CN105055516A - New anti-inflammatory medicine with bone protection function and composed of glucocorticoid and salvia extract - Google Patents
New anti-inflammatory medicine with bone protection function and composed of glucocorticoid and salvia extract Download PDFInfo
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- CN105055516A CN105055516A CN201510549013.9A CN201510549013A CN105055516A CN 105055516 A CN105055516 A CN 105055516A CN 201510549013 A CN201510549013 A CN 201510549013A CN 105055516 A CN105055516 A CN 105055516A
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Abstract
The invention relates to new anti-inflammatory medicine with a bone protection function and composed of glucocorticoid and salvia extract. The new medicine has a better curative effect than existing anti-inflammatory action obtained by singly using the glucocorticoid, is free from damage to bones by the glucocorticoid and is new medicine with the bone protection function. The new anti-inflammatory medicine is composed of prednisone acetate and tanshinol, the optimal ratio of the formula is 1:4, and namely the new anti-inflammatory medicine contains 5 mg of prednisone acetate and 20 mg of tanshinol. The new anti-inflammatory medicine comprises the optimal combination of the prednisone acetate, the tanshinol, salvianolic acid B and protocatechualdehyde. The selected salvia extract includes known components with definite chemical structures and stable ingredients and easy to extract, and the compound prescription can be registered as a chemical drug and be approved to produce. The new anti-inflammatory medicine can replace various kinds of glucocorticoid medicine used clinically in China currently.
Description
Technical field
The present invention relates to one group of antiinflammatory new drug with bone protective effect be made up of glucocorticoid and Radix Salviae Miltiorrhizae extract; this new drug has stronger than current alone glucocorticoid antiinflammatory action curative effect; and there is no the damaging action of glucocorticoids on bone, be the antiinflammatory new drug with bone protective effect.
Background technology
Glucocorticoid medicine is conventional anti-inflammatory drug, and this kind of medicine conventional has prednisolone acetate, cortisone, hydrocortisone, prednisone clinical, meticortelone, prednisolone, Methyllprednisolone, 6.alpha.-fluoro-16.alpha.-methylprednisolone, fluprednisolone, triamcinolone, betamethasone, dexamethasone, beclomethasone etc.The pharmacological action that glucocorticoid medicine has antiinflammatory, immunosuppressant and shock etc. important, but excusing from death reason dose glucocorticoid class medicine can cause many untoward reaction to body, this is because the impact of glucocorticoid medicine on body substance metabolism causes, some untoward reaction can cause more serious infringement to body as osteoporosis etc., limits glucocorticoid medicine application clinically.Glucocorticoid medicine has powerful antiinflammatory action, can resist the inflammation that following a variety of causes causes: 1. physical injury, as burn, wound etc.; 2. chemical injury, as acid, alkali damage, 3. biological injury, as antibacterial, viral infection, 4. immune injury, as each allergic reaction type, 5. aseptic inflammation, as ischemic tissue damage etc.Various in early days acutely inflamed, application glucocorticoid medicine can reduce inflammation early stage to ooze out, edema, telangiectasis, leukocyte infiltration and the reaction such as to engulf, thus clinical symptoms such as red, swollen, hot, the pain improving that inflammation occurs in early days; In the inflammation later stage, application glucocorticoid medicine can suppress blood capillary and fibroblastic hypertrophy, suppress synthesis and the granulation tissue hyperplasia of collagen protein, mucopolysaccharide, thus prevent adhesion and the cicatrization in inflammation later stage, the sequela reduced inflammation, but inflammatory reaction is a kind of defense function of body, the reaction in inflammation later stage is also the significant process of tissue repair, therefore glucocorticoid medicine is while inflammation-inhibiting, mitigation symptoms, also reduce defence and the repair function of body, can cause infecting diffusion and delaying wound healing.
Glucocorticoid medicine can suppress osteoblastic vigor, reduce the synthesis of collagen in bone, promote the decomposition of collagen and bone matrix, make bone mineral not easily calm, New bone formation generation obstacle and cause osteoporosis, osteoporosis is more common in glucocorticoid increase disease patient or is widely applied this class medicine person for a long time.When there is osteoporosis, particularly at vertebrae, can lumbago and backache be had, compression fracture, fishbone sample and wedge shape deformity even occurs.A large amount of glucocorticoid medicine also can promote calcium excretion in urine, and bone mineral is reduced further, and this is also that glucocorticoid medicine causes one of osteoporotic reason.Osteoporosis and vertebral compression fracture are that various age patient applies complication serious in glucocorticoid medicine treatment.Rib with and vertebrae have height beam column construction, usually influenced the most serious, this may be suppressed to bone cell activity with glucocorticoid medicine, increases the excretion of calcium phosphorus, suppresses the absorption of enteral calcium and increase osteocyte relevant to factors such as the sensitivity of parathyroid hormone.Clinical then must drug withdrawal immediately as there is osteoporosis, be that application glucocorticoid medicine must one of important indication of drug withdrawal.
The untoward reaction that long-term extensive application glucocorticoid medicine causes also comprises: 1. substance metabolism and water and salt metabolic disturbance long-term widely applies glucocorticoid medicine can cause substance metabolism and water and salt metabolic disturbance, there is hemo-hyperadrenocorticism syndrome, as symptoms such as edema, hypokalemia, hypertension, glycosuria, thinning of skin, moon face, buffalo hump, central obesity, hirsutism, acne, myasthenia and amyotrophy, generally do not need special treatment, can disappear voluntarily after drug withdrawal.But myasthenia recovery is slow and incomplete.Less salt, low sugar, high protein diet and add and can alleviate these symptoms with measures such as potassium chloride.In addition, glucocorticoid medicine, due to the synthesis of Profilin matter, can delay the wound healing of wounded patient.Child Ke Yin Developing restraint hormone secretion and cause negative nitrogen balance, growth promoter is affected.2. bring out or increase the weight of the immunologic function that infection glucocorticoid medicine can suppress body, and without antibacterial action, therefore prolonged application often can be brought out infection or be increased the weight of to infect, focus of infection diffusion potential in body or static focus of infection resume combustion can be made, particularly original resistance descender, as nephrotic syndrome, pulmonary tuberculosis, aplastic amenia people etc.3. digestive complications glucocorticoid medicine can stimulate gastric acid, pepsic secretion suppress gastric mucus secretion, reduce the resistance of gastric mucosa, therefore can bring out or aggravate peptic ulcer, glucocorticoid medicine also can cover the initial symptoms of ulcer, so that occur that burst is hemorrhage and wait severe complication with perforation, stomach or duodenal ulcer during life-time service, can be made to increase the weight of.4. cardiovascular complications prolonged application glucocorticoid medicine raises owing to can cause sodium, water retention and blood fat, can bring out hypertension and atherosclerosis.5. neuropsychiatric abnormalities glucocorticoid medicine can cause the dystropy of various ways, as glad phenomenon, nervousness, excitement, insomnia, Feeling changes or even occur obvious psychotic symptoms, some patient also has suicidal tendency, in addition, glucocorticoid medicine also may bring out epilepsy.6. cataract and glaucoma glucocorticoid medicine can bring out cataract, and whole body or topical all can occur.Cataractous generation may suppress lens epithelium Na with glucocorticoid medicine
+-K
+pumping function, causes crystal fibre hydrops relevant with protein coagulation.Glucocorticoid medicine can also make intraocular pressure raise, bring out glaucoma or glaucoma is worsened, whole body or topical all can occur, and the reason that intraocular pressure raises may be because glucocorticoid medicine makes the collagen bundle swelling of eye anterior chamber angle trabecular reticulum structure, hinders caused by aqueous humor circulation.
Radix Salviae Miltiorrhizae is Lamiaceae Salvia platymiscium, it is a kind of conventional Chinese medicine, there is promoting blood circulation to remove blood stasis, detumescence hemostasis, anti-inflammatory analgetic, menstruction regulating and pain relieving, coronary artery dilator, improve myocardial ischemia situation, reduce blood pressure, calm the nerves with all worries set aside, blood sugar lowering and the effect such as antibacterial, to menoxenia, amenorrhea dysmenorrhea, lump in the abdomen, breast ventral spine pain, pyretic arthralgia pain, skin infection swells and ache, dysphoria and insomnia; Hepatosplenomegaly, the diseases such as angina pectoris have certain curative effect.Modern medicine experiment proves, Radix Salviae Miltiorrhizae also has anti-platelet aggregation, reduces the function of blood viscosity and the inside and outside blood coagulation system of adjustment, is the natural Chinese medicine that a kind of safety treats again cardiovascular disease reliably.
This project team finds that salvia-soluble effective part group has good protective effect to the osteoporosis that glucocorticoid causes; (main component is danshensu to the water solublity effective part group of further research proof Radix Salviae Miltiorrhizae, salvianolic acid B and protocatechualdehyde) can antagonism glucocorticoid medicine to the suppression of osteoblastic vigor, alleviate the synthesis that glucocorticoid medicine suppresses collagen in bone, promote the decomposition of collagen and bone matrix, make the effect that bone mineral is not easily calm, the corticosteroid osteoporosis caused by New bone formation generation obstacle that prevention prolonged application glucocorticoid medicine causes.
Research shows, salviamiltiorrhizabung and water soluble ingredient danshensu thereof, salvianolic acid B and protocatechualdehyde, also good antibacterial and anti-inflammation functions is had, inhibitory action is had to most antibacterials such as escherichia coli, staphylococcus aureus, Staphylococcus albus, Radix Salviae Miltiorrhizae can also prevent the diffusion of inflammation, reduces leukocytic quantity, reduces the PGF in blood
2content, this antibacterial and anti-inflammation functions of Radix Salviae Miltiorrhizae can antagonism glucocorticoid excessive time bring out or increase the weight of infect untoward reaction, Radix Salviae Miltiorrhizae has immunoregulation effect and repair in trauma effect, after wound there is dysfunction in various degree in body immune system, the inflammation state that easy generation is excessive, cause systemic inflammatory response syndrome, cause tissue injury, and body anti-infectious immunity defence capability can decline, antibacterial is more easily invaded and infects, cause sepsis, finally cause prognosis mala, Radix Salviae Miltiorrhizae has regulating action to this immunologic function: adopt rats'liver macrophage (KC) separation and ientification technology, dynamic observation Radix Salviae Miltiorrhizae and effective ingredient danshensu induced by endotoxin thereof stimulate lower macrophages secrete interleukin 1 (IL-1), the impact of interleukin 8 poison 6 (IL-6) and tumor necrosis factor (TNF), result endotoxin has obvious stimulating expression of macrophage activation, within the scope of certain endotoxin concns, cytokine and the endotoxin irritaiting concentration of macrophages secrete are parallel relation, Radix Salviae Miltiorrhizae and danshensu induced by endotoxin stimulate the cytokine profiles of lower Kupffer cell secretion to have obvious inhibitory action, this inhibitory action is dose dependent.Its suppression mechanism may with the macrophages secrete immunosuppressive substance PGE promoting to activate
2.Radix Salviae Miltiorrhizae can obviously improve pancreatitis rats intestinal permeability, protection function of intestinal mucosa barrier in patient, synthesis and the secretion of intestinal mucosa SigA sIgA can be promoted simultaneously, strengthen intestinal immunity, realize the therapeutical effect to cell-stimulating albumen, salvianolate can suppress the maturation of culture system in vitro small mouse bone marrow dendritic cells, and to its partial immunity function, there is certain negativity regulating action, these results show, Radix Salviae Miltiorrhizae is by carrying out two-ways regulation to immunologic function, thus promote the healing of wound, thus antagonism glucocorticoid excessive cause delay the untoward reaction such as wound healing.Salvianolic acid, danshensu etc. all have significant protective effect to biomembrane peroxidating; permitted eurypalynous taste-blindness rate relevant with active oxygen; active oxygen directly or indirectly damages Gastric Mucosal Cells as a kind of important murder by poisoning factor; these antioxidant contents of Radix Salviae Miltiorrhizae have certain protective role to this kind of taste-blindness rate, can the excessive digestive complications caused of antagonism glucocorticoid.Radix Salviae Miltiorrhizae can increase coronary flow, improve microcirculation, promote the opening of Doppler flow mapping, improve hemorheological property, and improve anoxia endurance, anti peroxidation of lipid, remove harmful free radical, blood is regulated to redistribute at cardiac muscle, thus the effect of function of resisting myocardial ischemia and suppression left ventricular hypertrophy is had, danshensu significantly can expand coronary artery blood flow, simultaneously can to anti-morphine ab, propranolol shrinks effect coronarius, can also to lipoprotein, cell produces different Adjustment effect, its oxidation resistance and Radix Salviae Miltiorrhizae consumption size have direct relation, danshensu can produce inhibition to endogenous victory cholesterol biosynthesis, protective effect is formed to vascular barrier, avoid atherosclerosis, this blood vessel dilating of danshensu and antiatherogenic effect, can the excessive cardiovascular complications caused of antagonism glucocorticoid.Total salvianolic acid has protective effect to the brain injury that Cerebral Ischemia-reperfusion in Mice causes, MDA content in cerebral tissue can be reduced improve significantly to the memory dysfunction that cerebral ischemia re-pouring causes, total salvianolic acid can make the increase of MDA content in MCAO MCAO rat brain be suppressed, improve SOD active, reduce infarct size and alleviate degree of cerebral edema, the vitamin E of Isodose is then without obvious effect, salvianolic acid also can suppress content of nitric oxide and nitric oxide synthase type iNOS activity in ischemic tissue of brain, total red phenolase reduces TXB in Rats after Focal Cerebral Ischemia blood
2content, improve PGI2/TXA ratio and can also suppress increasing of concentration of endothelin in rats with cerebral ischemia blood, total salvianolic acid can suppress K
+the mouse brain synaptosomal glutamate release of induction, glutamic acid is the abundantest excitatory amino acid of brain intensive amount, all innervation can be produced when physiological amount or pharmacology dosage, under certain condition simultaneously, neurotoxic effect can be produced again, neurotoxicity and the cerebral ischemia of glutamic acid have substantial connection, are one of important mechanisms of cerebral ischemia, and total salvianolic acid produces protective effect by suppressing the release of glutamic acid to neurocyte.Danshensu also has protective effect to cerebral ischemic injury; experiment proves danshensu the having a significant effect of mitochondrial membrane potential (MMP) and apoptosis when damaging neurocyte SH-SY5Y induced by oxygen-glucose deprivation; danshensu can suppress the damage of induced by oxygen-glucose deprivation damage to cell mitochondrial; stablize MMP; improve the Mitochondria dysfunction caused by induced by oxygen-glucose deprivation damage; regulate cellular energy metabolism, suppress neuronal apoptosis.Danshensu has strong short migration to tire Mus stem cell of cranial nerve, and under promoting ependyma, neural stem cell is moved to other brain districts; Danshensu also improving significantly to neural cell injury; the reduction of SOD activity in the cell that damaged can be suppressed; obvious intervention effect is all had to each damage criterion; and there is concentration dependent; these results of study prompting danshensu has obvious protective effect to neural cell injury, has certain antagonism to untoward reaction such as the excessive neuropsychiatric abnormalities caused of glucocorticoid.Radix Salviae Miltiorrhizae and compound preparation Prevention and Curation cataract thereof and glaucoma with many reports, Radix Salviae Miltiorrhizae and effective ingredient thereof can antagonism glucocorticoid excessive cause bring out cataract, glaucoma or the untoward reaction that these two kinds of disease of eye are worsened.
Summary of the invention
The present invention proposes one group of antiinflammatory new drug with bone protective effect be made up of glucocorticoid and Radix Salviae Miltiorrhizae extract; this antiinflammatory new drug has the antiinflammatory action that glucocorticoid itself has; but the untoward reaction that the osteoporosis not having glucocorticoid to cause etc. are serious, glucocorticoid other untoward reaction original are also comparatively light or do not have.The danshensu that the present invention selects, salvianolic acid B, these Radix Salviae Miltiorrhizae extracts of protocatechualdehyde are all that known chemical constitution is clear and definite, and the composition of stable components can be used as chemical drugs registration, granted production.
The glucocorticoid that the present invention proposes refers to clinical conventional glucocorticoid medicine, these medicines are prednisolone acetates, prednisolone, cortisone, meprednisone, hydrocortisone, prednisolone, Methyllprednisolone, 6.alpha.-fluoro-16.alpha.-methylprednisolone, fluprednisolone, triamcinolone, triamcinolone acetonide, budesonide, betamethasone, dexamethasone, beclomethasone, fluticasone, mometasone, fludrocortisone, chlorine Pei Tasong, fluocinolone acetonide, fourth chlorine Pei Tasong, beclometasone, halcinonide, cloprednol, ground fluorine can be special, fluorometholone, alclometasone, halometasone, flurandrenolide etc.When these glucocorticoid medicines and Radix Salviae Miltiorrhizae extract form pharmaceutical preparation, all with them clinical common formulations and content, compound recipe is formed with Radix Salviae Miltiorrhizae extract, as prednisolone acetate, clinical preparation is every sheet 5mg, medicine novel formulation of the present invention is also that every sheet contains prednisolone acetate 5mg, and add Radix Salviae Miltiorrhizae extract, the formulation content of other glucocorticoid medicines too simultaneously.
Radix Salviae Miltiorrhizae extract of the present invention refers to danshensu, salvianolic acid B, protocatechualdehyde, rosmarinic acid, methyl rosmarinate, alkannic acid mono methyl ester, alkannic acid dimethyl ester, alkannic acid ethyl ester, alkannic acid, caffeic acid, Hesperetic acid, Tanshinone I, tanshinone ⅡA, Tanshinone II B, cryptotanshinone, iso tanshinone I, iso tanshinone II, , different cryptotanshinone, hydroxyl tanshinone ⅡA, saivianic acid A acid, danshenxinkun, dihydroisotanshinone I, new cryptotanshinone, remove the new cryptotanshinone of hydroxyl, nor-TANSHINONES, Radix Salviae Miltiorrhizae glycol, miltirone, 1-hydrogen miltirone, 1-hydrogen tanshinone ⅡA, 1-hydrogen is for different cryptotanshinone, 3 Alpha-hydroxy tanshinone ⅡAs, 1, 2-dihydro Radix Salviae Miltiorrhizae quinone, aldehyde radical TANSHINONES, methylene dihydrotanshinone, tanshinlactone, dihydro tanshinlactone, Radix Salviae Miltiorrhizae Spiroketals lactone, table Radix Salviae Miltiorrhizae Spiroketals lactone, Radix Salviae Miltiorrhizae Spiroketals lactone II.
The antiinflammatory new drug with bone protective effect be made up of glucocorticoid and Radix Salviae Miltiorrhizae extract of the present invention; refer to the antiinflammatory new drug be made up of prednisolone acetate and danshensu; the formula proportion of both is 1: 2 ~ 20; namely during the tablet of said preparation as clinical practice; every sheet contains prednisolone acetate 5mg, danshensu 10 ~ 100mg.The proportioning of this prescription the best is 1: 4, i.e. prednisolone acetate 5mg, danshensu 20mg.
The antiinflammatory new drug with bone protective effect be made up of glucocorticoid and Radix Salviae Miltiorrhizae extract of the present invention; refer to the antiinflammatory new drug be made up of prednisolone acetate and salvianolic acid B; the formula proportion of both is 1: 2 ~ 20; namely during the tablet of said preparation as clinical practice; every sheet contains prednisolone acetate 5mg, salvianolic acid B 10 ~ 100mg.The proportioning of this prescription the best is 1: 4, i.e. prednisolone acetate 5mg, salvianolic acid B 20mg.
The antiinflammatory new drug with bone protective effect be made up of glucocorticoid and Radix Salviae Miltiorrhizae extract of the present invention; refer to the antiinflammatory new drug be made up of prednisolone acetate and protocatechualdehyde; the formula proportion of both is 1: 2 ~ 20; namely during the tablet of said preparation as clinical practice; every sheet contains prednisolone acetate 5mg, protocatechualdehyde 10 ~ 100mg.The proportioning of this prescription the best is 1: 4, i.e. prednisolone acetate 5mg, protocatechualdehyde B20mg.
The antiinflammatory new drug with bone protective effect be made up of glucocorticoid and Radix Salviae Miltiorrhizae extract of the present invention; refer to by prednisolone acetate; the antiinflammatory new drug of danshensu and salvianolic acid B composition; this formula proportion is 1: 2 ~ 10: 2 ~ 10; namely during the tablet of said preparation as clinical practice; every sheet contains prednisolone acetate 5mg, danshensu 10 ~ 50mg, salvianolic acid B 10 ~ 50mg.The proportioning of this prescription the best is 1: 2: 2, and namely every sheet contains prednisolone acetate 5mg, danshensu 20 ~ mg, salvianolic acid B 20mg.
The antiinflammatory new drug with bone protective effect be made up of glucocorticoid and Radix Salviae Miltiorrhizae extract of the present invention; refer to by prednisolone acetate; the antiinflammatory new drug of danshensu and protocatechualdehyde composition; this formula proportion is 1: 2 ~ 10: 2 ~ 10; namely during the tablet of said preparation as clinical practice; every sheet contains prednisolone acetate 5mg, danshensu 10 ~ 50mg, protocatechualdehyde 10 ~ 50mg.The proportioning of this prescription the best is 1: 2: 2, and namely every sheet contains prednisolone acetate 5mg, danshensu 20 ~ mg, protocatechualdehyde 20mg.
The antiinflammatory new drug with bone protective effect be made up of glucocorticoid and Radix Salviae Miltiorrhizae extract of the present invention; refer to by prednisolone acetate; danshensu; the antiinflammatory new drug of salvianolic acid B and protocatechualdehyde composition, this formula proportion is 1: 2 ~ 10: 2 ~ 10: 2 ~ 10, namely during the tablet of said preparation as clinical practice; every sheet contains prednisolone acetate 5mg; danshensu 10 ~ 50mg, salvianolic acid B 10 ~ 50mg, protocatechualdehyde 10 ~ 50mg.The proportioning of this prescription the best is 1: 2: 2: 2, and namely every sheet contains prednisolone acetate 5mg, danshensu 20mg, salvianolic acid B 20mg, protocatechualdehyde 20mg.
The antiinflammatory new drug with bone protective effect be made up of glucocorticoid and Radix Salviae Miltiorrhizae extract of the present invention, glucocorticoid can time prednisolone acetate, also can be prednisolone, cortisone, meprednisone, hydrocortisone, prednisolone, Methyllprednisolone, 6.alpha.-fluoro-16.alpha.-methylprednisolone, fluprednisolone, triamcinolone, triamcinolone acetonide, budesonide, betamethasone, dexamethasone, beclomethasone, fluticasone, mometasone, fludrocortisone, chlorine Pei Tasong, fluocinolone acetonide, fourth chlorine Pei Tasong, beclometasone, halcinonide, cloprednol, ground fluorine can be special, fluorometholone, alclometasone, halometasone, flurandrenolide etc.When making new anti-inflammatory preparation, the dosage of unit is not had to add Radix Salviae Miltiorrhizae extract according to these medicines just passable.
The antiinflammatory new drug with bone protective effect be made up of glucocorticoid and Radix Salviae Miltiorrhizae extract of the present invention, Radix Salviae Miltiorrhizae extract can be danshensu, salvianolic acid B, protocatechualdehyde, also can replace with other Radix Salviae Miltiorrhizae extracts, comprise rosmarinic acid, methyl rosmarinate, alkannic acid mono methyl ester, alkannic acid dimethyl ester, alkannic acid ethyl ester, alkannic acid, caffeic acid, Hesperetic acid, Tanshinone I, tanshinone ⅡA, Tanshinone II B, cryptotanshinone, iso tanshinone I, iso tanshinone II, , different cryptotanshinone, hydroxyl tanshinone ⅡA, saivianic acid A acid, danshenxinkun, dihydroisotanshinone I, new cryptotanshinone, remove the new cryptotanshinone of hydroxyl, nor-TANSHINONES, Radix Salviae Miltiorrhizae glycol, miltirone, 1-hydrogen miltirone, 1-hydrogen tanshinone ⅡA, 1-hydrogen is for different cryptotanshinone, 3 Alpha-hydroxy tanshinone ⅡAs, 1, 2-dihydro Radix Salviae Miltiorrhizae quinone, aldehyde radical TANSHINONES, methylene dihydrotanshinone, tanshinlactone, dihydro tanshinlactone, Radix Salviae Miltiorrhizae Spiroketals lactone, table Radix Salviae Miltiorrhizae Spiroketals lactone, Radix Salviae Miltiorrhizae Spiroketals lactone II.
The antiinflammatory new drug with bone protective effect be made up of glucocorticoid and Radix Salviae Miltiorrhizae extract of the present invention, its clinical practice dosage form can be tablet, also can be capsule, granule, electuary, oral liquid, injection and external preparation.
Embodiment one
For verifying the bone protective effect of the antiinflammatory new drug be made up of glucocorticoid and Radix Salviae Miltiorrhizae extract; devise application glucocorticoid separately and cause rat bone injury experiment; whether observe the antiinflammatory new drug be made up of glucocorticoid and Radix Salviae Miltiorrhizae extract, observing this antiinflammatory new drug has protective effect to the bone injury that glucocorticoid causes simultaneously.
Experimental design and grouping: 70 SPF level female sd inbred rats are divided into 7 groups at random by weight, often organize 10, model group adopts the continuous gavage of prednisolone acetate suspension within 14 weeks, to set up rat bone loss model, No. 1, antiinflammatory employing prednisolone acetate and danshensu are prepared by 1: 2 and are formed, No. 2, antiinflammatory employing prednisolone acetate and danshensu are prepared by 1: 4 and are formed, No. 3, antiinflammatory employing prednisolone acetate and danshensu are prepared by 1: 8 and are formed, No. 4, antiinflammatory employing prednisolone acetate and salvianolic acid B are prepared by 1: 4 and are formed, positive control drug adopts the administration of calcitriol suspension oral gavage to intervene, weigh rat weight once weekly, and adjust dosage in time according to weight.At the end of experiment, after rat anesthesia, heart blood drawing is put to death, and isolates rapidly corresponding osseous tissue and careful preservation.It is each once that all rats kill first 13,14 days subcutaneous injection 25mg.kg-1 quadracyclines, and in killing, first 3,4 two days subcutaneous injection calcein 5mg.kg-1 are each once, two 10 days, fluorescent labeling intervals.Weigh a body weight weekly, feeding of freely drinking water.After experiment terminates, thoroughly to draw blood execution (to reduce erythrocyte in bone marrow, exclusive PCR, making osteocomma be easier to observation analysis) with right ventricle after 3% pentobarbital sodium (1.5ml.kg-1) row intraperitoneal injection of anesthesia.Testing index: right side tibia epimere makes undecalcified bone section, stage casing bone makes undecalcified bone abrasive disc, carries out bone histomorphometric parameters detection.
What several antiinflammatory new drug caused the Trabecular area static parameter of bone injury on steroid affects experimental result in table 1:
Several antiinflammatory new drug of table 1 causes the Trabecular area static parameter of bone injury to steroid
| Group | ％Tb.Ar(％) | Tb.Th(μm) | Tb.N(#/mm) | Tb.Sp(μm) |
| Normal group | 32.6±4.13 | 5.21±0.38 | 62.6±6.48 | 130±15.9 |
| Prednisone model group | 23.9±4.23 ** | 4.48±0.48 ** | 53.1±4.52 ** | 173±28.1 ** |
| Antiinflammatory No. 1 group | 27.4±4.23 | 5.15±0.61 Δ | 52.7±6.22 | 144±29.5 |
| Antiinflammatory No. 2 groups | 33.9±5.35 ΔΔ | 5.72±0.36 ΔΔ | 59.1±7.01 ΔΔ | 116±15.4 ΔΔ |
| Antiinflammatory No. 3 groups | 27.1±3.95 | 5.01±0.61 Δ | 54.1±4.41 | 149±26.6 |
| Antiinflammatory No. 4 groups | 29.8±3.58 ΔΔ | 5.51±0.46 ΔΔ | 54.2±4.57 | 129±14.9 ΔΔ |
| Calcitriol matched group | 31.3±3.46 ΔΔ | 5.30±0.43 ΔΔ | 59.2±3.91 ΔΔ | 131±16.6 ΔΔ |
*p < 0.05vs Normal group,
*p < 0.01vs Normal group, Δ P < 0.05vs model group,
Δ Δp < 0.01vs model group
From table 1: compare with Normal group group, prednisone model group rats bone trabecula area percent decline 27% (p < 0.01), bone trabecula number decline 14% (p < 0.01), bone trabecula width decline 15% (p < 0.01), bone trabecula separating degree increases by 32% (p < 0.01).Compare with prednisone model group, No. 1, antiinflammatory group rat bone Trabecular number rising 15% (p < 0.01), osteoblast girth percent rising 201% (p < 0.01), bone trabecula area percent is on the rise, there is no significant difference, bone trabecula separating degree, bone trabecula width are without obvious change; Antiinflammatory No. 2 group group rat bone trabecular area percents rising 42% (p < 0.01), bone trabecula number rising 28% (p < 0.01), bone trabecula width rising 11% (p < 0.05), bone trabecula separating degree decline 33% (p < 0.05); No. 3, antiinflammatory group rat bone Trabecular number rising 12% (p < 0.05), bone trabecula area percent is on the rise, there is no significant difference, bone trabecula separating degree, unit bone trabecula girth osteoclast number and osteoclast girth percent have downward trend, also no difference of science of statistics, bone trabecula width is without obvious change; No. 4, antiinflammatory group rat bone trabecular area percent rising 25% (p < 0.01), bone trabecula number rising 23% (p < 0.01), bone trabecula separating degree decline 25% (p < 0.05), bone trabecula width is without obvious change; Calcitriol control rats bone trabecula area percent rising 31% (p < 0.01), bone trabecula number rising 18% (p < 0.01), bone trabecula width rising 12% (p < 0.05), bone trabecula separating degree decline 24% (p < 0.05).
These results suggest that; the static parameter that tibia epimere is observed in the Trabecular area research of prednisone model group has obvious bone injury to cause bone loss effect; and compare with prednisone model group; four antiinflammatory new drug groups and calcitriol matched group all have certain bone protective effect to the bone loss that prednisone causes; No. 4 effects organized of antiinflammatory No. 2 groups and antiinflammatory are better than other effects of two groups, and positive control drug calcitriol also has the effect of protection bone injury preferably.
What several antiinflammatory new drug caused the Trabecular area dynamic parameter of bone injury on steroid affects experimental result in table 2:
Several antiinflammatory new drug of table 2 causes the Trabecular area dynamic parameter of bone injury to steroid
*p < 0.05vs Normal group,
*p < 0.01vs Normal group, Δ P < 0.05vs model group,
Δ Δp < 0.01vs model group
From table 2, compare with Normal group, prednisone model group rats fluorescent labeling girth percent decline 45% (p < 0.01), mineralising deposition decline 22% (p < 0.01), bone formation rate (BFR/BS) declines 56% (p < 0.01), bone formation rate (BFR/BV) declines 48% (p < 0.01), and bone formation rate (BFR/TV) declines 63% (p < 0.01).Compare with prednisone model group group, No. 1, antiinflammatory group rat fluorescent labeling girth percent rising 57% (p < 0.01), bone formation rate (BFR/BS) rises 62% (p < 0.01), bone formation rate (BFR/BV) rises 65% (p < 0.01), bone formation rate (BFR/TV) rises 87% (p < 0.01), mineralising deposition is on the rise, there is no significant difference; No. 2, antiinflammatory group rat fluorescent labeling girth percent rising 55% (p < 0.01), mineralising deposition rising 10% (p < 0.05), bone formation rate (BFR/BS) rises 70% (p < 0.01), bone formation rate (BFR/BV) rises 56% (p < 0.01), and bone formation rate (BFR/TV) rises 118% (p < 0.01); No. 3, antiinflammatory group rat fluorescent labeling girth percent rising 41% (p < 0.01), bone formation rate (BFR/BS) rises 49% (p < 0.01), bone formation rate (BFR/BV) rises 46% (p < 0.01), bone formation rate (BFR/TV) rises 66% (p < 0.01), mineralising deposition is on the rise, there is no significant difference; No. 4, antiinflammatory group rat fluorescent labeling girth percent rising 46% (p < 0.01), mineralising deposition rising 9% (p < 0.05), bone formation rate (BFR/BS) rises 57% (p < 0.01), bone formation rate (BFR/BV) rises 55% (p < 0.01), and bone formation rate (BFR/TV) rises 94% (p < 0.01); Calcitriol group rat fluorescent labeling girth percent rising 40% (p < 0.01), mineralising deposition rising 10% (p < 0.05), bone formation rate (BFR/BS) rises 53% (p < 0.01), bone formation rate (BFR/BV) rises 37% (p < 0.05), and bone formation rate (BFR/TV) rises 80% (p < 0.01).
These results suggest that, the dynamic parameter that tibia epimere is observed in the Trabecular area research of prednisone model group has obvious bone injury effect, obviously decline as represented osteoplastic leading indicator rat fluorescent labeling girth percent, obvious mineralising deposition declines, simultaneously three important bone formation rates (BFR/BS), bone formation rate (BFR/BV) and bone formation rate (BFR/TV) all obviously decline, describe application prednisone separately and obviously can cause bone injury, bone formation is caused obviously to lower, there is bone loss, form steroidal sex osteoporosis.And compare with prednisone model group; four antiinflammatory new drug groups and calcitriol matched group all have certain bone protective effect to the steroidal sex osteoporosis that prednisone causes; can prevent bone loss well, positive control drug calcitriol also has the effect of protection bone injury preferably.
No. 1, antiinflammatory, No. 2, antiinflammatory and No. 3, antiinflammatory are all adopt prednisolone acetate and danshensu to combine, and wherein the ratio of antiinflammatory No. 1 prednisolone acetate and danshensu is 1: 2; The ratio of antiinflammatory No. 2 prednisolone acetates and danshensu is 1: 4; The ratio of antiinflammatory No. 3 prednisolone acetates and danshensu is 1: 8; This research proves, antiinflammatory No. 2 osteoporotic effects of prevention of steroid are best, therefore, can think, as the antiinflammatory new drug with bone protective effect, the formula proportion 1: 4 of prednisolone acetate and danshensu is optimal proportion.The formula proportion of antiinflammatory No. 4 prednisolone acetates and salvianolic acid B is also 1: 4, and experimental result is also good, and these results have been pointed out, when adopting Radix Salviae Miltiorrhizae extract and glucocorticoid compatibility, not that dosage is more high better, but have an optimum proportioning, just can obtain best clinical efficacy.
Claims (10)
1. there is an antiinflammatory new drug for bone protective effect, it is characterized in that being made up of glucocorticoid and Radix Salviae Miltiorrhizae extract.
2. one kind has the antiinflammatory new drug of bone protective effect, it is characterized in that described glucocorticoid refers to prednisolone acetate, prednisolone, cortisone, meprednisone, hydrocortisone, prednisolone, Methyllprednisolone, 6.alpha.-fluoro-16.alpha.-methylprednisolone, fluprednisolone, triamcinolone, triamcinolone acetonide, budesonide, betamethasone, dexamethasone, beclomethasone, fluticasone, mometasone, fludrocortisone, chlorine Pei Tasong, fluocinolone acetonide, fourth chlorine Pei Tasong, beclometasone, halcinonide, cloprednol, ground fluorine can be special, fluorometholone, alclometasone, halometasone, flurandrenolide.
3. one kind has the antiinflammatory new drug of bone protective effect, it is characterized in that described Radix Salviae Miltiorrhizae extract refers to danshensu, salvianolic acid B, protocatechualdehyde, rosmarinic acid, methyl rosmarinate, alkannic acid mono methyl ester, alkannic acid dimethyl ester, alkannic acid ethyl ester, alkannic acid, caffeic acid, Hesperetic acid, Tanshinone I, tanshinone ⅡA, Tanshinone II B, cryptotanshinone, iso tanshinone I, iso tanshinone II, different cryptotanshinone, hydroxyl tanshinone ⅡA, saivianic acid A acid, danshenxinkun, dihydroisotanshinone I, new cryptotanshinone, remove the new cryptotanshinone of hydroxyl, nor-TANSHINONES, Radix Salviae Miltiorrhizae glycol, miltirone, 1-hydrogen miltirone, 1-hydrogen tanshinone ⅡA, 1-hydrogen is for different cryptotanshinone, 3 Alpha-hydroxy tanshinone ⅡAs, 1, 2-dihydro Radix Salviae Miltiorrhizae quinone, aldehyde radical TANSHINONES, methylene dihydrotanshinone, tanshinlactone, dihydro tanshinlactone, Radix Salviae Miltiorrhizae Spiroketals lactone, table Radix Salviae Miltiorrhizae Spiroketals lactone, Radix Salviae Miltiorrhizae Spiroketals lactone II.
4. a kind of antiinflammatory new drug with bone protective effect as described in claim 1,2,3, it is characterized in that being made up of prednisolone acetate and danshensu, the formula proportion of both is 1: 2 ~ 20, and optimum formula ratio is 1: 4.
5. a kind of antiinflammatory new drug with bone protective effect as described in claim 1,2,3, it is characterized in that being made up of prednisolone acetate and salvianolic acid B, the formula proportion of both is 1: 2 ~ 20; Optimum formula ratio is 1: 4.
6. a kind of antiinflammatory new drug with bone protective effect as described in claim 1,2,3, it is characterized in that being made up of prednisolone acetate and protocatechualdehyde, the formula proportion of both is 1: 2 ~ 20, and optimum formula ratio is 1: 4.
7. a kind of antiinflammatory new drug with bone protective effect as described in claim 1,2,3, is characterized in that by prednisolone acetate, and danshensu and salvianolic acid B composition, this formula proportion is 1: 2 ~ 10: 2 ~ 10, and the proportioning of this prescription the best is 1: 2: 2.
8. a kind of antiinflammatory new drug with bone protective effect as described in claim 1,2,3, is characterized in that by prednisolone acetate, and danshensu and protocatechualdehyde composition, this formula proportion is 1: 2 ~ 10: 2 ~ 10, and the proportioning of this prescription the best is 1: 2: 2.
9. a kind of antiinflammatory new drug with bone protective effect as described in claim 1,2,3, is characterized in that by prednisolone acetate, danshensu, salvianolic acid B and protocatechualdehyde composition, and this formula proportion is 1: 2 ~ 10: 2 ~ 10: 2 ~ 10; The proportioning of this prescription the best is 1: 2: 2: 2.
10. a kind of antiinflammatory new drug with bone protective effect as described in claim 1,2,3,4,5,6,7,8,9, is characterized in that said composition can add the adjuvant of pharmaceutics aspect, makes tablet; capsule, granule, electuary; oral liquid, external preparation, injection.
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| CN111494356A (en) * | 2020-04-28 | 2020-08-07 | 广州中医药大学第一附属医院 | Application of salvianolic acid B in preparing medicine for treating osteoporosis and osteoporosis fracture |
| CN112138170A (en) * | 2020-09-28 | 2020-12-29 | 广东药科大学 | Conjugate for preventing cisplatin drug-induced deafness and preparation method and application thereof |
| CN117982555A (en) * | 2024-04-03 | 2024-05-07 | 广东医科大学附属医院 | Application of salvia miltiorrhiza-derived exosome nano vesicles in preparation of GC-resistant myopathy medicines |
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| CN1543940A (en) * | 2003-11-17 | 2004-11-10 | 广东医学院 | Medicine for prevention and treatment of osteoporosis by red sage root and water extract thereof |
| CN1709423A (en) * | 2005-06-06 | 2005-12-21 | 广东医学院 | Medicinal formulation of glucocorticoid and Chinese medicine for preventing and treating asthma and COPD |
| CN1887309A (en) * | 2006-04-09 | 2007-01-03 | 广东医学院 | Extraction of effective red sage components for preventing and treating osteoporosis and depression |
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| CN112138170A (en) * | 2020-09-28 | 2020-12-29 | 广东药科大学 | Conjugate for preventing cisplatin drug-induced deafness and preparation method and application thereof |
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