CN103816146A - Application of FSK (forskolin) in preventing COPD (chronic obstructive pulmonary disease) - Google Patents

Application of FSK (forskolin) in preventing COPD (chronic obstructive pulmonary disease) Download PDF

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CN103816146A
CN103816146A CN201410083162.6A CN201410083162A CN103816146A CN 103816146 A CN103816146 A CN 103816146A CN 201410083162 A CN201410083162 A CN 201410083162A CN 103816146 A CN103816146 A CN 103816146A
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fsk
copd
mice
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model
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杨为民
王蕾
翁稚颖
许云龙
刘霞
杜晓华
彭沛华
王友兰
卿晨
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Kunming Medical University
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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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Abstract

The invention provides a novel application of compound FSK (forskolin) in preventing the COPD (chronic obstructive pulmonary disease). The FSK can be used as an effective component for drug use or health-care use and can be prepared into tablets, buccal tablets, capsules, granules, oral solutions, injection, aerosol, emplastrum and the like with other components free from repulsive interaction. According to the application, administration methods such as FSK oral intragastric administration, intraperitoneal injection and the like are adopted, and experiment researches are performed on a cigarette smoke inhalation induction mouse COPD model and an elastase induction mouse COPD model to prove that FSK has remarkable preventive treatment functions on the cigarette smoke inhalation induction COPD and the elastase induction COPD. Besides, acute toxicity and long term toxicity tests of FSK prove that the application is safe, the dosage of an adult every day is 10-120 mg, and the administration methods comprise oral administration, injection and spraying.

Description

Forskolin is in the application preventing and treating in chronic obstructive pulmonary disease
Technical field
The invention belongs to pulmonary disease medicine field, relate in particular to a kind of Forskolin in the application preventing and treating in chronic obstructive pulmonary disease.
Background technology
Chronic obstructive pulmonary disease (COPD) is mainly caused by smoking, atmospheric pollution and pulmonary's chronic infection etc., and its interim process mainly comprises chronic bronchitis, emphysema and asthma etc.COPD is that terminal bronchiole distal portions (comprising respiratory bronchioles, alveolar duct, alveolar sac and alveolar) expands, and with the destruction of air cavity wall, it is a kind of pulmonary disease take flow limitation as feature, flow limitation is not exclusively reversible, be and carry out sexual development and become COPD, mainly involve pulmonary, but also can cause pulmonary's infringement of each organ in addition.COPD occupies the 4th of the current whole world cause of death, and because its number of patients is many, mortality rate is high, and social economical burden weight becomes an important public health problem.
Forskolin (Forskolin, FSK) is that the main active in Coleus forskohlii Briq. (Coleusforskolin) plant is produced in the Yunnan that is only distributed in Yunnan Province of China northeast, belongs to diterpene-kind compound, and molecular formula is C 22h 34o 7, molecular weight is 410, structural formula is as shown in the formula shown in (1):
Figure BDA0000474380410000011
The effects such as FSK has spasmolytic, eliminates the phlegm, antiinflammatory, blood pressure lowering, antiplatelet aggregation, reduction intraocular pressure.
Summary of the invention
The object of the present invention is to provide a kind of Forskolin (FSK) in the application preventing and treating in chronic obstructive pulmonary disease (COPD), be intended to excavate the new function of FSK and by FSK, COPD carried out to active and effective prevention and treatment.
The present invention is achieved in that a kind of Forskolin is in the application preventing and treating in chronic obstructive pulmonary disease.
Preferably, described Forskolin can be prepared as tablet, buccal tablet, capsule, granule, oral liquid, injection, aerosol, spray or emplastrum.
The present invention overcomes the deficiencies in the prior art, the application of a kind of FSK in control COPD is provided, FSK can be separately as medicinal or health care effective ingredient, also can with other component compatibility without repulsive interaction, make medicament or the health product of corresponding dosage form, for example can be prepared into the multiple peroral dosage forms such as tablet, buccal tablet, capsule, granule, oral liquid, also can be prepared into the dosage forms such as injection, aerosol, emplastrum.
The present invention adopts the administering modes such as the administration of FSK oral administration gavage and lumbar injection, suck to bring out on two kinds of animal models of mice COPD in elastoser, smoke from cigarette and carry out experimentation, proves that FSK brings out COPD to elastoser and smoke from cigarette suction and has obvious prophylactic treatment effect.Wherein, in elastoser inducing mouse COPD experiment, with model group comparison, FSK(1mg/kg) group can significantly reduce elastoser and bring out the lung volume weight ratio (P<0.01) of mice Model of Emphysema; FSK(1,4mg/kg) group can obviously reduce average alveolar area (MAA) that elastoser brings out mice Model of Emphysema (P<0.05), can obviously increase the average alveolar number (MAN) of emphysema mice (P<0.05), the pathological lesion that prompting FSK brings out mice Model of Emphysema to elastoser improves significantly; And pulmonary's histopathology section demonstration, compared with model group, the alveolar ectasia of the each dosage group of FSK, the situations such as alveolar septum fracture and alveolar fusion are all significantly improved.Suck in (3 months) inducing mouse COPD experiment FSK(gastric infusion at smoke from cigarette) pathological lesion of smoke from cigarette suction COPD model mice is improved significantly; And pulmonary's histopathology section demonstration, compared with model group, the alveolar ectasia of the each dosage group of FSK, the situations such as alveolar septum fracture and alveolar fusion are all significantly improved; With model group comparison, FSK(2,8mg/kg) group can reduce the content of IL-6 in serum very significantly.
In addition, FSK of the present invention proves that through acute toxicity and long term toxicity test result application is safe.Every consumption per day of being grown up is 10～120mg, and that administering mode comprises is oral, injection, spraying.
Accompanying drawing explanation
Fig. 1 is that in the embodiment of the present invention 2, FSK affects result figure to the PPE induction COPD morphologic impact of mouse lung histopathology and the average alveolar area on COPD mice and average alveolar number.
Fig. 2 be in the embodiment of the present invention 2 the lung volume weight ratio of FSK on PPE induction COPD mice affect result figure;
What Fig. 3 was that in the embodiment of the present invention 3, FSK sucks induction the COPD morphologic impact of mouse lung histopathology and the average alveolar area on COPD mice and average alveolar number to smoke from cigarette affects result figure;
What Fig. 4 was that in the embodiment of the present invention 3, FSK sucks induction COPD mouse lung volume anharmonic ratio to smoke from cigarette affects result figure;
What Fig. 5 was that in the embodiment of the present invention 3, FSK sucks IL-6 content in induction COPD mice serum to smoke from cigarette affects result figure.
The specific embodiment
In order to make object of the present invention, technical scheme and advantage clearer, below in conjunction with drawings and Examples, the present invention is further elaborated.Should be appreciated that specific embodiment described herein, only in order to explain the present invention, is not intended to limit the present invention.
Embodiment 1FSK preparation
(1) get 10Kg Yunnan and produce Coleus forskohlii Briq. (Coleus forskohlii) dry product, at room temperature use 50 liter of 95% ethanol (ethanol) to extract 3 times, extracting solution obtains ethanol extraction through concentrating under reduced pressure, after extract adds a small amount of water to mix thoroughly, distribute with petroleum ether, chloroform, n-butyl alcohol successively, after concentrating under reduced pressure, obtain extract separately.
(2) get the upper silicagel column of chloroform extract 120g, with the petroleum ether-acetone eluting that increases progressively ratio, with thin layer chromatography TLC monitoring eluting result, obtain effective site CF-E.
(3) effective site CF-E, again through chromatography and recrystallization purifying repeatedly, can obtain the pure Forskolin of Coleus forskohlii Briq..
(4) FSK is added to starch or corresponding adjuvant, mix rear granulation, be pressed into the oral formulations such as tablet or capsule, or add other adjuvants to make oral liquid, atomizing aerosol, emplastrum etc., or add injection solvent and other adjuvants etc. to make injection.
Embodiment 2 on elastoser (PPE) inducing mouse COPD model, the preventive and therapeutic effect experimentation of Forskolin (FSK) to COPD
1, test method
Model is set up and experiment packet transaction: mice is divided into Normal group and modeling group at random, and porcine pancreatic elastase (PPE, 0.3U/10g body weight) is splashed into mice nasal cavity, preparation mice COPD model.Normal group adopts identical method to splash into the normal saline of equivalent in mice nasal cavity.Become mould mice to be divided at random 3 groups: COPD model control group, FSK(1,4mg/kg) group and aminophylline (20mg/kg) matched group.Each group mice intraperitoneal injection every day 1 time, Normal group and COPD model control group wait capacity solvent, successive administration 11 days.
The mensuration of blood oxygen pressure: common carotid artery blood is got blood and measured immediately, is used the portable blood gas analyzer of the i-stat300 of Abbott Laboratories (Abbotti-STATSystem).
The mensuration of left lung volume and histopathologic examination of pulmonary: get the left lung of mice and immerse in 10% formalin solution, measure its lifting rate, obtain left lung tissue volume (V), more than fixing 24h.Every mice is got left lung maximum transverse diameter place lung tissue, routine paraffin wax embedded section, and row HE dyeing, observes histopathology and changes.Two sections of every mice observation simultaneously, every random selection of section, is avoided bronchus and large, medium vessels at 5 visuals field when measurement.
2, experimental result
(1) impact of FSK on the PPE induction COPD morphologic impact of mouse lung histopathology and the average alveolar area (MAA) on COPD mice and average alveolar number (MAN), result is as Fig. 1 and as shown in table 1 below:
Figure BDA0000474380410000041
Table 1FSK induces the average alveolar area of COPD mice and the impact of average alveolar number to PPE
In table 1, data are expressed as mean ± SE, and data statistics method adopts one way ANOVA method(Student-Newman-keuls test), vs Model, * p<0.05, * * P<0.01.
From Fig. 1 and table 1, can find out, with model group comparison, FSK(1,4mg/kg) group can significantly reduce average alveolar area (MAA) that PPE brings out mice COPD model (P<0.05), all can significantly increase the average alveolar number (MAN) of COPD mice (P<0.05), the pathological lesion that prompting FSK and FSK bring out mice COPD model to PPE improves significantly.
(2) impact of the lung volume weight ratio (V/W) of FSK on PPE induction COPD mice, result is as Fig. 2 and as shown in table 2 below:
Figure BDA0000474380410000052
The impact of the lung volume weight ratio of table 2FSK/FSK on PPE induction COPD mice
In table 2, data are expressed as mean ± SE, and data statistics method adopts one way ANOVA method(Student-Newman-keulstest), vs Model, * p<0.05, * * P<0.01.
Can find out from Fig. 2 and table 2, with model group comparison, FSK(1mg/kg) group can reduce PPE and bring out the lung volume weight ratio (P<0.01) of mice COPD model very significantly, and the COPD situation that prompting FSK brings out COPD mouse model to PPE improves significantly.
(3) impact of the blood oxygen pressure of FSK on PPE induction COPD mice, result is as shown in table 3 below:
Figure BDA0000474380410000061
The impact of the blood oxygen pressure of table 3FSK on PPE induction COPD mice
In table 3, data are expressed as mean ± SE, and data statistics method adopts Kruskal-Wallis One Way Analysis of Variance on Rank, vs Model.
As can be seen from Table 3, with model group comparison, FSK(1mg/kg) group can improve PPE and bring out the blood oxygen pressure of mice COPD model, but not statistically significant (P>0.05).
Embodiment 3 sucks on inducing mouse COPD model at smoke from cigarette, the preventive and therapeutic effect experimentation of FSK to COPD
1, experimental technique
Model is set up and experiment packet transaction: mice is divided into Normal group and COPD modeling group at random.COPD modeling group mice smoke from cigarette sucks after two months gastric infusion 1 time every day, and successive administration 30 days, continues during this time smoke from cigarette and suck, smoke inhalation 3 months altogether.Normal group mice is also put into another lucite case, breathe air simultaneously.Modeling mice is divided into 3 groups at random: COPD model control group, FSK(2,8mg/kg) group.Normal group and COPD model control group wait capacity solvent.
The mensuration of left lung volume and histopathologic examination of pulmonary: get the left lung of mice and immerse in 10% formalin solution, measure its lifting rate, obtain left lung tissue volume (V), more than fixing 24h.Every mice is got left lung maximum transverse diameter place lung tissue, routine paraffin wax embedded section, and row HE dyeing, observes histopathology and changes.Two sections of every mice observation simultaneously, every random selection of section, is avoided bronchus and large, medium vessels at 5 visuals field when measurement.
The mensuration of blood serum IL-6: common carotid artery is got blood, centrifugal specimen under low temperature, gets serum supernatant ,-80 ℃ of preservations.The content of measuring IL-6 in serum by enzyme linked immunosorbent assay (ELISA method), concrete operations are carried out according to reagent description.
2, result of the test
(1) FSK sucks the impact of the induction COPD morphologic impact of mouse lung histopathology and the average alveolar area (MAA) on COPD mice and average alveolar number (MAN) on smoke from cigarette, and result is as Fig. 3 and as shown in table 4 below:
Figure BDA0000474380410000071
Table 4FSK sucks the impact of induction COPD mice average alveolar area and average alveolar number on smoke from cigarette
In table 4, data are expressed as mean ± SE, and data statistics method adopts one way ANOVA method(Student-Newman-keuls test), vs Model, * p<0.05.
From table 4 and Fig. 3, can find out, compared with model group, ISOF group alveolar interstitial inflammation obviously alleviates, and alveolar ectasia fusion and alveolar septum fracture all have clear improvement.With model group comparison; ISOF(2,8mg/kg) group all can significantly reduce COPD mice average alveolar area (MAA) (P<0.05); all can significantly increase the average alveolar number (MAN) of COPD mice (P<0.05), the pathological lesion that prompting ISOF sucks COPD model mice to smoke from cigarette has obvious preventive effect.
(2) impact of FSK on mouse lung volume anharmonic ratio (V/W), result is as Fig. 4 and as shown in table 5 below:
Figure BDA0000474380410000081
Table 5FSK sucks the impact of induction COPD mouse lung volume anharmonic ratio on smoke from cigarette
In table 5, data are expressed as mean ± SE, and data statistics method adopts Kruskal-Wallis One Way Analysis of Variance on Rank, vs Model, * p<0.05.
From table 5 and Fig. 4, can find out, with the comparison of COPD model group, FSK(8mg/kg) group can reduce lung volume weight ratio, but no difference of science of statistics.
(3) FSK sucks the impact of IL-6 content in induction COPD mice serum on smoke from cigarette, and result is as Fig. 5 and as shown in table 6 below:
Figure BDA0000474380410000082
Table 6FSK sucks the impact of IL-6 content in induction COPD mice serum on smoke from cigarette
In table 6, data are expressed as mean ± SE, and data statistics method adopts one way ANOVA method(Fisher LSD Method), vs Model, * p<0.05, * * P<0.01, * * * P<0.001.
From Fig. 5 and table 6, can find out, with model group comparison, FSK(2mg/kg) group all can reduce the content (P<0.001) of IL-6 in serum very significantly.
Compare the shortcoming and defect with prior art, the present invention has following beneficial effect: the present invention can be separately as medicinal or health care effective ingredient, also can with other component compatibility without repulsive interaction, make medicament or the health product of corresponding dosage form, be applied to and prevent and treat in chronic obstructive pulmonary disease, there is good prevention and therapeutic effect, and safety non-toxic.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any modifications of doing within the spirit and principles in the present invention, be equal to and replace and improvement etc., within all should being included in protection scope of the present invention.

Claims (2)

1. a Forskolin is in the application preventing and treating in chronic obstructive pulmonary disease.
2. Forskolin as claimed in claim 1, in the application preventing and treating in chronic obstructive pulmonary disease, is characterized in that, described Forskolin is tablet, buccal tablet, capsule, granule, oral liquid, injection, aerosol, spray or emplastrum.
CN201410083162.6A 2014-03-07 2014-03-07 Application of FSK (forskolin) in preventing COPD (chronic obstructive pulmonary disease) Pending CN103816146A (en)

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PCT/CN2015/000010 WO2015131655A1 (en) 2014-03-07 2015-01-06 Use of fsk in preventing and treating chronic obstructive pulmonary disease

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109966282A (en) * 2019-03-20 2019-07-05 昆明医科大学 Acetyl Forskolin is gone to prevent and treat the application in chronic obstructive pulmonary disease in preparation

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CN112843044A (en) * 2021-01-19 2021-05-28 天津中医药大学 Application of alpinetin in preparing medicament for treating airflow-limited lung disease

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109966282A (en) * 2019-03-20 2019-07-05 昆明医科大学 Acetyl Forskolin is gone to prevent and treat the application in chronic obstructive pulmonary disease in preparation

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Application publication date: 20140528