CN101371832A - Medical use of triacetyl andrographolide as proinflammatory cytokine inhibitor - Google Patents
Medical use of triacetyl andrographolide as proinflammatory cytokine inhibitor Download PDFInfo
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Abstract
The invention relates to an application of 3,14,9-acetyl andrographolide in the preparation of an proinflammatory cytokine, wherein, the proinflammatory cytokine comprises any one of TNF-Alpha, IL-1Alpha, IL-1Beta, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-Gamma and NO.
Description
Technical field
The present invention relates to the application of triacetyl andrographolide in the preparation inhibitors of inflammatory cytokines.
Background technology
Inflammatory cytokine is mainly by macrophage secretion, comprises proinflammatory cytokines such as TNF-α, IL-1 α, IL-1 β, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-γ and the nitric oxide (NO) with inflammatory factor characteristic etc.Wherein study maximum be TNF-α, IL-1 β, IL-6, NO.The excessive secretion of inflammatory cytokine plays an important role in the developing of numerous disease.As: systemic inflammatory response syndrome (SIRS), pyemia, septic shock, septic shock, multiple organ dysfunction syndrome, rheumatoid arthritis, osteoarthritis, SpA, rheumatic arthritis, hypertension, coronary heart disease, myocardial infarction, heart failure, diabetes, systemic lupus erythematosus (sle), lupus nephritis, scleroderma, sarcoidosis, dermatomyositis, behcets disease, psoriasis, depression, respiratory virus infection, chronic obstructive pulmonary disease, asthma, pancreatitis, liver cirrhosis, inflammatory bowel, acquired immune deficiency syndrome (AIDS), the CastlemanShi disease, Parkinson's disease, presenile dementia, vascular headache, central nervous system injury, cerebral infarction, acute cerebral hemorrhage, brain injury, brain injury postoperative infection complication, the influenza virus encephalopathy (HIE), chronic renal insufficiency, primary nephrotic syndrome, reflux nephropathy, glomerulonephritis, hemorrhagic shock, obstructive sleep apnea syndrome, myxoma of heart, acute myeloid leukaemia, multiple myeloma, myelodysplastic syndrome, tumor, Pyoderma gangrenosum, graft versus host disease, uveitis, periodontal disease, bacterial infection, obesity etc.So the exploitation of inhibitors of inflammatory cytokines has become the hot fields that the medical research worker pays close attention to.
TNF-α is a kind of proinflammatory cytokine, is mainly produced by mononuclear cell and macrophage, participates in the process of various inflammatory reactions.Endotoxin (LPS) is the derivant of TNF-α.Discover that TNF-α has killing and wounding or suppresses biological activitys such as the phagocytic activity of tumor cell, raising neutrophilic granulocyte, the generation of increase superoxide anion, participation inflammatory reaction, infection.According to the literature, the release that suppresses TNF-α can be used for multiple treatment of diseases, comprises the systemic inflammatory response syndrome, pyemia, septic shock, multiple organ dysfunction syndrome, rheumatoid arthritis, osteoarthritis, SpA, inflammatory bowel, heart failure, diabetes, systemic lupus erythematosus (sle), scleroderma, sarcoidosis, dermatomyositis, psoriasis, acute myeloid leukaemia, Parkinson's disease, presenile dementia, depression, behcets disease, chronic obstructive pulmonary disease, asthma, acute pancreatitis, central nervous system injury, respiratory virus infection, multiple myeloma, myelodysplastic syndrome, Pyoderma gangrenosum, graft versus host disease, uveitis, periodontal disease, fat.
IL-1 β is a kind of proinflammatory cytokine that is produced by mononuclear phagocyte, dendritic cell, fibroblast etc.It can stimulate propagation and differentiation, the hemopoietic of T cell and B cell and participate in inflammatory reaction.According to the literature, the IL-1 beta inhibitor can be used for rheumatoid arthritis, systemic inflammatory response syndrome (SIRS), pyemia, septic shock, septic shock, multiple organ dysfunction syndrome, periodontal disease, heart failure, dermatomyositis, acute pancreatitis, chronic obstructive pulmonary disease, osteoarthritis, bacterial infection, multiple myeloma, presenile dementia, osteoarthritis, respiratory virus infection, asthma, depression, scleroderma etc.
IL-6 is a kind of proinflammatory cytokine that is produced by lymph sample and some non-lymphoid cell.It has stimulating cellular growth, promotes cell differentiation, quickens the growth of synthesizing, suppress the M1 HL-60 of hepatocyte acute phase protein (acute phase protein), promotes its maturation and differentiation to wait biological activity.Certain relation that has of IL-6 and multiple disease clinically is as autoimmune diseasees such as rheumatoid arthritis, systemic inflammatory response syndrome (SIRS), septic shock, septic shock, multiple organ dysfunction syndrome, septicemia, acquired immune deficiency syndrome (AIDS), myxoma of heart, CastlemanShi diseases; [Mu Lan such as acute cerebral hemorrhage, acute cerebral infarction, brain injury, brain injury postoperative infection complication, influenza virus encephalopathy (HIE), coronary heart disease, severe pancreatitis, lupus nephritis, chronic renal insufficiency, primary nephrotic syndrome, reflux nephropathy, hemorrhagic shock, obstructive sleep apnea syndrome, tumor, Wei Lianbo, Li Xue. the progress of interleukin 6. Shenzhen combination of Chinese and Western medicine magazine, 2003,13 (3): 185-188; Zhao Youcheng, Nan Qiong, Ke Qing. the clinical evaluation of sepsis patient blood serum IL-6 horizontal detection. Chinese doctor's magazine, 2006, (5): 608-610 etc.].
Nitric oxide participates in many physiology of body and pathological process, participates in cell toxicant and immunomodulating, loose vascular smooth muscle, anticoagulant and the transmission information etc. of macrophage, also brings into play complexing action simultaneously in inflammatory reaction.The nitric oxide generation is excessive or not enough all to play an important role in the generation of numerous disease.Wherein nitric oxide generates excessive being found in: osteoarthritis, rheumatoid arthritis, rheumatic arthritis, systemic lupus erythematosus (sle), systemic inflammatory response syndrome, pyemia, septic shock, multiple organ dysfunction syndrome, septic shock, cerebral infarction, hypertension, myocardial infarction, congestive heart failure, glomerulonephritis, liver cirrhosis, inflammatory bowel, diabetes, acquired immune deficiency syndrome (AIDS), vascular headache, asthma, tumor [surplus jumping. nitric oxide and disease. Beijing; Science Press].
3,14, the chemical compound that 19-triacetyl andrographolide (being called for short the triacetyl andrographolide) obtains behind structure of modification for andrographolide, structural formula is as follows:
This chemical compound has report in Japanese documentation, i.e. structural formula, preparation method and the anticancer usage thereof of the open triacetyl andrographolide of JP63088124; Chinese patent literature CN1695612 also discloses structure, preparation method and antiinflammatory, immunosuppressant and the antitumor action of this chemical compound in addition.But above-mentioned document only discloses this chemical compound to triacetyl andrographolide antiinflammatory, immunosuppressant, antineoplastic action influence, the mice carbon granule of rat paw edema animal model due to the Ovum Gallus domesticus album is cleaned up experiment, DNCB acetone excited the influence and the inside and outside antineoplastic antitumor activity of mice delayed allergy, and do not study and disclose antiinflammatory, immunosuppressant, the antineoplastic mechanism of this chemical compound, also this chemical compound was not studied the inhibitory action of inflammatory cytokine.From the disclosed analysis of experimental data of Chinese patent literature CN1695612, the triacetyl andrographolide to influence, the mice carbon granule of rat paw edema animal model due to the Ovum Gallus domesticus album clean up experiment, though anti-tumor activity is strong than andrographolide, but active raising spoke degree is very little, and excites the influence experiment of mice delayed allergy to show active not raising to DNCB acetone.From above analysis as seen, how the variation of various pharmacologically actives later on of andrographolide triacetylization is still needed and is studied and can learn.
Open andrographolide of Chinese patent literature CN1666985 and the external inhibition activity of derivant thereof to TNF-α, IL-1 β, but its disclosed chemical compound general formula is 3 had not carried out structural change, be the andrographolidume derivative of hydroxyl, and several representative andrographolide compounds suppress in the activity of TNF-α, IL-1 β with andrographolide for the strongest among the wherein disclosed embodiment, and according to its disclosed experimental data as can be known, the activity of andrographolide inhibition TNF-α, IL-1 β is the several times of other andrographolidume derivative.As seen this patent documentation and unexposed triacetyl andrographolide are to the inhibitory action of inflammatory cytokine.
In sum as seen, even with above-mentioned all disclosed contents combinations about andrographolide and triacetyl andrographolide, also can't infer how whether the triacetyl andrographolide has inflammatory cytokine inhibitory action and activity.
Summary of the invention
The objective of the invention is to study the inhibition activity of triacetyl andrographolide to inflammatory cytokine.Wherein said inflammatory cytokine comprises TNF-α, IL-1 α, IL-1 β, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-γ, NO.
The invention provides of the application of triacetyl andrographolide as inhibitors of inflammatory cytokines.Wherein said inflammatory cytokine comprises TNF-α, IL-1 α, IL-1 β, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-γ, NO.
The present invention especially provides the purposes of triacetyl andrographolide in preparation TNF-alpha inhibitor, IL-1 beta inhibitor, IL-6 inhibitor, nitric oxide production inhibitor.
Foregoing triacetyl andrographolide can be used for treating following disease as inhibitors of inflammatory cytokines, includes but not limited to: systemic inflammatory response syndrome (SIRS), pyemia, septic shock, septic shock, multiple organ dysfunction syndrome, rheumatoid arthritis, osteoarthritis, SpA, rheumatic arthritis, inflammatory bowel, hypertension, coronary heart disease, myocardial infarction, heart failure, diabetes, systemic lupus erythematosus (sle), lupus nephritis, scleroderma, sarcoidosis, dermatomyositis, behcets disease, psoriasis, depression, respiratory virus infection, chronic obstructive pulmonary disease, asthma, pancreatitis, liver cirrhosis, acquired immune deficiency syndrome (AIDS), the CastlemanShi disease, Parkinson's disease, presenile dementia, vascular headache, central nervous system injury, cerebral infarction, acute cerebral hemorrhage, brain injury, brain injury postoperative infection complication, the influenza virus encephalopathy (HIE), chronic renal insufficiency, primary nephrotic syndrome, reflux nephropathy, glomerulonephritis, hemorrhagic shock, obstructive sleep apnea syndrome, myxoma of heart, acute myeloid leukaemia, multiple myeloma, myelodysplastic syndrome, tumor, Pyoderma gangrenosum, graft versus host disease, uveitis, periodontal disease, bacterial infection, fat.
Foregoing triacetyl andrographolide can be used for treating following disease as the TNF-alpha inhibitor, includes but not limited to: the systemic inflammatory response syndrome, pyemia, septic shock, multiple organ dysfunction syndrome, rheumatoid arthritis, osteoarthritis, SpA, inflammatory bowel, heart failure, diabetes, systemic lupus erythematosus (sle), scleroderma, sarcoidosis, dermatomyositis, psoriasis, acute myeloid leukaemia, Parkinson's disease, presenile dementia, depression, behcets disease, chronic obstructive pulmonary disease, asthma, acute pancreatitis, central nervous system injury, respiratory virus infection, multiple myeloma, myelodysplastic syndrome, Pyoderma gangrenosum, graft versus host disease, uveitis, periodontal disease, fat.
Foregoing triacetyl andrographolide can be used for treating following disease as the IL-1 beta inhibitor and includes but not limited to: rheumatoid arthritis, systemic inflammatory response syndrome (SIRS), pyemia, septic shock, septic shock, multiple organ dysfunction syndrome, periodontal disease, heart failure, dermatomyositis, acute pancreatitis, chronic obstructive pulmonary disease, osteoarthritis, bacterial infection, multiple myeloma, presenile dementia, osteoarthritis, respiratory virus infection, asthma, depression, scleroderma etc.
Foregoing triacetyl andrographolide can be used for treating following disease as the IL-6 inhibitor, includes but not limited to: autoimmune diseasees such as rheumatoid arthritis, systemic inflammatory response syndrome (SIRS), pyemia, septic shock, septic shock, multiple organ dysfunction syndrome, acquired immune deficiency syndrome (AIDS), myxoma of heart, CastlemanShi disease; Acute cerebral hemorrhage, acute cerebral infarction, brain injury, brain injury postoperative infection complication, influenza virus encephalopathy (HIE), coronary heart disease, severe pancreatitis, lupus nephritis, chronic renal insufficiency, primary nephrotic syndrome, reflux nephropathy, hemorrhagic shock, obstructive sleep apnea syndrome, tumor.
Foregoing triacetyl andrographolide can be used for treating following disease as nitric oxide production inhibitor, includes but not limited to: osteoarthritis, rheumatoid arthritis, rheumatic arthritis, systemic lupus erythematosus (sle), systemic inflammatory response syndrome, pyemia, septic shock, multiple organ dysfunction syndrome, septic shock, cerebral infarction, hypertension, myocardial infarction, congestive heart failure, glomerulonephritis, liver cirrhosis, inflammatory bowel, diabetes, acquired immune deficiency syndrome (AIDS), vascular headache, asthma, tumor.
State in realization in the process of goal of the invention, produce following 2 beyond thought technique effects:
1, the external proinflammatory factor of triacetyl andrographolide suppresses active in andrographolide raising 1 times and even several times.
2, discovering in a large number by the inventor: the inflammatory cytokine that can improve the andrographolide compounds after 3 or 14 acetylations greatly suppresses active.
Triacetyl andrographolide of the present invention can use separately or use with the form of pharmaceutical composition.Pharmaceutical composition comprises triacetyl andrographolide and the pharmaceutically suitable carrier as active component.Pharmaceutically suitable carrier can not destroy the activity of this chemical compound.
Triacetyl andrographolide of the present invention is 0.003-6mg/kg/ day/people as the effective dosage ranges of inhibitors of inflammatory cytokines.Above consumption is calculated according in vitro tests and animal pharmacology experimental result, because of the diversity of human body and animal, the diversity of inside and outside, the diversity of disease, the diversity of concrete inflammatory cytokine, so allow the clinical practice consumption to adjust to some extent.
Usage: can select according to disease specific.Following experimental example is to be example with inflammatory cytokine abnormal secretion model in the endotoxin induced rabbit body, is intended to illustrate the effect that also has the anti-inflammatory cytokines supersecretion in the triacetyl andrographolide body, but not to the restriction of route of administration.
Provide specific embodiment below in order to the present invention is made an explanation.
The specific embodiment
The andrographolide crude product can be bought commercially available product, as Guanghan, Sichuan book on Chinese herbal medicine plant company limited; Also can adopt the conventional method extraction separation to obtain.All the other chemical reagent are commercially available product (analytical pure); Oleic acid, refine yolk lecithin (injection): available from Shanghai Dong Shang Industrial Co., Ltd.; Midchain oil, soybean oil (injection): available from Tieling Beiya Medical Oil Co., Ltd.; Glycerol (injection) is available from Suichang, Zhejiang Hui Kang pharmaceutcal corporation, Ltd.
The preparation of preparation example 1 andrographolide
Get andrographolide crude product 20g, 72 ℃ are dissolved in the 450mL methanol, leave standstill 24 hours sucking filtration and get white crystal, the dry andrographolide that gets.
The preparation of preparation example 2 triacetyl andrographolide
The 1g andrographolide is dissolved in 10mLAc
2O, reflux 2 hours, reactant mixture ethyl acetate extraction, organic layer be water, saturated NaHCO successively
3With saturated common salt washing, anhydrous MgSO
4Dry.Get triacetyl andrographolide white solid through silica gel column chromatography.Molecular formula is: C
26H
36O
8
Chemical compound confirms that data are as follows:
1H(400MHz，CDCl
3):δ
7.00(td，J＝6.84，1.48Hz，1H，H-12)，5.92(d，J＝5.96Hz，1H，H-14)，4.90(bs，1H，H-17a)，4.60(dd，J＝11.68，4.26Hz，1H，H-15a)，4.55(dd，J＝11.24，6.08Hz，1H，H-15b)，4.53(bs，1H，H-17b)，4.36(d，J＝11.80Hz，1H，H-19a)，4.25(dd，J＝11.24，1.80Hz，1H，H-3)，4.12(d，J＝11.80Hz，1H，H-19b)，2.52～2.37(m，3H)，2.12(s，3H)，2.05(s，6H)，2.00～1.96(m，1H)，1.90～1.86(m，2H)，1.80～1.77(m，2H)，1.73～1.66(m，1H)，1.57～1.47(m，1H)，1.37～1.31(m，2H)，1.03(s，3H，CH
3-8)，0.76(s，3H，CH
3-20)。
13C-NMR(100MHz，CDCl
3)：δ
170.8，170.4，170.3，168.9，150.0，146.5，124.0，108.8，79.6，71.5，67.7，64.6，55.8，55.2，41.2，38.9，37.8，37.0，25.1，24.6，24.2，22.6，21.1，21.0，20.6，14.4。
MS(ESI)m/z(％)：499([M+Na]
+，100％)，477([M+H]
+，13％)。
Preparation example 33,19-diacetyl andrographolide, 14-acetyl andrographolide, 14, the preparation of 19-diacetyl andrographolide
The 5g andrographolide adds 30mL acetic acid and is heated with stirring to 80 ℃, and reaction is spent the night.Use ethyl acetate extraction, organic layer is water and saturated common salt washing successively, anhydrous MgSO
4Dry.Column chromatography gets 3,19-diacetyl andrographolide (AP11), 14,19-diacetyl andrographolide (AP12), 14-acetyl andrographolide (AP13).
The AP11 chemical compound confirms that data are as follows:
Molecular formula: C
24H
34O
7(434)
1H(400MHz，CDCl
3)：6.97(1H，m，H-12)，5.03(1H，d，J＝5.6Hz，H-14)，4.92(1H，s，H-17)，4.62(1H，s，H-17)，4.59(1H，dd，J＝11.2，4.8Hz，H-3)，4.47(1H，dd，J＝10.4，6.0Hz，H-15)，4.38(1H，d，J＝11.6Hz，H-19)，4.26(1H，dd，J＝10.4，2.0Hz，H-15)，4.11(1H，d，J＝12.0Hz，H-19)，2.05(6H，s，CH
3CO-)，1.04(3H，s，H-18)，0.78(3H，s，H-20)。
The AP12 chemical compound confirms that data are as follows:
Molecular formula: C
24H
34O
7(434)
1H(400MHz，CDCl
3)：7.00(1H，m，H-12)，5.91(1H，d，J＝6.0Hz，H-14)，4.90(1H，s，H-17)，4.55(1H，dd，J＝11.2，6.0Hz，H-15)4.52(1H，s，H-17)，4.35(1H，d，J＝13.6Hz，H-19)，4.25(1H，dd，J＝11.2，1.6Hz，H-15)，4.13(1H，d，J＝11.6Hz，H-19)，3.33(1H，dd，J＝12.0，4.0Hz，H-3)，2.13(3H，s，CH
3CO-)，2.06(3H，s，)，1.16(3H，s，H-18)，0.71(3H，s，H-20)。
13C-NMR(100MHz，CDCl
3)：170.9，170.5，169.0，150.3，146.6，124.0，108.8，78.8，71.6，67.8，64.9，55.8，55.3，42.4，39.0，37.8，37.2，27.8，25.2，24.2，22.5，21.0，20.7，14.7。
The AP13 chemical compound confirms that data are as follows:
Molecular formula: C
22H
32O
6(392) m.p.169 ℃
1H(400MHz，Acetone)：
6.88(1H，td，J＝6.8，1.6Hz，H-12)，6.03(1H，d，J＝6.0Hz，H-14)，4.87(1H，d，J＝1.2Hz，H-17)，4.59(1H，d，J＝1.2Hz，H-17)，4.58(1H，dd，J＝11.2，6.0Hz，H-15)，4.26(1H，dd，J＝11.0，1.6Hz，H-15)，4.11(1H，d，J＝10.8Hz，H-19)，3.42(1H，m，H-3)，3.28(1H，t，J＝10.4Hz，H-19)，2.08(3H，s，CH
3CO-)，1.20(3H，s，H-18)，0.70(3H，s，H-20)。
MS(ESI)m/z(％)：415([M+Na]
+，100％)，393([M+H]
+，56％)。
The preparation of preparation example 4 triacetyl andrographolide Emulsions
With triacetyl andrographolide 1.0g, Ovum Gallus domesticus Flavus lecithin 12g, join in the miscella of midchain oil 20g and soybean oil 80g, add oleic acid 0.4g, be heated to 60～80 ℃, stir to make and be dissolved as clear and bright solution, oil phase; Glycerol 22.5g is dissolved in the 80ml water forms water, be heated to 60-80 ℃; The oil phase that contains the triacetyl andrographolide is added to aqueous phase is emulsified into colostrum with high-speed stirred, after the gained colostrum added water and is settled to 1000ml, after emulsifying under the condition of pressure 100Mpa, 121 ℃ of sterilizations were 15 minutes after the packing, promptly through high pressure homogenizer.Gained Emulsion is uniform white emulsion, mean diameter 164nm.
The preparation of preparation example 5 blank breasts
With Ovum Gallus domesticus Flavus lecithin 12g, join in the miscella of midchain oil 20g and soybean oil 80g, add oleic acid 0.4g, be heated to 60～80 ℃, stir to make and be dissolved as clear and bright solution, oil phase; Glycerol 22.5g is dissolved in the 80ml water forms water, be heated to 60-80 ℃; Oil phase is added to aqueous phase is emulsified into colostrum with high-speed stirred, after the gained colostrum added water and is settled to 1000ml, after emulsifying under the condition of pressure 100Mpa, 121 ℃ of sterilizations were 15 minutes after the packing, promptly through high pressure homogenizer.Gained Emulsion is uniform white emulsion, mean diameter 176nm.
The external TNF-α of experimental example 1 triacetyl andrographolide suppresses activity research
1, medicine and instrument:
(lipopolysaccharide is LPS) available from Sigma company for lipopolysaccharide; Mouse macrophage RAW264.7 is available from Chinese Academy of Sciences's cell bank (ATCC); RPMI RPMI-1640, penicillin, streptomycin, hyclone are available from Gibco company; Other biochemical reagents commonly used are homemade analytical pure; Full-automatic microplate reader (U.S., Biotek); Constant temperature CO
2Incubator (U.S., Thermo company).Mouse TNF-α ELISA test kit is R﹠amp; D company product is by the packing of the U.S. biological engineering company limited of crystalline substance.Andrographolide, triacetyl andrographolide sample: by preparation example 1,2 preparation, and with the DMSO dissolving and be diluted to suitable concn.
2, mouse macrophage RAW264.7 cultivates:
Mouse macrophage RAW 264.7 be incubated at contain 10% hot deactivation (56 ℃, 30min) in the RPMI RPMI-1640 of hyclone (FBS), 100U/mL penicillin sodium, 100 μ g/mL streptomycins, 37 ℃,
(CO
2Hatch growth in the constant incubator of)=5%.
3, the mensuration of TNF-α burst size:
With the RPMI RPMI-1640 mouse macrophage RAW264.7 is diluted to 5 * 10
5Cells/mL is inoculated in the 96 porocyte culture plates, and every hole adds 200 μ L cell suspending liquids.CO
2After cultivating 1h in the incubator, every hole adds the specimen 0.4 μ L of LPS (1 μ g/mL) and variable concentrations, establishes LPS group (not adding tested sample) and blank group (DMSO) simultaneously, and each sample is established 3 parallel holes.At 37 ℃, CO
2Draw the culture fluid supernatant after cultivating 6h in the constant incubator, carry out standard curve according to ELISA test kit description method and draw and sample determination.
4, experimental result: triacetyl andrographolide and andrographolide all can significantly suppress the secretion of the inductive TNF-α of LPS, and the former is IC
50Be more than 5 times of the latter, both activity are higher than hydrocortisone all far away.See following table 1 for details.
Table 1 is respectively tried the outer TNF-α of object and is suppressed active
Annotate: compare with model group:
*P＜0.05;
*P＜0.01;
* *P＜0.001.
The external IL-6 of experimental example 2 triacetyl andrographolide suppresses activity research
1, medicine and instrument:
(lipopolysaccharide is LPS) available from Sigma company for lipopolysaccharide; Mouse macrophage RAW 264.7 is available from Chinese Academy of Sciences's cell bank (ATCC); RPMI RPMI-1640, penicillin, streptomycin, hyclone are available from Gibco company; Other biochemical reagents commonly used are homemade analytical pure; Full-automatic microplate reader (U.S., Biotek); Constant temperature CO
2Incubator (U.S., Thermo company).Mouse IL-6ELISA test kit is R﹠amp; D company product is by the packing of the gloomy male company in Shanghai.Andrographolide, triacetyl andrographolide sample: by preparation example 1,2 preparation, and with the DMSO dissolving and be diluted to suitable concn.
2, mouse macrophage RAW 264.7 cultivates:
Mouse macrophage RAW264.7 be incubated at contain 10% hot deactivation (56 ℃, 30min) in the RPMI RPMI-1640 of hyclone (FBS), 100U/mL penicillin sodium, 100 μ g/mL streptomycins, 37 ℃,
(CO
2Hatch growth in the constant incubator of)=5%.
3, the mensuration of IL-6 burst size:
With the RPMI RPMI-1640 mouse macrophage RAW 264.7 is diluted to 5 * 10
5Cells/mL is inoculated in the 96 porocyte culture plates, and every hole adds 200 μ L cell suspending liquids.CO
2After cultivating 1h in the incubator, every hole adds the specimen 0.4 μ L of LPS (1 μ g/mL) and variable concentrations, establishes LPS group (not adding tested sample) and blank group (DMSO) simultaneously, and each sample is established 3 parallel holes.At 37 ℃, CO
2Draw the culture fluid supernatant after cultivating 6h in the constant incubator, carry out standard curve according to ELISA test kit description method and draw and sample determination.
4, experimental result: triacetyl andrographolide and andrographolide all can significantly suppress the secretion of LPS inductive IL-6, and the former is IC
50Be 2 times of the latter, both activity are higher than hydrocortisone all far away.See table 2 for details.
Table 2 is respectively tried the outer IL-6 of object and is suppressed active
Annotate: compare with model group:
*P＜0.05;
*P＜0.01;
* *P＜0.001.
The external NO of experimental example 3 triacetyl andrographolide suppresses activity research
1, medicine and instrument:
Lipopolysaccharide (lipopolysaccharide, LPS), MTT is available from Sigma company; Mouse macrophage RAW264.7 is available from Chinese Academy of Sciences's cell bank (ATCC); RPMI 1640 culture medium, penicillin, streptomycin, hyclone are available from Gibco company; Other biochemical reagents commonly used are homemade analytical pure; Full-automatic microplate reader (U.S., Biotek group produces); Constant temperature CO2 incubator (U.S., Thermo company produces).Andrographolide, triacetyl andrographolide, 14-acetyl andrographolide, 3,19-diacetyl andrographolide, 14,19-diacetyl andrographolide sample: prepare by preparation example 1,2,3, and be used for the cell in vitro experiment with the DMSO dissolving.
2, mouse macrophage RAW 264.7 cultivates:
Mouse macrophage RAW 264.7 be incubated at contain 10% hot deactivation (56 ℃, 30min) in the RPMI1640 culture medium of hyclone (FBS), 100U/mL penicillin sodium, 100 μ g/mL streptomycins, 37 ℃,
(CO
2Hatch growth in the constant incubator of)=5%.
3, the mensuration of NO burst size:
Because NO is extremely unstable, is metabolized to nitrito-(NO in cell culture supernatant very soon
2-), so adopt NO in the Griess method working sample
2-Concentration as the index of weighing the NO level.Griess reagent A: w (N-naphthodiamide hydrochlorate)=0.1% is soluble in water; Griess reagent B:w (P-aminobenzene-sulfonamide)=1% is dissolved in
(H
3PO
4In)=5%, equal-volume mix reagent A and B before using.With the RPMI1640 culture medium mouse macrophage RAW264.7 is diluted to 5 * 10
5Cells/mL is inoculated in the 96 porocyte culture plates, and every hole adds 200 μ L cell suspending liquids.CO
2After cultivating 1h in the incubator, every hole adds the specimen 0.4 μ L of LPS (1 μ g/mL) and variable concentrations (0.1-200 μ mol/L), establishes LPS group (not adding tested sample) and blank group (DMSO) simultaneously, 4 repetitions of each sample.At 37 ℃, CO
2Draw culture fluid supernatant 100 μ L to ELISA Plate after cultivating 24h in the constant incubator, add isopyknic Griess reagent, measure the light absorption value at 540nm place behind the room temperature reaction 10min.Be respectively the NaNO of 1,5,10,50 μ mol/L with concentration
2The drawing standard curve is according to NaNO
2Standard curve calculates NO in the cell culture supernatant
2-Concentration and the suppression ratio that NO is discharged, the suppression ratio computing formula is:
4, result: after recording suppression ratio, calculate the IC of each sample
50See following table 3 for details.
Table 3 is respectively tried the outer NO of object and is suppressed active
From last table as seen, though the triacetyl andrographolide than 3,19-diacetyl andrographolide only differs from 14 acetyl group, NO suppresses activity and improves nearly 6 times.The 14-acetyl andrographolide also differs from 14 acetyl group than andrographolide, but NO suppress activity improve 4 times surplus.As seen 14 acetylation is remarkable to the activity influence of andrographolide compounds.Though the triacetyl andrographolide is than 14,19-diacetyl andrographolide only differs from 3 acetyl group, and NO suppresses activity and improves nearly 6 times.As seen 3 acetylation is remarkable to the activity influence of andrographolide compounds.
Because endotoxin shock model is the representative model of systemic inflammatory response syndrome (SIRS), pyemia, septic shock, septic shock, multiple organ dysfunction syndrome, septicemia, and inflammatory cytokine plays crucial effects in the generation evolution of above-mentioned disease, and this model is the most representative in setting forth inflammatory cytokine and the inflammatory cytokine relation between diseases related, so be representative with the rabbit endotoxin shock model below, several respects content below setting forth:
1, inflammatory cytokine inhibitory action in the body of triacetyl andrographolide;
2, the triacetyl andrographolide is to the therapeutical effect of systemic inflammatory response syndrome (SIRS), pyemia, septic shock, septic shock, multiple organ dysfunction syndrome, septicemia;
3, the triacetyl andrographolide can be in order to the foundation of disease described in the treatment summary of the invention as inhibitors of inflammatory cytokines.
Experimental example 4 triacetyl andrographolide are to the influence (the interior inhibitory action to inflammatory cytokine of triacetyl andrographolide body) of rabbit endotoxin shock model
1, test material
1.1 be subjected to test product and positive control drug: triacetyl andrographolide Emulsion and blank breast: by preparation example 4,5 preparations; Dexamethasone injection, Tianjin Pharmaceutical Group Xinzheng Co., Ltd.'s product.
1.2 animal: Japan large ear rabbit, the male and female dual-purpose, body weight 2.5～3.0kg, the quality certification number: SCXK-(Ji) 2003-0004, available from Changchun High-technology Medical Animal Experiment Research Center.
1.3 reagent: (LPS E.coli0111:B4), is Sigma company product to escherichia coli endotoxin.Interleukin-1 ' beta ' (IL-1 β), tumor necrosis factor (TNF-α) ria-determination test kit, PLA General Hospital Science and Technology Development Center put exempt from produce.Nitric oxide (NO) detection kit, Nanjing are built up bio-engineering research institute product.
1.4 instrument: BL-820 type eight is led physiograph, and Chengdu TME Technology Co., Ltd. produces.WMY-01 type digital thermometer, Huachen Medical Meters Co Ltd, Shanghai produces.The automatic γ immunity of F1-2008P type numeration instrument, state-run Xi'an 262 factory's products.
2, test method
2.1 modeling: reference literature method [Zhu Yu, Deng. the septic shock that bacterial endotoxin etc. bring out. the disease model of laboratory animal. Tianjin: the Tianjin Scientific English Translation .1997 of publishing house front page in March: 372], rabbit is anaesthetized with 40mg/kg (5ml/kg) pentobarbital sodium lumbar injection (ip), separate common carotid artery, common carotid artery inserts the venous cannulation that is connected with threeway, leading physiograph by pressure transducer and eight is connected, be used to measure mean arterial blood pressure (MAP) and blood sampling, closed system adopts 0.3% anticoagulant heparin.The extremity marks II connection electrode of leading, eight lead physiograph measures changes in heart rate.Digital thermometer is measured the anus temperature and is changed.Rabbit ear vein injection LPS300 μ g/kg (1ml/kg) back forms the rabbit endotoxin shock model.
2.2 administration: behind the rabbit injection LPS immediately ear vein slowly push and be subjected to reagent thing, administration group to be respectively dexamethasone 5mg/kg group; Blank Emulsion matched group; Triacetyl andrographolide Emulsion senior middle school low dose group (0.25mg/kg, 0.5mg/kg, 1mg/kg), normal control group and model control group give with the volume normal saline.Blank Emulsion matched group gives with the blank Emulsion of volume.
2.3 detect:
1. mean arterial pressure (MAP), heart rate (HR), anus temperature measurement: rabbit is in giving LPS before and after 30min, 60min, 120min, 180min, 240min, 300min leads physiograph with eight respectively and measures MAP by pressure transducer, with the limbs marks II measurement heart rate that leads, measures the variation of anus temperature with digital thermometer.
2. serum TNF-α, IL-1 β, NO measure: rabbit is in giving LPS before and after 30min, 60min, 120min, 180min, 240min, 300min be respectively at the common carotid artery 1ml that takes a blood sample, 2500rpm centrifugal serum, measure serum TNF-α and IL-1 β content to put the method for exempting from, measure serum NO levels with nitrate reductase method.
3, result of the test
3.1 the influence that the triacetyl andrographolide changes endotoxin shock rabbit mean arterial pressure (MAP), heart rate (HR), anus temperature
After rabbit gives LPS, model control group and normal control group relatively, each the time point MAP that surveys of institute is obviously decline all, drops to minimum point during 120min.Dexamethasone, each dosage treatment group of triacetyl andrographolide all can obviously suppress MAP and reduce; Statistical analysis shows, with model control group relatively, significant difference (P＜0.05) is arranged during 60min after the dexamethasone 5mg/kg administration, highly significant difference (P＜0.01) is arranged during 120min; Compare with model control group, highly significant difference (P＜0.01) is arranged during 120min after the administration of triacetyl andrographolide 1mg/kg group, significant difference (P＜0.05) is arranged during 60min, significant difference (P＜0.05) is arranged during 120min after the triacetyl andrographolide 0.5mg/kg administration, significant difference (P＜0.05) is arranged during 120min after the triacetyl andrographolide 0.25mg/kg administration; Triacetyl andrographolide 1mg/kg is approaching with dexamethasone 5mg/kg action intensity, in triacetyl andrographolide 0.25mg/kg～1mg/kg scope dose-dependence is arranged, and the results are shown in Table 4.
After rabbit gives LPS, compare with the normal control group, model control group is surveyed each time point HR all the trend of slowing down, but not statistically significant, each administration group and model control group be no significant difference relatively, the results are shown in Table 4.
After rabbit gave LPS, model control group anus temperature continued to descend, and compared with the normal control group, and each time point of surveying all has highly significant difference (P＜0.01).Corresponding time point with model control group relatively has highly significant difference (P＜0.01) during 30min after the dexamethasone 5mg/kg administration～120min; Highly significant difference (P＜0.01) is arranged during 120min after the administration of triacetyl andrographolide 1mg/kg group; Highly significant difference (P＜0.01) is arranged during 60min after the triacetyl andrographolide 0.5mg/kg administration～120min; Each time point effect is all not obvious after the triacetyl andrographolide 0.25mg/kg administration, and dexamethasone 5mg/kg is the rapid-action but weak point of holding time than triacetyl andrographolide 1mg/kg.The triacetyl andrographolide has dose-dependence in 0.25mg/kg～1mg/kg scope, the results are shown in Table 4.
3.2. the triacetyl andrographolide is to the influence of endotoxin shock rabbit anteserum TNF-α, IL-1 β, NO content
After rabbit gives LPS, model control group with the normal control group relatively, institute's each time point serum TNF-α, IL-1 β, NO content surveyed is obviously rising (P＜0.01) all.Wherein TNF-α, IL-1 β reach peak value respectively when 120min and 60min, and NO content gives to continue to increase behind the LPS.With the model matched group relatively, the TNF-alpha content is obviously reduced during 120min after the dexamethasone 5mg/kg administration, IL-1 β content is obviously reduced, 120min can make NO content obviously reduce.During 30min after the administration of triacetyl andrographolide 1mg/kg group～120min the TNF-alpha content is obviously reduced, IL-1 content is obviously reduced, 60min～120min can make NO content obviously reduce.NO content is obviously reduced during 120min after the triacetyl andrographolide 0.5mg/kg administration, not obvious to TNF-α and IL-1 effect.The above-mentioned effect of triacetyl andrographolide 0.25mg/kg is all not obvious, the results are shown in Table 5.
4 conclusions
In sum, the triacetyl andrographolide can obviously improve the several important life index of endotoxin shock rabbit, i.e. body temperature, blood pressure; And can significantly reduce TNF-α, IL-1 β, the NO level of endotoxin shock rabbit.Illustrate that the triacetyl andrographolide has therapeutical effect to the endotoxin shock rabbit.
Claims (9)
1.3, the application of 14,19-triacetyl andrographolide in the preparation inhibitors of inflammatory cytokines.
2. claim 1 is described 3,14, and the application of 19-triacetyl andrographolide in the preparation inhibitors of inflammatory cytokines is characterized in that described inflammatory cytokine is the proinflammatory cytokine.
3. claim 1 is described 3,14, and the application of 19-triacetyl andrographolide in the preparation inhibitors of inflammatory cytokines is characterized in that described inflammatory cytokine is the nitric oxide (NO) with inflammatory speciality.
4. claim 2 described 3,14, the application of 19-triacetyl andrographolide in the preparation inhibitors of inflammatory cytokines, it is characterized in that described proinflammatory cytokine is any among TNF-α, IL-1 α, IL-1 β, IL-2, IL-4, IL-6, IL-8, IL-10, the IFN-γ.
5. claim 1 described 3,14, the application of 19-triacetyl andrographolide in the preparation inhibitors of inflammatory cytokines, it is characterized in that described inhibitors of inflammatory cytokines can be used for treating any or several in the following disease: systemic inflammatory response syndrome (SIRS), pyemia, septic shock, septic shock, multiple organ dysfunction syndrome, rheumatoid arthritis, osteoarthritis, SpA, rheumatic arthritis, hypertension, coronary heart disease, myocardial infarction, heart failure, diabetes, systemic lupus erythematosus (sle), lupus nephritis, scleroderma, sarcoidosis, dermatomyositis, behcets disease, psoriasis, depression, respiratory virus infection, chronic obstructive pulmonary disease, asthma, pancreatitis, liver cirrhosis, inflammatory bowel, acquired immune deficiency syndrome (AIDS), the CastlemanShi disease, Parkinson's disease, presenile dementia, vascular headache, central nervous system injury, cerebral infarction, acute cerebral hemorrhage, brain injury, brain injury postoperative infection complication, the influenza virus encephalopathy (HIE), chronic renal insufficiency, primary nephrotic syndrome, reflux nephropathy, glomerulonephritis, hemorrhagic shock, obstructive sleep apnea syndrome, myxoma of heart, acute myeloid leukaemia, multiple myeloma, myelodysplastic syndrome, tumor, Pyoderma gangrenosum, graft versus host disease, uveitis, periodontal disease, bacterial infection, fat.
6. claim 3 described 3,14, the application of 19-triacetyl andrographolide in the preparation inhibitors of inflammatory cytokines, it is characterized in that, when described inflammatory cytokine is NO, 3,14,19-triacetyl andrographolide can be used for treating one or more in the following disease: osteoarthritis, rheumatoid arthritis, rheumatic arthritis, systemic lupus erythematosus (sle), systemic inflammatory response syndrome, pyemia, septic shock, multiple organ dysfunction syndrome, septic shock, cerebral infarction, hypertension, myocardial infarction, congestive heart failure, glomerulonephritis, liver cirrhosis, inflammatory bowel, diabetes, acquired immune deficiency syndrome (AIDS), vascular headache, asthma, tumor.
7. claim 4 described 3,14, the application of 19-triacetyl andrographolide in the preparation inhibitors of inflammatory cytokines, it is characterized in that, when described proinflammatory cytokine is TNF-α, 3,14,19-triacetyl andrographolide can be used for treating one or more in the following disease: the systemic inflammatory response syndrome, pyemia, septic shock, multiple organ dysfunction syndrome, rheumatoid arthritis, osteoarthritis, SpA, inflammatory bowel, heart failure, diabetes, systemic lupus erythematosus (sle), scleroderma, sarcoidosis, dermatomyositis, psoriasis, acute myeloid leukaemia, Parkinson's disease, presenile dementia, depression, behcets disease, chronic obstructive pulmonary disease, asthma, acute pancreatitis, central nervous system injury, respiratory virus infection, multiple myeloma, myelodysplastic syndrome, Pyoderma gangrenosum, graft versus host disease, uveitis, periodontal disease, fat.
8. claim 4 described 3,14, the application of 19-triacetyl andrographolide in the preparation inhibitors of inflammatory cytokines, it is characterized in that, when described proinflammatory cytokine is IL-1 β, 3,14,19-triacetyl andrographolide can be used for treating one or more in the following disease: rheumatoid arthritis, systemic inflammatory response syndrome (SIRS), pyemia, septic shock, septic shock, multiple organ dysfunction syndrome, periodontal disease, heart failure, dermatomyositis, acute pancreatitis, chronic obstructive pulmonary disease, osteoarthritis, bacterial infection, multiple myeloma, presenile dementia, osteoarthritis, respiratory virus infection, asthma, depression, scleroderma.
9. claim 4 described 3,14, the application of 19-triacetyl andrographolide in the preparation inhibitors of inflammatory cytokines, it is characterized in that, when described proinflammatory cytokine is IL-6,3,14,19-triacetyl andrographolide can be used for treating one or more in the following disease: rheumatoid arthritis, systemic inflammatory response syndrome (SIRS), pyemia, septic shock, septic shock, multiple organ dysfunction syndrome, acquired immune deficiency syndrome (AIDS), myxoma of heart, the CastlemanShi disease, acute cerebral hemorrhage, acute cerebral infarction, brain injury, brain injury postoperative infection complication, the influenza virus encephalopathy (HIE), coronary heart disease, severe pancreatitis, lupus nephritis, chronic renal insufficiency, primary nephrotic syndrome, reflux nephropathy, hemorrhagic shock, obstructive sleep apnea syndrome, tumor.
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| EP2897608A4 (en) * | 2013-04-22 | 2016-04-13 | Innobioscience Llc | Treatment of alzheimer's and cognitive impairment with andrographolides |
| CN106800551A (en) * | 2015-11-26 | 2017-06-06 | 南京明德新药研发股份有限公司 | Andrographolide changes structure compound |
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| CN100367955C (en) * | 2005-06-06 | 2008-02-13 | 韩光 | Compsn. of medication of containing creat lactone of triacetyl and usages |
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| EP2897608A4 (en) * | 2013-04-22 | 2016-04-13 | Innobioscience Llc | Treatment of alzheimer's and cognitive impairment with andrographolides |
| CN106800551A (en) * | 2015-11-26 | 2017-06-06 | 南京明德新药研发股份有限公司 | Andrographolide changes structure compound |
| EP3381912A4 (en) * | 2015-11-26 | 2019-01-09 | Heilongjiang Zhenbaodao Pharmaceutical Co., Ltd. | Modified compound of andrographolide |
| US10717720B2 (en) | 2015-11-26 | 2020-07-21 | Heilongjiang Zhenbaodao Pharmaceutical Co., Ltd. | Modified compound of andrographolide |
| CN106800551B (en) * | 2015-11-26 | 2021-05-11 | 黑龙江珍宝岛药业股份有限公司 | Andrographolide modified compound |
| ES2908500A1 (en) * | 2020-10-29 | 2022-04-29 | Consejo Superior Investigacion | Andrographic derivatives for use in the treatment of inflammatory diseases associated with a cytokine storm (Machine-translation by Google Translate, not legally binding) |
| WO2022090605A1 (en) * | 2020-10-29 | 2022-05-05 | Consejo Superior De Investigaciones Cientificas (Csic) | Andrographolide derivative for use in the treatment of inflammatory diseases associated with a cytokine storm |
| CN114028386A (en) * | 2021-12-22 | 2022-02-11 | 河南大学 | Application of triacetyl andrographolide as medicine for regulating degradation of autophagosome |
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