CN113491679A - Application of phytol in preparation of anti-migraine drug - Google Patents
Application of phytol in preparation of anti-migraine drug Download PDFInfo
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Abstract
The invention relates to application of diterpenoid phytol in preparing an anti-migraine medicament. The phytol can be a naturally-occurring organic compound or a synthetic organic compound, has strong anti-migraine activity, and is used as an active ingredient to be prepared into an anti-migraine medicine or a pharmaceutical composition together with a pharmaceutically acceptable carrier or auxiliary material.
Description
Technical Field
The invention relates to application of diterpenoid compounds in preparation of anti-migraine drugs, in particular to application of phytol in preparation of anti-migraine drugs.
Background
Migraine is the most common type of headache in clinic, generally without organic lesions, and clinically with paroxysmal moderate-severe and pulsatile headache as the main manifestations, mainly pain on one side or two sides of the head. Migraine is often genetically related and is more likely to develop in people with poor physical fitness, poor sports, and mental work. Migraine mainly includes three major classes of typical migraine, common migraine and cluster migraine. Typical migraine headache patients usually have periodic attacks, and are common to women. Most patients before the onset of the disease can have blurred vision, flash vision, pseudoscopic vision, blind spots, eye swelling and emotional instability, almost all patients are afraid of light, and one-sided headache appears after a few minutes, and the parts such as the front of the head, the temples, the periphery of the eye sockets, the temples and the like are mainly used. Pain usually reaches a peak in 1-2 hours, lasting 4-6 hours or more than ten hours, and may last for several days in severe cases. Common migraine accounts for 80% of migraine patients, is common, has no obvious aura symptoms before onset, and has symptoms of mental disorder, fatigue, yawning, inappetence, general malaise and the like before onset of some patients. The cluster migraine attack has no aura symptoms, and the time of each attack is approximately the same. The symptoms of swelling of eye socket, lacrimation, conjunctival congestion, nasal obstruction, sweating, etc. appear during the attack of the disease. In addition, migraine includes neuropsychiatric migraine, abdominal migraine, familial hemiplegic migraine, and the like. The prevalence of migraine is 15% to 18% in women and 6% -12% in men. The incidence of migraine in age samples 25 to 64 years old is 8.1 people per thousand per year.
Currently, the drugs commonly used for treating migraine mainly comprise ibuprofen, mexican, nimodipine, aspirin, ergotamine preparation, sumatriptan, propranolol, amitriptyline, clonidine, flunarizine, sodium valproate and other chemical drugs. Although the medicine has better therapeutic effect on migraine, the medicine also shows serious adverse reaction in clinical application, and causes harm to organisms when being applied for many times or for a long time, and the medicine is highly regarded in recent years. The adverse reactions mainly comprise fatigue, nausea, lethargy, weakness, dry mouth, emesis, dyspepsia, gastrointestinal reaction, colitis, mental disorder, blood system damage, liver and kidney damage, etc., and serious adverse events comprise myocardial infarction, arrhythmia and apoplexy.
At present, researchers at home and abroad pay great attention to exploring and searching anti-migraine treatment medicines with good curative effect and small adverse reaction from natural medicines. The anti-migraine active ingredients of the botanical drugs such as the dahurian angelica root, the divaricate saposhnikovia root, the Szechuan lovage rhizome, the tetrandra root, the dolichos root and the like are researched, and a group of compounds with excellent activity, including alkaloids, diterpenes, triterpenes, coumarins, steroids, volatile oil and the like, are obtained. Although more active compounds were found, the efficacy was less strong. At present, there are also anti-migraine drugs or pharmaceutical compositions prepared from various medicinal plants, but the therapeutic effect is not ideal.
During migraine attack, trigeminal-vascular system is activated, and various neuropeptides closely related to pain transmission are released in an increased manner, are mutually promoted, and exert synergistic action, such as CGRP, substance P, cholecystokinin and the like. CGRP is the most potent vasoactive peptide species released from the perivascular nerves, and its level changes can affect the pathological course of migraine to some extent, as known endogenous vasodilatory vasoactive peptides with the strongest effect in vivo. Meanwhile, CGRP and a receptor thereof are widely expressed in a central nervous system, and CGRP specific binding sites are found in the hypothalamus, the midbrain, the pons and other areas and participate in the generation of neurogenic inflammation and pain transmission. CGRP induces vasodilation and mast cell degranulation, further causing neurogenic inflammation, while activating satellite glial cells, triggering an inflammatory cascade. The increase of CGRP release can lead to the increase of the release of brain-derived neurotrophic factor (BDNF), adenosine triphosphate receptor (P2X3), NO and the like, and aggravate pain (the influence of the effector components of Wangqing, Shenlan, Zhang Jun, Linxian, Von Yi. Ligusticum wallichii on the calcitonin gene-related peptide of migraine rats and the receptor expression thereof [ J ].2018,40(1):14-20 ]. Thus, migraine attacks can be alleviated by reducing the production and release of CGRP, inhibiting neurogenic inflammation, interfering with pain signaling.
Disclosure of Invention
Technical problem to be solved
The invention aims to solve the technical problem that the compound in the prior art has poor treatment effect on migraine.
(II) technical scheme
In order to solve the problems in the prior art, the invention provides an application of diterpenoid phytol in treating migraine, a medicine or a pharmaceutical composition for treating migraine and a preparation method thereof.
(1) Use of phytol for the preparation of an anti-migraine medicament, said phytol having the structure:
(2) the use according to (1), wherein the phytol is present in and used in the form of an extract obtained by extracting silkworm excrement with a solvent; wherein the solvent is 70-100 vol% ethanol/water, 70-100 vol% methanol/water, or 50-80 vol% acetone/water, wherein the faeces Bombycis is dry feces of Bombyx mori larva of Bombycidae.
(3) The use according to (1) to (2), wherein the phytol is used as an active ingredient to prepare a pharmaceutical composition together with a pharmaceutically acceptable carrier or auxiliary material.
(4) The use according to any one of (1) to (3), wherein the pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, and injections.
(5) The use according to any one of (1) to (4), wherein the pharmaceutical composition is selected from a sustained release preparation or a controlled release preparation.
(6) The use according to any one of (1) to (5), wherein the pharmaceutically acceptable carrier or adjuvant comprises oral preparation adjuvant, parenteral administration adjuvant or external administration adjuvant, and the administration route can be oral administration, injection, external local administration and the like; the administration dosage form can be liquid dosage form, solid dosage form, the liquid dosage form can be syrup, injection solution, non-aqueous solution, suspension or emulsion, the solid dosage form can be tablet, lozenge, capsule, dripping pill, granule, powder, cream, solution, suppository, dispersible powder such as lyophilized powder for injection, aerosol, etc.; the used auxiliary materials comprise: lactose, calcium carbonate, calcium phosphate, sodium phosphate, starch, cyclodextrin, sucrose, mannitol, microcrystalline cellulose sodium, calcium sulfate, water, ethanol, propanol, glycerol, propylene glycol, isopropanol, syrup, honey, glucose, gelatin syrup, sodium carboxymethylcellulose, potassium phosphate, dried starch, agar powder, calcium carbonate, sodium bicarbonate, sodium dodecyl sulfonate, methyl cellulose, glyceryl tristearate, cocoa butter, hydrogenated oil, quaternary ammonium salt, talc, triethylamine magnesium stearate, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin.
The invention also provides the use of the diterpenoid phytol as a medicament for reducing the level of calcitonin gene-related peptide (CGRP) in a second aspect.
(7) Use of phytol for the manufacture of a medicament for reducing the level of calcitonin gene-related peptide (CGRP), said phytol having the structure:
the invention also provides the application of the diterpenoid phytol as a Calcitonin Gene Related Peptide (CGRP) receptor antagonist in the third aspect.
(8) Use of phytol for the preparation of a calcitonin gene-related peptide (CGRP) receptor antagonist, said phytol having the structure:
(III) advantageous effects
The technical scheme of the invention has the following advantages:
(1) the diterpenoid phytol compound can obviously reduce the times of rat head scratching and down-regulate the content of calcitonin gene-related peptide (CGRP) in hypothalamus and plasma of a migraine rat in a nitroglycerin migraine experiment, and is prompted to have good anti-migraine activity.
(2) The silkworm excrement adopted in the preparation method of phytol is rich in domestic resources, and the raw material source is simple; the phytol in the invention has higher content in silkworm excrement and is easy to obtain.
(3) The preparation method of phytol can adopt a conventional column chromatography preparation method, the preparation operation flow of the compound is simple, the purity of the obtained compound is high, and the subsequent industrial production is easy to realize.
(4) The invention discovers that phytol has a better treatment effect on migraine for the first time. The compound can be used as an anti-migraine active ingredient or a lead compound and has good application prospect.
Drawings
FIG. 1 is a flow chart of activity tracing and separation of diterpenoid phytol according to the present invention;
FIG. 2 is the NMR spectrum of phytol of the present invention: (1H NMR)；
FIG. 3 is the NMR spectrum of phytol of the present invention (C13C NMR)；
FIG. 4 shows the mass spectrum (EI-MS) of phytol according to the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
The diterpenoid phytol can be a naturally-occurring compound or an artificially synthesized compound.
The anti-migraine component can also be an extract obtained by extracting silkworm excrement by using a solvent; wherein the solvent is 70-100 vol% ethanol/water, 70-100 vol% methanol/water, or 50-80 vol% acetone/water.
Silkworm excrement Faeces bombycis is a traditional Chinese medicine, also known as original silkworm excrement, horned liver, silkworm excrement and silkworm excrement, is dry excrement of Bombyx mori L. After eating the mulberry leaves, part of protein, sugar and fat substances in the mulberry leaves are digested, and most of effective components in the mulberry leaves are excreted to the outside along with excrement. The dried silkworm excrement is cylindrical small granules, has little grass smell, and is black, solid and uniform. Silkworm excrement is warm in nature, sweet and pungent in flavor, enters liver, spleen and stomach meridians, and has the functions of dispelling wind, eliminating dampness, clearing heat, improving eyesight, promoting blood circulation and relieving pain. Mainly treats wind-heat eye pain, rheumatic heart disease, arthritis, limb numbness, rubella pruritus, headache and the like, and silkworm excrement is commonly used in some compound medicines for treating diabetes. The chemical components of silkworm excrement mainly comprise amino acids, chlorophyll, alkaloids, flavonoids, saccharides, trace elements and the like (Li Xiyan, Chen Gu, Xideing pine and the like, the amino acid composition and analysis of silkworm moth and silkworm excrement, silkworm mulberry report, 1987,18(3):48, Cigui celery, Octopus, Wang \26877and the like, the extraction and analysis and determination of silkworm excrement chlorophyll, forestry science 2008,33(4):60-62, Zhongguang Xiong, Rujie Wu, Huangmeiyan and the like, the research of alkaloid components in silkworm excrement, traditional Chinese medicinal materials 2007,30(11):1384 + 1385, Zhu Xiang Runhui, Jiang Dong, Tang Meng, the research of flavone compounds in silkworm excrement, silkworm science 1996,2(22):90-92, Lu Lin, Xujun Liang, Chun, the determination of water-soluble monosaccharide and disaccharide in silkworm excrement, the research of silkworm sugar, the silkworm report, 1989,20(1): 54-55). Besides, there are also a lot of carotenoid, pectin, leaf protein and other components (Cutin, Li xing Cui, Wang Yi, Chen Run, silkworm excrement chemical component research, Chinese traditional medicine J2008, 33(21): 2493-. Pharmacological tests prove that the silkworm excrement has the effects of reducing blood sugar, improving and treating anemia, diminishing inflammation, inhibiting bacteria, promoting wound healing, resisting oxidation, resisting ulcer, resisting tumors and the like (Liu Jiang Chi, Xuli, Liang Yang, Huang Xianzhi. pharmacological research and clinical application research progress of silkworm excrement. silkworm communication 2010,30(3): 14-17).
The invention finds that the solvent (such as 95 volume percent ethanol/water) extract of silkworm excrement has better anti-migraine activity, and chemical composition research is carried out on the extract under the guidance of a biological activity test, so that phytol ((2E,7R,11R) -3,7,11,15-tetramethyl-2-hexadecen-1-ol) with better anti-migraine activity is obtained.
The structural formula of phytol ((2E,7R,11R) -3,7,11,15-tetramethyl-2-hexadecen-1-ol) is as follows:
the diterpenoid phytol compound has an obvious inhibition effect on rat migraine induced by nitroglycerin, and is applied to preparation of an anti-migraine drug or a pharmaceutical composition.
The invention adopts the currently recognized nitroglycerin migraine headache model at home and abroad to carry out the migraine activity test on phytol. The experimental result shows that the phytol can obviously reduce the times of rat head scratching and reduce the content of CGRP in the hypothalamus and plasma of the migraine rat, and the phytol is prompted to have good anti-migraine activity.
The invention also provides a preparation method of the diterpenoid phytol, which comprises the step of preparing the compound from silkworm excrement. Preferably, phytol is prepared from silkworm faeces. Preferably, the method has the following steps:
(1) pulverizing faeces Bombycis, extracting with solvent, and mixing extractive solutions;
(2) concentrating the extracting solution in the step (1) under reduced pressure to obtain extract;
(3) suspending the extract in the step (2) in water, sequentially extracting with petroleum ether, ethyl acetate and n-butanol, and evaporating the solvent with a rotary evaporator to obtain petroleum ether, ethyl acetate and n-butanol extracts respectively;
(4) and (3) separating the petroleum ether extract in the step (3) by silica gel column chromatography, and performing gradient elution by using petroleum ether-ethyl acetate (the volume ratio is 200: 1-0: 1) to obtain 10 components (Fr.1-10).
(5) Subjecting Fr.2 in the step (4) to silica gel column chromatography, and performing gradient elution by using petroleum ether-ethyl acetate (volume ratio is 100: 1-10: 1) to obtain a component Fr.3-1-4. Fr.2-2 is subjected to silica gel column chromatography, and eluted by petroleum ether-ethyl acetate (volume ratio 50:1) to obtain diterpenoid phytol ((E) -3,7,11, 15-tetramethyl-2-hexadecene-1-ol).
In the step (1), the solvent can be 70-100% ethanol/water, 70-100% methanol/water, or 50-80% acetone/water by volume percentage, the solvent amount is 6-10 times of the weight of the silkworm excrement, the reflux extraction time is 2 hours each time, the reflux extraction is repeated for 3 times, and the filtrate is combined to obtain the silkworm excrement medicinal material extract solution.
The invention also provides the application of the phytol in preparing the anti-migraine medicine or the pharmaceutical composition: the phytol is used as an active ingredient and is prepared into an anti-migraine drug or a pharmaceutical composition together with a pharmaceutically acceptable carrier or auxiliary material.
The anti-migraine drug or the pharmaceutical composition can be administered in a unit dosage form, and the administration route can be intestinal tract or parenteral tract, such as oral administration, muscle administration, nasal cavity administration, oral mucosa administration, skin administration, transdermal administration, subcutaneous administration, intradermal administration, peritoneal administration, rectal administration, intravenous administration, intramuscular administration, epidural administration, intraocular administration, intracranial administration, vaginal administration and the like;
the administration route of the anti-migraine drug or the pharmaceutical composition of the present invention may be injection administration. The injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection, intrathecal injection, peritoneal injection, etc.
The administration dosage form can be liquid dosage form or solid dosage form. The solution properties of the liquid dosage form can be true solutions, colloids, microparticles, emulsions, and suspensions. The liquid dosage form can be syrup, injection solution, non-aqueous solution, suspension or emulsion; solid dosage forms such as tablets, lozenges, capsules, dripping pills, granules, powders, creams, solutions, suppositories, dispersible powders such as lyophilized powder injections, aerosols, and the like.
The anti-migraine drug or the pharmaceutical composition can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various microparticle drug delivery systems.
The pharmaceutically acceptable carrier or auxiliary material comprises an oral preparation auxiliary material and an auxiliary material for parenteral administration or external administration. The adjuvants include excipient such as lactose, calcium carbonate, calcium phosphate, and sodium phosphate; diluents and absorbents such as starch, cyclodextrin, lactose, sucrose, mannitol, microcrystalline cellulose sodium, calcium sulfate, and the like; wetting agents and binders such as water, ethanol, propanol, glycerol, propylene glycol, isopropanol, syrup, honey, glucose, gelatin syrup, sodium carboxymethylcellulose, potassium phosphate, etc.; disintegrating agents such as dry starch, agar powder, calcium carbonate, sodium bicarbonate, sodium dodecylsulfate, methylcellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil, etc.; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants such as talc, triethylamine magnesium stearate, silica, corn starch, stearate, boric acid, liquid paraffin, and the like. The tablets may be further prepared into coated tablets such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets, in order to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period.
In order to better understand the present invention, the following further explains or illustrates the present invention by specific examples, but these examples should not be construed as limiting the scope of the present invention.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
In order to better understand the present invention, the following further explains or illustrates the present invention by specific examples, but these examples should not be construed as limiting the scope of the present invention.
Example 1: silkworm excrement extract anti-migraine activity test
Material sources are as follows: the silkworm excrement is collected from Yunnan Kunming and identified as Faeces bombycis by the auxiliary professor of Populus verniciflua of national medical college of Yunnan national university. The specimens are stored in the specimen museum of national institute of medicine and medicine of Yunnan national university.
Preparation of silkworm excrement extract: pulverizing dried faeces Bombycis to obtain faeces Bombycis fragments; then reflux-extracting the fragments of faeces Bombycis with 95 vol% ethanol/water for 3 times, each for 2 hr to obtain extractive solution; filtering the faeces Bombycis extractive solutions respectively, and concentrating under reduced pressure with rotary evaporator to obtain extract.
The 95% ethanol extract of faeces Bombycis was tested for anti-migraine activity using the nitroglycerin migraine headache rat model (see scientific literature: Zhang Xiao-Fan, Zhang Wen-Jun, Dong Cui-Lan et al, Analgesia effect of basic in against NTG-induced migaine in rats [ J ]. biomed. Pharmacother, 2017,90: 116-. 60 male healthy SD rats with the weight of 180-220 g are randomly divided into 6 groups, and 10 rats are taken. The groups are as follows in sequence: blank control group (distilled water), negative control group (distilled water), positive control group (ibuprofen tablet, 80mg/kg), and faeces Bombycis high, medium and low dose groups (2.0g/kg, 0.5g/kg, 0.13g/kg), and continuously administering for 7 d. After 60min of the last administration, except for the blank group, each group was injected with nitroglycerin 10mg/kg subcutaneously in the right shoulder, 30min was taken as a time period, and the number of times of head bending of the rats in 6 time periods after molding was observed and recorded. The experimental result shows that the silkworm excrement extract has obvious migraine resisting effect in high and medium dosage groups. The results are shown in Table 1.
TABLE 1 Effect of silkworm excrement 95% ethanol extract on the number of times of head-bending of migraine rats
n＝10
Note:#comparison with blank control, P<0.05，##Comparison with blank control, P<0.01；*Comparison with negative control group, P<0.05，**Comparison with negative control group, P<0.01。
Example 2: further testing with silkworm excrement
Example 1 was repeated using 95% methanol/water, 70% ethanol/water and 80% acetone/water, respectively, by volume as extraction solvents. The experimental result shows that the silkworm excrement 95% methanol extract, the silkworm excrement 70% ethanol extract and the silkworm excrement 80% acetone/water extract which are respectively obtained by using 95% methanol/water, 70% ethanol/water and 80% acetone/water as extraction solvents also have remarkable anti-migraine effect on rats, so that the anti-migraine active ingredients in the silkworm excrement can also be obtained by using ethanol/water, methanol/water or acetone/water with different concentrations as the extraction solvents. The results are shown in Table 2.
TABLE 2 influence of different solvent extracts of faeces Bombycis on the number of migraine headaches in rats
n＝10
Note:#comparison with blank control, P<0.05，##Comparison with blank control, P<0.01；*Comparison with negative control group, P<0.05，**Comparison with negative control group, P<0.01。
Example 3: isolation and identification of anti-migraine active compounds from silkworm excrement whole plant
(1) Airing 10Kg of silkworm excrement and crushing the silkworm excrement into particles with the particle size of 0.1cm to obtain silkworm excrement powder, ultrasonically extracting the silkworm excrement powder for 4 times at the temperature of 70-74 ℃ by 60Kg of 95% ethanol for 2 hours each time, and combining ethanol extracting solutions for later use;
(2) filtering the ethanol extract prepared in the step (1) by 80-120 micron filter paper, and performing reduced pressure concentration by using a rotary evaporator at the temperature of 45 ℃ to obtain 1129g of extract for later use;
(3) suspending 1129g of the extract in (2) in 4500ml of water, sequentially extracting with 4500ml of petroleum ether, 4500ml of ethyl acetate and 4500ml of n-butanol, extracting each solvent for 5 times, and evaporating the solvents by using a rotary evaporator to obtain a petroleum ether extract (207g), an ethyl acetate extract (214g) and an n-butanol extract (406 g);
(4) subjecting the petroleum ether extract prepared in the step (3) to 100-mesh 200-mesh silica gel column chromatography, and performing gradient elution by using petroleum ether-ethyl acetate (volume ratio of 200: 1-0: 1) to obtain 10 components (Fr.1-10). Subjecting Fr.2(33.0g) to 200-mesh 300-mesh silica gel column chromatography, and gradient eluting with petroleum ether-ethyl acetate (volume ratio 100: 1-10: 1) to obtain components Fr.2-1-4. Fr.2-2 is subjected to silica gel column chromatography, eluted with petroleum ether-ethyl acetate (volume ratio 50:1), and repeatedly purified to obtain diterpenoid phytol (3.6 g). The separation and identification process of the anti-migraine active ingredient in silkworm excrement is shown in figure 1.
Nuclear magnetic resonance spectrum for chemical structure of compound of the present invention (1H NMR,13C NMR, DEPT, COSY, HSQC, HMBC), EI-MS, IR and other spectrograms. According to the spectral data of the compound 1, the diterpenoid phytol (phytol) is identified by analyzing the spectral data of the compound and referring to relevant documents (Shan M.D., An T.Y., Hu L.H., Chen Z.L.Diterpen derivative and chromone from Hypericum perforatum. Natural Product Research,2004,18(1): 15-19; horse, Lu hong Xiang, Kouyang. hard finger leaf moss chemical composition Research. Chinese herbal medicine, 2006,37(5):660 shell 662.).
Physicochemical data for compound 1: the compound (phytol) is colorless viscous liquid, EI-MS M/z is 278[ M-H ]2O]+(8%), 123 (56%), 109 (27%), 95 (75%), 81 (72%), 71 (93%), 57 (76%), 43 (100%), presumed to be C20H40O。1H NMR(400MHz,CDCl3)δH:4.15(2H,d,J＝7.2Hz,H-1),5.41(1H,t,J＝7.2Hz,H-2),1.99(2H,t,J＝7.2Hz,H-4),1.67(3H,s,H-20),0.83–0.87(12H,H-16–H-19),0.95–1.60(19H,m,H-5–H-15)；13C NMR(100MHz,CDCl3)δC:59.6(C-1),123.2(C-2),140.5(C-3),40.0(C-4),25.3(C-5),36.8(C-6),32.9(C-7),37.5(C-8),24.6(C-9),37.6(C-10),32.8(C-11),37.4(C-12),25.0(C-13),39.5(C-14),28.1(C-15),22.8(C-16),22.9(C-17),19.9(C-18,19),16.3(C-20).
Example 4: anti-migraine activity assay of the phytol
The anti-migraine activity of phytol was tested using a nitroglycerin migraine headache rat model. Male SD rats are measured according to the number of experimental needs, the weight of the male SD rats is 180-220 g, the male SD rats are randomly grouped, and 10 rats are taken in each group. The groups are as follows in sequence: blank control group (distilled water), negative control group (distilled water), sample group (phytol), positive control group (ibuprofen tablet dosage is 80mg/kg respectively), and continuous administration is carried out for 7 d. After 60min of the last administration, nitroglycerin was subcutaneously injected into the right shoulder of each group at 10mg/kg, except for the blank group to which physiological saline was administered. After the injection of nitroglycerin, the number of times of head bending of the rat in 6 time periods after the molding was observed for 30min as one time period and recorded. Injecting nitroglycerin into rat subcutaneously for 4h, anesthetizing with 10% chloral hydrate, opening abdominal cavity, collecting blood from abdominal aorta, centrifuging at 4 deg.C for 15min (1000g/min), and separating plasma; cutting off head to obtain brain, and separating hypothalamusStoring at-80 deg.C, and detecting calcitonin gene-related peptide (CGRP) content in hypothalamus and blood plasma of migraine rat by enzyme-linked immunosorbent assay (ELISA). The measured data is averaged + -SD
Showing that the prism 6 statistical software is adopted for statistical processing. The results are shown in tables 3 and 4. Experimental results show that the phytol can obviously reduce the frequency of rat head scratching and reduce the content of CGRP in the hypothalamus and plasma of a migraine rat, and the phytol is prompted to have good anti-migraine activity and can be used as an anti-migraine component or a lead compound.
TABLE 3 Effect of phytol on the number of migraine headaches in rats
n＝10
Note:#comparison with blank control, P<0.05，##Comparison with blank control, P<0.01，###Comparison with blank control, P<0.001；*Comparison with negative control group, P<0.05，**Comparison with negative control group, P<0.01，***Comparison with negative control group, P<0.001。
TABLE 4 Effect of phytol on the content of CGRP in the hypothalamus and plasma of migraine rats
n＝10
Note:#comparison with blank control, P<0.05，##Comparison with blank control, P<0.01，###Comparison with blank control, P<0.001；*Comparison with negative control group, P<0.05，**Comparison with negative control group, P<0.01，***Comparison with negative control group, P<0.001。
Example 5
The phytol obtained by the preparation method of example 3 is added with common auxiliary materials of tablets, and the tablets are prepared by the conventional preparation process.
Example 6
The phytol prepared by the method of example 3 is added with common auxiliary materials of injection and prepared into injection by the conventional preparation process.
Example 7
The phytol obtained by the preparation method of the embodiment 3 is added with common capsule auxiliary materials and prepared into capsules by a conventional preparation process.
Example 8
The phytol obtained by the preparation method is added with common auxiliary materials of the cataplasm according to the method of the embodiment 3, and the cataplasm is prepared by the conventional preparation process.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (9)
1. Use of phytol for the preparation of an anti-migraine drug, wherein the phytol has the following structure:
2. the use according to claim 1, wherein the phytol is present in and used in the form of an extract obtained by extracting silkworm excrement with a solvent; wherein the solvent is 70-100 vol% ethanol/water, 70-100 vol% methanol/water, or 50-80 vol% acetone/water. Wherein the faeces Bombycis is dry feces of larva of Bombyx mori of Bombycidae.
3. The use according to any one of claims 1-2, wherein the phytol is prepared as an active ingredient in a pharmaceutical composition with a pharmaceutically acceptable carrier or adjuvant.
4. Use according to any one of claims 1 to 3, wherein the pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, injections.
5. Use according to any one of claims 1 to 4, wherein the pharmaceutical composition is selected from a sustained release formulation or a controlled release formulation.
6. The use according to any one of claims 1 to 5, wherein the pharmaceutically acceptable carrier or adjuvant comprises oral preparation adjuvant, parenteral administration adjuvant or topical administration adjuvant, and the administration route can be oral administration, injection, topical administration, etc.; the administration dosage form can be liquid dosage form, solid dosage form, the liquid dosage form can be syrup, injection solution, non-aqueous solution, suspension or emulsion, the solid dosage form can be tablet, lozenge, capsule, dripping pill, granule, powder, cream, solution, suppository, dispersible powder such as lyophilized powder for injection, aerosol, etc.; the used auxiliary materials comprise: lactose, calcium carbonate, calcium phosphate, sodium phosphate, starch, cyclodextrin, sucrose, mannitol, microcrystalline cellulose sodium, calcium sulfate, water, ethanol, propanol, glycerol, propylene glycol, isopropanol, syrup, honey, glucose, gelatin syrup, sodium carboxymethylcellulose, potassium phosphate, dried starch, agar powder, calcium carbonate, sodium bicarbonate, sodium dodecyl sulfonate, methyl cellulose, glyceryl tristearate, cocoa butter, hydrogenated oil, quaternary ammonium salt, talc, triethylamine magnesium stearate, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin.
7. Use of phytol for the manufacture of a medicament for reducing the level of calcitonin gene-related peptide (CGRP), said phytol having the structure:
8. use of phytol for the preparation of a calcitonin gene-related peptide (CGRP) receptor antagonist, said phytol having the structure:
9. the use according to claim 7 or 8, wherein the phytol is present in and used in the form of an extract obtained by extracting silkworm excrement with a solvent; wherein the solvent is 70-100 vol% ethanol/water, 70-100 vol% methanol/water, or 50-80 vol% acetone/water, wherein the faeces Bombycis is dry feces of Bombyx mori larva of Bombycidae.
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| CN202110291719.5A CN113491679A (en) | 2021-03-18 | 2021-03-18 | Application of phytol in preparation of anti-migraine drug |
| PCT/CN2022/079445 WO2022193969A1 (en) | 2021-03-18 | 2022-03-07 | Use of phytol in preparation of anti-migraine drug |
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| CN202110291719.5A CN113491679A (en) | 2021-03-18 | 2021-03-18 | Application of phytol in preparation of anti-migraine drug |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111329866A (en) * | 2020-04-12 | 2020-06-26 | 云南民族大学 | Application of pentacyclic triterpenoid in preparation of anti-migraine medicine |
| WO2022193969A1 (en) * | 2021-03-18 | 2022-09-22 | 云南民族大学 | Use of phytol in preparation of anti-migraine drug |
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| WO2021033149A1 (en) * | 2019-08-19 | 2021-02-25 | Buzzelet Development And Technologies Ltd. | Compositons for the treatment of a condition characterized by anandamide deficiency and uses thereof |
| CN113491679A (en) * | 2021-03-18 | 2021-10-12 | 云南民族大学 | Application of phytol in preparation of anti-migraine drug |
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- 2021-03-18 CN CN202110291719.5A patent/CN113491679A/en active Pending
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111329866A (en) * | 2020-04-12 | 2020-06-26 | 云南民族大学 | Application of pentacyclic triterpenoid in preparation of anti-migraine medicine |
| WO2022193969A1 (en) * | 2021-03-18 | 2022-09-22 | 云南民族大学 | Use of phytol in preparation of anti-migraine drug |
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