PQQs are to the influence of Co radiation gamma mouse bone marrow cells hematopoietic function
1 test objective
Utilize mice
60Co gamma-ray irradiation model is observed the influence of PQQ to mouse hemopoietic system.
2 experiment materials
With embodiment 1
2.3 laboratory animal
With embodiment 1
3 experimental techniques
3.1 illuminate condition
60The Co gamma-rays, absorbed dose rate 236.05cGy/min.Exposure mice survival rate test absorbed dose are 4.0Gy.The result of embodiment 1 shows; 8.0Gy be fatal dose, 4.0Gy is a sublethal dose, because will study the therapeutical effect of PQQ to the bone marrow hematogenesis radiation injury; If adopt fatal dose can cause mice dead in experimentation, thereby influence the analysis of experimental result.Therefore present embodiment adopts sublethal dose whole body once irradiating.
3.2 group technology
Three groups are established in the test of mice survival rate: irradiation control group, positive drug control group (nilestriol 10mg/kg), PQQ organize (4mg/kg).Every group 20, male and female half and half.
3.3 medication
Each group is the oral administration gavage administration, and the administration time scheme sees the following form 5.
Table 5 administration time calendar
3.4 detect index and method
Press such scheme irradiation and administration,
60After the Co 4.0Gy dose irradiation, the blood sampling of pre-irradiation afterbody, after each leading indicator irradiation of mensuration hematology, afterbody blood sampling in per 3 days is once measured hematology's leading indicator, and the observation period is limited to 21 days.After the last blood sampling, put to death animal, measure the dna content and the cell quantity of femur bone marrow.
The hematological indices detection method: cytometry is measured with Sysmex F820 blood analyser, and used main agents comprises: hemolysin-SYS-II, No. the 1400019th, Shandong Ji food medicine prison tool (standard) word 2007, Shandong STAC Medical Science And Technology Co., Ltd.; Diluent-SYS, No. the 1400018th, Shandong Ji food medicine prison tool (standard) word 2007, Shandong STAC Medical Science And Technology Co., Ltd..
The reticulocyte count method is that afterbody is taken a blood sample the adding of 50 μ l blood with the yellow cresyl blue dyeing of volume, hatches 30min for 37 ℃, smear, microscopically counting.
3.5 observation index and date processing
Data represent that with mean ± standard deviation enumeration data is used X
2Check, measurement data is carried out statistical procedures with the T method of inspection.
4 experimental results
4.1 the variation of leucocyte content
Mice received roentgenization 21 days, the leukocyte Changing Pattern: drop to minimum according to the 3rd day leukocyte in back, return to basically in the time of 21 days near normal (referring to table 6 and table 7).Since in the blood before the WBC medicine with medicine after the fluctuation of detected value bigger, mainly through its with medicine before the relative value that compares judge the influence that receives the reagent thing, the practical measurement value is through for referencial use.Played the administration group in 12 days and raise obviously (P＜0.05, relative value) with positive group leukocyte, prompting receives the reagent thing can promote the recovery of the PBL of acute radiation sickness mice.
Table 6 receives to shine 21 days leukocyte changing values of mice, and (WBC 10
9/ L)
Table 7 receives according to 21 days leukocyte relative changing values (WBC) of mice
Annotate: compare " * " P＜0.05 with irradiation control group; " * * " P＜0.01
4.2 the variation of erythrocyte content
Mice received roentgenization 21 days, the change of red blood cell rule: dropped to minimum on the 6th day according to the back, return to normal (seeing table 8 and table 9) in the time of 21 days.It is bigger that each group is measured numerical fluctuations, do not see evident difference.
Table 8 receives to shine 21 days change of red blood cell values of mice, and (RBC 10
12/ L)
Table 9 receives according to 21 days erythrocyte relative changing values (RBC) of mice
Annotate: compare " * " P＜0.05 with irradiation control group; " * * " P＜0.01
4.3 the variation of content of hemoglobin
Mice received roentgenization 21 days, the hemoglobin Changing Pattern: bigger according to the back fluctuation, return to basically in the time of 21 days near normal (seeing table 10 and table 11).It is bigger that each group is measured numerical fluctuations, do not see evident difference.
Table 10 receives according to 21 days hemoglobin changing values (HGB g/L) of mice
Table 11 receives according to 21 days hemoglobin relative changing values (HGB) of mice
4.4 the variation of platelet content
Mice received roentgenization 21 days, the platelet Changing Pattern: dropped to minimum on the 6th to 9 day according to the back, return to normal (table 12 and table 13) in the time of 21 days.And each group does not have evident difference.
Table 12 receives to shine 21 days platelet changing values of mice, and (PLT 10
9/ L)
Table 13 receives according to 21 days platelet relative changing values (PLT) of mice
4.5 the variation of reticulocyte content
Mice received roentgenization 21 days, the Reticulocyte Changing Pattern: the photograph back was increased to the highest on the 3rd day, returned to basically in the time of 21 days near normal (table 14).And the administration group obviously reduces (P＜0.05) with positive group after 9 days, shows the recovery that receives the reagent thing can promote the peripheral blood Reticulocyte of acute radiation sickness mice.
Table 14 receives according to 21 days reticulocyte changing values (‰) of mice
Annotate: compare " * " P＜0.05 with irradiation control group; " * * " P＜0.01
4.6 the variation of medullary cell quantity and bone marrow dna content
Mice received roentgenization 21 days; Bone marrow cell changes: the bone marrow cell of administration group and positive drug group is apparently higher than irradiation control group (P＜0.05); And the bone marrow cell of administration group is also apparently higher than the positive drug group; Show the recovery that receives the reagent thing can promote the medullary cell of acute radiation sickness mice, and recovery capability is superior to positive drug (table 15).
Mice received roentgenization 21 days, and medullary cell DNA changes: the bone marrow DNA of administration group and positive group shows to receive the reagent thing to recover to have certain facilitation (table 16) for the bone marrow DNA that promotes the acute radiation sickness mice a little more than irradiation control group.
Table 16 receives according to 21 days bone marrow cells of mice and bone marrow DNA numerical value
Annotate: compare " * " P＜0.05 with irradiation control group; " * * * " P＜0.001
4.8 the measurement of relevant organ weights
Mice received roentgenization 21 days, and each organizes body weight does not have significant difference, and the spleen weight of PQQ group and positive drug group is light than matched group, but organ coefficient does not have marked difference.Dissect the back spleen tuberosity is observed, do not see that each group has significant change (table 17 and table 18).
Table 17 receives according to 21 days body weight of mice and organ weights
Table 18 receives according to 21 days body weight of mice and organ weights coefficient
7 conclusions
To receiving
60After the administration of Co irradiation mouse model, receive reagent thing PQQ certain facilitation to be arranged, promote the elimination of damage erythroid hematopoiesis factor, help the recovery of Reticulocyte ratio for leukocytic recovery.The bone marrow cell that is tried thing group and positive drug group is higher than matched group, and the bone marrow dna content also has the tendency that increases.It is thus clear that tried the recovery Effects that thing has certain promotion bone marrow hematogenesis function.
Embodiment 3 PQQ solutions
Prescription: PQQ 40mg
0.9% normal saline 100mL
Take by weighing 40mg PQQ powder, add the 100mL normal saline, stirring is dissolved powder fully, processes the PQQ aqueous solution preparation of 0.4mg/mL.
Embodiment 4 PQQ capsules
Prescription: PQQ 500mg
Starch 10g
10% starch slurry is an amount of
Process 500 capsules altogether, contain PQQ1mg in each capsule.
Earlier PQQ is mixed with starch, pulverize with colloid mill.With 10% starch slurry system soft material, soft material is crossed 20 mesh sieve system wet granulars, in 60～70 ℃ of oven dry, dried granule is with 20 mesh sieve granulate with wet granular.The capsule board that the preparation of capsule adopts lucite to process is filled.Earlier capsule medicated cap, capsule status are opened, the capsule body inserts in the capsule board hole, regulates the levels distance, makes the capsule mouth equal with the plate face.Granule is laid on the plate face, vibrates capsule board gently, make particles filled even.After filling up each capsule, with the unnecessary granule cleaning of plate face, jack-up capsule body, fit capsule medicated cap takes out capsule, promptly gets.
The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from know-why of the present invention; Can also make some improvement and retouching, these improvement and retouching also should be regarded as protection scope of the present invention.
Claims (7)
1. PQQ or its pharmaceutically acceptable salt, or contain in them any the application of pharmaceutical composition in the destructive medicine of preparation treatment hemopoietic function of bone marrow.
2. application according to claim 1 is characterized in that, described hemopoietic function of bone marrow destroys and caused by acute radiation injury.
3. application according to claim 2 is characterized in that, causes that the destructive radiological dose of said hemopoietic function of bone marrow is 3～5Gy.
4. application according to claim 1 is characterized in that, described PQQ pharmaceutically acceptable salt is potassium salt or sodium salt.
5. application according to claim 1 is characterized in that described pharmaceutical composition also contains one or more in amifostine, nilestriol, superoxide dismutase, vitamin C and the vitamin E.
6. according to each described application of claim 1～5, it is characterized in that described medicine is tablet, pill, capsule, powder, granule, solution, suspending agent or syrup.
7. application according to claim 6 is characterized in that, said amount of drug is counted 0.001-10mg/kg body weight every day by the PQQ active component.
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| CN105963297A (en) * | 2016-05-11 | 2016-09-28 | 深圳市太生源健康产业有限公司 | Application of pyrroloquinoline quinone in post-chemotherapeutic adjuvant therapy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996001635A1 (en) * | 1994-07-12 | 1996-01-25 | The Children's Medical Center Corporation | Controlling bone resorption with pyrroloquinoline quinone (pqq) and related compounds |
| CN101959528A (en) * | 2008-03-04 | 2011-01-26 | 辉瑞有限公司 | Methods of treating chronic pain |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996001635A1 (en) * | 1994-07-12 | 1996-01-25 | The Children's Medical Center Corporation | Controlling bone resorption with pyrroloquinoline quinone (pqq) and related compounds |
| CN101959528A (en) * | 2008-03-04 | 2011-01-26 | 辉瑞有限公司 | Methods of treating chronic pain |
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