CN104721174A - New use of multiprenylmenaquinone compounds - Google Patents
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- CN104721174A CN104721174A CN201410017193.1A CN201410017193A CN104721174A CN 104721174 A CN104721174 A CN 104721174A CN 201410017193 A CN201410017193 A CN 201410017193A CN 104721174 A CN104721174 A CN 104721174A
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Abstract
The invention provides a new use of multiprenylmenaquinone compounds in preparation of drugs and health products for preventing and treating spinal cord injury and related diseases. The multiprenylmenaquinone compounds provided by the invention have important application value for treating related diseases of spinal cord injury, provide a foundation for screening new drugs and have an important application prospect.
Description
The invention belongs to field of medicaments, be specifically related to the application of multiprenylmenaquinone compounds in the medicine preparing treatment or prevention spinal cord injury relevant disease and health product.
Background technology
Vitamin K has the bioactive class material of phylloquinone, reaches nurse find from animal liver and flaxseed oil and extract early than nineteen twenty-nine by Denmark chemist.Vitamin K is yellow crystals, and fusing point is 52 DEG C ~ 54 DEG C, usually in oily liquids or solid, water insoluble, can be dissolved in the organic solvent such as oils and fats and ether.There is several form such as K1, K2, K3, K4, the most important thing is Agua-Mephyton 1 and K2, namely the Menaquinone K6 that the vitamin K1 extracted from green plants and intestinal bacteria (as escherichia coli) are synthesized, having bioactive is in animal body Menaquinone K6, and vitamin K1 will be converted into Menaquinone K6 just can work.
Menaquinone K6 is the general designation of the terpenes side chain compound of a series of isoprene structures unit having number not etc. containing 2-MNQ parent nucleus and C3 bit strip, is also called multiprenylmenaquinone.According to the number of carbon on terpenes side chain, K2 (10), K2 (20), K2 (35), K2 (40) etc. can be divided into.Menaquinone K6 is synthesized by some antibacterial, and contained by the hydrophobic substituent on its C3-position of Menaquinone K6 of different bacterium synthesis, unsaturated iso-amylene group numbers is different.Such as, Menaquinone K6 (20) is then for terpenes side chain there being the Menaquinone K6 of 20 carbons; Menaquinone K6 (20) is also called MK-4, and this is according to its terpenes side chain there being 4 isoprene side chains names.Menaquinone K6 treats some shortage property hemorrhages except can be used in clinical practice, is mainly used in treatment and prevention of osteoporosis disease, prevents calcium in eparterial deposition, and prevention liver cirrhosis progress is the diseases such as hepatocarcinoma.Also certain protective effect may be had to Parkinson's disease patient.
Current Menaquinone K6 is mainly as health product, Natto Pharma health products Co., Ltd of Norway is proposed first the Menaquinone K6 bone health health product MenaQ7 in the whole world, other health products Co., Ltd of world Purita, Thorn Research, Frutarom, Kappa, PL Thomas etc. is also proposed corresponding product.Menaquinone K6 containing prevention of osteoporosis disease in the agate rope board natto polypeptide capsule of Qingdao Bei Meisheng company Development and Production.
Within 2005, Japan's approval Menaquinone K6 goes on the market as osteosporosis resistant medicament, and patent drug is declared by Japanese OYAKA company.In January, 2008, Menaquinone K6 is assert by U.S. food Drug Administration (FDA) safety, on April 22nd, 2009 European Parliament and EU Council agree to that Menaquinone K6 can be used as the raw material (2009/345/EC) of health food or nutrition enhancer.No. [2005] 202, state's food medicine prison note, Menaquinone K6 has just been listed in " vitamin, the mineral cpd list " of State Food and Drug Administration's " supplementary declare with evaluate specify (trying) ", can be used as the raw material of health food or nutrition enhancer.
" Gu rising Menaquinone K6 soft capsule " of Guangdong Goodscend Pharmaceutical Science & Technology Co., Ltd. in 2012 (the strong word G20110562 of state's food) granted for domestic take high activity Menaquinone K6 as the new type bone health food of unique functional component, they obtain innovation independent intellectual property right (patent ZL200710066045.9; 200710066044.4; 200810058363.5).
Summary of the invention
The present invention against the background of the prior art, provides multiprenylmenaquinone compounds, i.e. the application of Menaquinone K6 family in the medicine preparing treatment or prevention spinal cord injury relevant disease and health product.
The concrete technical scheme of the present invention is as follows:
The application of multiprenylmenaquinone compounds as shown in formula I in the medicine preparing treatment or prevention spinal cord injury and relevant disease thereof and health product,
formula I,
The wherein integer of n=0-12, the integer of preferred n=1-7, more preferably n=1,3,6,7 or 9.
Particularly, as n=3, formula I is Menaquinone K6 (20), terpenes side chain has 4 isoprene side chains, and be also called Menaquinone K6 (20), (Menaquinone-4), is abbreviated as MK4, molecular formula C
31h
40o
2, CAS 11032-49-8
Structural formula:
As n=6, formula I is Menaquinone K6 (35), and terpenes side chain has 7 isoprene side chains, be also called menaquinone-7, (Menaquinone-7), is abbreviated as MK7, molecular formula C
46h
64o
2, CAS 27670-94-6.
Above-mentioned spinal cord injury comprise acute stage and chronic phase spinal cord injury, preferred acute spinal cord injury.
The medicine of above-mentioned preparation treatment or prevention spinal cord injury and relevant disease thereof is containing type I compound and pharmaceutically acceptable carrier.
The health product of above-mentioned preparation treatment or prevention spinal cord injury and relevant disease thereof are the health product relevant to motor function and drinks.
Spinal cord injury (SCI) is that a kind of disability rate is high, mainly causes the cental system nerve injury of sensation and motor function permanent loss, often causes patient's paralysis in various degree.Spinal cord injury is a disease occurred frequently clinically, is complication the most serious in spinal injury, often causes damaging sections with the serious dysfunction of lower limb body.According to statistics, China SCI patient has reached millions of, and mostly occur teenager to the age level in the prime of life, this must give patient, and family and entire society bring heavy economy and mental burden.But the medicine of domestic and international treatment SCI and surgical operation all do not obtain gratifying clinical efficacy.Therefore, the treatment of SCI and research are extremely important and are worth.At present about spinal cord injury not good Therapeutic Method, methyl meticortelone (Methylprednisolone, MP) is uniquely by treatment spinal cord injury (spinal cordinjury, SCI) medicine that FDA ratifies.
Applicant's Late Cambrian Menaquinone K6 family, particularly terpenes side chain there is 2-10 isoprene side chains Menaquinone K6 have the effect for the treatment of and prevention spinal cord injury.
Menaquinone K6 of the present invention can adopt the method described in document to prepare.(as Cawthorne, M.A., Jeffries, L.R., Harris, M., Price, S.A., Diplock, A.T.and Green, J. (1967) ' Menaquinone-4and-5in a bacterium ', Biochem J, 104 (2), 35contd-36c.Dialameh, G.H., Taggart, W.V., Matschiner, J.T.and Olson, R.E. (1971) ' Isolation and characterization of menaquinone-4as a product of menadionemetabolism in chicks and rats ', Int J Vitam Nutr Res, 41 (3), 391-400.Tani, Y. (1992) ' Microbialprocess of menaquinone production ', J Nutr Sci Vitaminol (Tokyo), Spec No, 251-4. in document).Also can business purchase obtain.
Type I compound of the present invention, particularly Menaquinone K6 (10), K2(20), K2(35) K2(40) can with the form of single medicine by administration or can with other medicines administering drug combinations.
Compound of the present invention can be used alone or uses with the form of pharmaceutical composition.Pharmaceutical composition comprises compound or pharmaceutically acceptable salt thereof of the present invention as active component and pharmaceutically suitable carrier.Preferably, pharmaceutical composition of the present invention has the compound or pharmaceutically acceptable salt thereof of the present invention as active component of 0.1-99.9% percentage by weight." pharmaceutically suitable carrier " can not destroy the pharmaceutical active of compound or pharmaceutically acceptable salt thereof of the present invention, simultaneously its effective dose, and consumption when namely can play pharmaceutical carrier effect is to human non-toxic.
" pharmaceutically suitable carrier " includes but not limited to: ion exchange material, aluminium oxide, aluminium stearate, lecithin, self-emulsifying drug delivery system (SEDDS) is as d-TPGS 1000, the surfactant of the pharmaceutical preparatioies such as tween or other similar polymerisation mediums, serum albumin is as human serum albumin, buffer substance is as phosphate, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid partial glyceride mixes, water, salt, electrolyte is as sulfate protamine, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium silicate etc.Polyvidon, cellulosic material, polyvinyl alcohol, sodium carboxymethyl cellulose, polyacrylate, ethylene-polyoxyethylene-block polymer and lanoline, cyclodextrin as α-, β-, gamma-cyclodextrin or its derivant such as the hydroxyalkyl cyclodextrin such as 2-and 3-HP-β-CD or other soluble derivatives etc. through chemical modification all can be used for the drug delivery promoting compound of the present invention, its pharmaceutical salts or prodrug.
Other pharmaceutically acceptable auxiliaries such as filler (as Lactis Anhydrous, starch, lactose beadlet and glucose), binding agent (as microcrystalline Cellulose), disintegrating agent (as crosslinked carboxymethyl fecula sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and cross-linked pvp), lubricant (as magnesium stearate), absorption enhancer, flavouring agent, sweeting agent, diluent, excipient, wetting agent, solvent, solubilizing agent and coloring agent etc. also can add in pharmaceutical composition of the present invention.
The compound of the invention described above and pharmaceutical composition are by intestinal or parenteral administration.Non-intestinal drug delivery agent comprises injection, cream, ointment, patch, spray etc.Route of administration comprises in subcutaneous, Intradermal, intra-arterial, intravenous, intramuscular, intraarticular, synovial fluid, in breastbone, in sheath, intralesional, intracranial injection or infusion, or, oral, locally, rectum, per nasal, through cheek, vagina, Sublingual, Intradermal, mucosa, trachea, urethral administration, or by suck aerosol or implant accumulation or the administration of acupuncture mode.
The compound or pharmaceutically acceptable salt thereof of the invention described above and the treatment effective dose of pharmaceutical composition are between 0.001-100mg/kg/d, and can be used for single drug or the drug combination treatment of relevant disease, is the scope that those skilled in the art can understand.
The technical solution used in the present invention is: with IH impact spinal cord beating instrument, 200gSD rat is prepared spinal cord injury model, then gives experimental group lumbar injection Menaquinone K6 (20) respectively, matched group injection equivalent drug solvent DMSO.Medication component is individually dosed group and acute spinal cord injury front and rear continuous use group after acute spinal cord injury.7 days are continued, once a day for starting lumbar injection Menaquinone K6 (20) injection of solution after treatment group spinal cord injury after acute spinal cord injury immediately; For continuous use group before and after spinal cord injury, damage within first 2 days, start injection last till damage latter 7 days, once a day.Can determine that Menaquinone K6 (20) is treated and preventive effect for spinal cord injury by the difference of motor function recovery scoring (BBB scoring) of each time point of 3,7,14,21 and 28 days after detecting each group of spinal cord injury.
Beneficial effect of the present invention is mainly reflected in: provide for spinal cord injury, the particularly treatment of acute spinal cord injury and the novel drugs of prevention, Menaquinone K6 can be played a role in vivo by abdominal cavity or intramuscular injection, for providing the foundation for the new medicament screen of spinal cord injury treatment and prevention, there is important application prospect.
Accompanying drawing explanation
Fig. 1 is SD Model of Rat Spinal Cord Injury BBB motor function scores result.
Fig. 2 is SD Model of Rat Spinal Cord Injury afterbody pain sensation test experiments result.
Fig. 3 is the fast blue staining experimental result of SD Model of Rat Spinal Cord Injury.
Fig. 4 is SD Model of Rat Spinal Cord Injury HE staining experimental result.
Detailed description of the invention
Concrete steps of the present invention are described by the following examples, but do not limit by embodiment.
Term used in the present invention, except as otherwise noted, generally has the implication that those of ordinary skill in the art understand usually.
Below in conjunction with specific embodiment and comparable data describes in further detail the present invention.Should be understood that these embodiments just in order to demonstrate the invention, but not limit the scope of the invention by any way.
In the examples below, the various process do not described in detail and method are conventional methods as known in the art.
Experiment material:
Laboratory animal: female sd inbred rats, 200g, from Nantong University's Experimental Animal Center
Medicine and reagent: Menaquinone K6 (20) is purchased from Sen Fo high-tech Industrial Co., Ltd. (CAS 11032-49-8), and dimethyl sulfoxine (DMSO) Luxol Fast Blue is from Sigma company.
Experimental apparatus: IH impact whipping tester (IH-0400, PSI, the U.S.).
Experimental technique:
Get female 200g SD rat 45, be divided into 3 groups at random, often organize 15, be respectively the treatment group (injuerd+K2post SCI) of the treatment group (injuerd+K2) of continuous use and only medication after injury before and after nonuser matched group (injuerdonly), damage.The preparation of Menaquinone K6 (20) solution: Menaquinone K6 (20) is dissolved in DMSO, is mixed with the solution that concentration is 100mg/ml.Only the treatment group of medication after injury starts lumbar injection Menaquinone K6 (20) injection of solution immediately and continues 7 days after spinal cord injury, once a day; Injected dose is 100mg Menaquinone K6 (20)/kg body weight, and the treatment group of continuous use before and after damage, damages and within first 2 days, start injection, and last till latter 7 days of damage, once a day, injected dose is 100mg Menaquinone K6 (20)/kg body weight.Matched group injects mutually commensurability solvent (DMSO) in the corresponding time.
Prepared by spinal cord injury model: be T8, T9 sections according to the high disease locus of clinical spinal cord injury, the position that in the present invention, Spinal Cord Injury in Rats is chosen is T9 sections, clashes into, clash into the degree of depth all at 1100 μm-1300 μm after exposing T9 sections by the dynamics of IH impact spinal cord beating instrument 150k.
Evaluation index:
The index recovered after the spinal cord injury that the present invention adopts is BBB motor function scores.Within 3,7,14,21 and 28 days after spinal cord injury, carry out BBB scoring respectively, evaluated the drug effect of Menaquinone K6 (20) by statistics medication group and matched group mark difference.
The present invention additionally uses afterbody pain sensation test experiments to evaluate medication group and matched group to the sensitivity of the pain sensation to observe the impact of sensory nervous system, the instrument adopted is whipping tester (model 37360, place of production Italy), testing time point is identical with BBB scoring testing time point.
Present invention employs fast blue staining evaluation and have myelin fibre bundle reserving degree to spinal cord after rats with spinal cord injury medication.Within 28 days, by fixing after perfusion, section is rear with Luxol Fast Blue dyeing, Taking Pictures recording after injury for rat.
Present invention employs HE staining and evaluate reserving degree to cord cell and fibre composition after rats with spinal cord injury medication.Rat is fixing after within 28 days, passing through perfusion after injury, with HE dyeing after section, and Taking Pictures recording.
Experimental result:
SD Model of Rat Spinal Cord Injury BBB motor function scores the results are shown in Figure 1.* to represent and independent damage group compares and has notable statistics difference (P<0.05).* represents and damage group separately compares and has very significant significant difference (P<0.01).In Acute spinal injury model, the function score starting medication two medication groups before and after medication and damage after damage is all higher than the scoring of damage matched group at corresponding time point, and that is the spinal function recovery effects of two medication groups is all good than matched group.Medication effect is started relatively better before damage.
SD Model of Rat Spinal Cord Injury afterbody pain sensation test experiments the results are shown in Figure 2, * and to represent and damage group separately compares and has notable statistics difference (P<0.05).In Acute spinal injury model, start the more relative than matched group short to the response time of the pain sensation at corresponding time point of medication and damage front and back medication two medication groups after damage, sensory function recovers quicker relatively.
The fast blue staining experimental result of SD Model of Rat Spinal Cord Injury is shown in Fig. 3, is presented in Acute spinal injury model after fast blue myelin stock-dye, and before and after starting medication and damage after damage, medication two medication groups remain more fiber tracts of spinal cord.
SD Model of Rat Spinal Cord Injury HE staining experimental result is shown in Fig. 4, is presented in Acute spinal injury model after conventional H E dyeing, and before and after starting medication and damage after damage, medication two medication groups remain more spinal nervous tissue.
Conclusion: the present invention, by showing that Menaquinone K6 contributes to the recovery after acute spinal cord injury to the experiment of recovery situation after Spinal Cord Injury in Rats medication, discloses the active drug that Menaquinone K6 of the present invention can be used as treatment acute spinal cord injury and prevention.
Claims (6)
1. the application of the multiprenylmenaquinone compounds as shown in formula I in the medicine preparing treatment or prevention spinal cord injury and relevant disease thereof and health product,
formula I,
The wherein integer of n=0-12.
2. apply as claimed in claim 1, it is characterized in that the integer of described n=1-7.
3. apply as claimed in claim 2, it is characterized in that described n=1,3,6,7 or 9.
4. apply as claimed in claim 1, it is characterized in that described spinal cord injury is acute spinal cord injury.
5. the application as described in one of claim 1-4 item, is characterized in that described medicine is containing type I compound and pharmaceutically acceptable carrier.
6. the application as described in one of claim 1-4 item, is characterized in that described health product are the health product relevant to motor function and drinks.
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| CN109223732A (en) * | 2018-09-29 | 2019-01-18 | 南通市第人民医院 | A kind of medical chitose nanosphere and preparation method thereof treated spinal cord injury and carry methylnaphthoquinone -4 |
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| DE102010015242A1 (en) * | 2010-04-15 | 2011-10-20 | Fresenius Medical Care Deutschland Gmbh | Combination of vitamin K and nicotinamide |
| WO2013100873A1 (en) * | 2011-12-19 | 2013-07-04 | Mahmut Bilgic | Pharmaceutical formulation of pregabalin (particle size 300-2500 micrometer) |
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| CN109223732A (en) * | 2018-09-29 | 2019-01-18 | 南通市第人民医院 | A kind of medical chitose nanosphere and preparation method thereof treated spinal cord injury and carry methylnaphthoquinone -4 |
| CN109223732B (en) * | 2018-09-29 | 2020-09-01 | 南通市第一人民医院 | Menadione-4-loaded medical chitosan nano-microsphere for treating spinal cord injury and preparation method thereof |
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Effective date of registration: 20210618 Address after: 226019 No.205, building 6, Nantong University, No.9, Siyuan Road, Nantong City, Jiangsu Province Patentee after: Center for technology transfer, Nantong University Address before: 226019 Jiangsu city of Nantong province sik Road No. 9 Patentee before: NANTONG University |
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