CN103272235A - Pharmaceutical composition for preventing or treating cold injury and thrombus - Google Patents
Pharmaceutical composition for preventing or treating cold injury and thrombus Download PDFInfo
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Abstract
The invention belongs to the technical field of a medicine, relates to a pharmaceutical composition for preventing or treating cold injury and thrombus, and particularly relates to use of a pharmaceutical composition including an M cholinoceptor blocking drug and an alpha1 receptor antagonist drug, and use of the pharmaceutical composition for preparing a drug for preventing or treating the cold injury, chimatlon, thrombus or protecting vascular endothelial cells. The invention is confirmed that the cold injury can be effectively prevented or treated by combination of the M cholinoceptor blocking drug and the alpha1 receptor antagonist drug; the thrombus can be effectively reduced; the thrombus forming length is shortened; the pharmaceutical composition has the function of protecting the vascular endothelial cells; the effect is much superior to that of a single drug; and the two drugs have synergistic effects by combination.
Description
Technical field
The invention belongs to medical technical field; relate to for the pharmaceutical composition that prevents or treat cold damage; the pharmaceutical composition that particularly comprises M cholinoceptor blocking agent and α 1 receptor antagonist, and described pharmaceutical composition is for the preparation of the purposes of the medicine that prevents or treat cold damage, cold injury, thrombosis or protection vascular endothelial cell.
Background technology
Cold damage is the damage that body is caused by cold stimulation, is divided into the cold damage of general and the cold damage of locality clinically.The cold damage of general comprises " hypothermia " (numb with cold), and the cold damage of locality comprises the property freezed damage and the non-property freezed damage.The property freezed damage is called for short cold injury; The non-property freezed damage comprises chilblain, trench foot, immersion foot etc., and wherein cold injury and chilblain are comparatively common.The power of cold strength becomes positive correlation with the degree of cold damage.After human body is caught a cold, at first be that the temperature of baring skin descends, along with cold open-assembly time prolongs, skin occur flushing, cold, bloated, bitterly, symptom such as fiber crops, dermal sensation after this weakens gradually even disappears, and occurs cold injury in the time of seriously.The cold environment that is in varying strength for a long time such as can cause body microcirculation disturbance and blood coagulation system be unusual in various degree at the generation of cold damage phenomenon.As long as ambient temperature is lower than 35 ℃, long-time exposure can cause hypothermia, is down to when core temperature can cause freezing below 20 ℃ dying; The optimum ambient temperature of human body is 27-29 ℃, so the residing natural environment of human body is cold relatively environment mostly.When the human body mean skin temperature is 22 ℃, then be the cold tolerance of human body lower limit (referring to Wang Hai chief editor, occupational altitude sickness pharmacotherapeutics, p180, p185-186,2010).
Cold injury be a kind of by cold exposure cause that tissue freezes, microcirculation disturbance and blood coagulation system be unusual, develops into the disease of tissue local necrosis then.Cold injury be the process of a complexity, pathophysiological mechanism about cold injury also imperfectly understands at present, the pathophysiological mechanism progress that relevant cold injury takes place is found, the changes of the change that is accompanied by injury of vascular endothelial cells, inner skin cell function of cold injury, the change of blood coagulation system, hemorheological change and tissue metabolism's function etc. are (referring to PLA's preventive medicine magazine, the cold injury Study on Pathogenesis, 15(5): 416-418,1995).
Studies confirm that cold injury forms divides two stages.Phase I is that tissue freezes, and causes the histiocyte coup injury, and the scope of tissue injury and the degree of depth depend primarily on degree and the persistent period of cold exposure.After second stage mainly betided and freezes to organize rewarming to melt, tissue blood recovered, and occurred gradual microcirculation disturbance, pathological change development then rapidly, caused the histiocyte ischemic necrosis, was indirect injury.At present therapeutic scheme clinically mainly comprises rewarming treatment, infection, improvement endure cold part and systemic blood circulation, antioxidant and whole body supporting treatment (referring to Wang Hai chief editor, occupational altitude sickness pharmacotherapeutics, p172-180,2010).
Be not specifically designed at present the medicine that prevents and treat cold damage clinically, therefore, research has the medicine that prevents or treat cold damage and has the important clinical meaning.
Summary of the invention
The present inventor is surprisingly found out that M cholinergic receptor-blocking agent and α by making great efforts untiringly
1The receptor blocking agent coupling can effectively prevent or treat cold damage, has finished the present invention thus.
First aspect present invention relates to pharmaceutical composition, and it comprises the M cholinergic receptor-blocking agent of prevention or treatment effective dose, and the α of prevention or treatment effective dose
1Receptor blocking agent.
According to each pharmaceutical composition of first aspect present invention, wherein said M cholinergic receptor-blocking agent is selected from atropine, Anisodamine, scopolamine or their pharmaceutically acceptable salt.
In embodiments of the invention, described M cholinergic receptor-blocking agent is Anisodamine or its pharmaceutically acceptable salt.Described pharmaceutically acceptable salt for example can be hydrogen salt hydrochlorate, hydrobromate, hydriodate, sulfate or phosphate etc., preferred hydrobromate.
According to each pharmaceutical composition of first aspect present invention, wherein said α
1Receptor blocking agent is selected from tolazoline, prazosin, terazosin, doxazosin or their pharmaceutically acceptable salt.
In embodiments of the invention, described α
1Receptor blocking agent is prazosin or pharmaceutically acceptable salt.Described pharmaceutically acceptable salt for example can be tartrate, hydrochlorate, sulfate, citrate etc., preferred salt hydrochlorate or tartrate.
According to each pharmaceutical composition of first aspect present invention, wherein said M cholinergic receptor-blocking agent and α
1The weight ratio of receptor blocking agent is 1:11～36:1, is preferably 2～10:1,3～8:1 more preferably, 3～5:1 more preferably again.
Each pharmaceutical composition of a first aspect of the present invention, it also comprises pharmaceutically acceptable carrier or excipient.
A second aspect of the present invention relates to the medicine box product, and it comprises at least one first pharmaceutical preparation unit and at least one second pharmaceutical preparation unit, and the described first medication preparation unit and the second pharmaceutical preparation unit are optional to be present in this medicine box product independently of each other; The described first pharmaceutical preparation unit comprises M cholinergic receptor-blocking agent and optional pharmaceutically acceptable carrier or the excipient of prevention or treatment effective dose, and the described second pharmaceutical preparation unit comprises the α of prevention or treatment effective dose
1Receptor blocking agent and optional pharmaceutically acceptable carrier or excipient.
According to each medicine box product of second aspect present invention, wherein said M cholinergic receptor-blocking agent is selected from atropine, Anisodamine, scopolamine or their pharmaceutically acceptable salt.
In embodiments of the invention, described M cholinergic receptor-blocking agent is Anisodamine or its pharmaceutically acceptable salt.Described pharmaceutically acceptable salt for example can be hydrogen salt hydrochlorate, hydrobromate, hydriodate, sulfate or phosphate etc., preferred hydrobromate.
According to each medicine box product of second aspect present invention, wherein said α
1Receptor blocking agent is selected from tolazoline, prazosin, terazosin, doxazosin or their pharmaceutically acceptable salt.
In embodiments of the invention, described α
1Receptor blocking agent is prazosin.Described pharmaceutically acceptable salt for example can be tartrate, hydrochlorate, sulfate, citrate etc., preferred salt hydrochlorate or tartrate.
According to each medicine box product of second aspect present invention, wherein said M cholinergic receptor-blocking agent and α
1The weight ratio of receptor blocking agent is 1:11～36:1, is preferably 2-10:1,3～8:1 more preferably, 3～5:1 more preferably again.
Fourth aspect present invention relate to first aspect present invention each pharmaceutical composition or second aspect each the medicine box product preparation prevention treat cold damage or the medicine of cold injury, thrombosis, protection vascular endothelial cell in purposes.
In the present invention, can be with M cholinergic receptor-blocking agent and α
1Receptor blocking agent is made preparation respectively, and description to specifications simultaneously or take in order also can be combined said medicine and make clinically or pharmaceutically acceptable any dosage form in use.As tablet, capsule, granule, injection, injectable powder, transdermal patch, ointment, gel, suppository, oral administration solution, oral administration mixed suspension, injectable emulsion, Orally taken emulsion etc., slow releasing tablet, controlled release tablet etc.Peroral dosage forms such as preferred tablet, capsule and powder.
Pharmaceutical composition of the present invention or medicine box product can be solid dosage forms for oral administration, oral solid formulation of the present invention, can be according to needs pharmaceutically, can add pharmaceutically acceptable carrier or excipient, described excipient can be one or several the compositions in pharmaceutically acceptable disintegrating agent, filler, binding agent and the lubricant etc.As a) filler or extender such as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) binding agent such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and Radix Acaciae senegalis; C) wetting agent such as glycerol; D) disintegrating agent such as agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some silicate and sodium carbonate; E) solution blocker such as paraffin; F) absorb accelerator such as quaternary ammonium compound; G) wetting agent such as spermol and glyceryl monostearate; H) adsorbent such as Kaolin and bentonite and i) lubricant such as Pulvis Talci, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.Under the situation of capsule, tablet and pill, also can comprise buffer agent in the described dosage form.
Pharmaceutical composition of the present invention or medicine box product can be liquid dosage form for oral administration, and described liquid dosage form for oral administration comprises the acceptable Emulsion of medicine, solution, suspensoid, syrup and elixir.Liquid dosage form also can contain this area inert diluent commonly used except containing the active ingredient beyond the region of objective existence, for example water or other solvents, solubilizing agent and emulsifying agent be ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), Polyethylene Glycol and the fatty acid ester of sorbitan and their mixture for example.
Term used herein " prevention or treatment effective dose " is to cause research worker, veterinary, doctor or tissue that other people look for, system, animal or human's biology or medicine that medical science is replied or the amount of pharmaceutical preparation.
When being used for above-mentioned treating and/or preventing, total consumption per day of pharmaceutical composition of the present invention must be examined the doctor by the master and maked decision in the medical judgment scope reliably.For any concrete patient, the concrete horizontal fibrous root for the treatment of effective dose is decided according to multiple factor, and described factor comprises the order of severity of the obstacle for the treatment of and this obstacle; The activity of the particular compound that adopts; The concrete compositions that adopts; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound that adopts, route of administration and excretion rate; The treatment persistent period; The medicine that is used in combination or uses simultaneously with the particular compound that adopts; Ratio between the medicine; And the known similar factor of medical field.For example, the way of this area is that the dosage of chemical compound increases dosage gradually from being lower than for obtaining the level that required therapeutic effect requires, up to obtaining required effect.In general, particularly people's dosage can be between 0.001～1000mg/kg body weight/day, for example between 0.01～100mg/kg body weight/day, for example between 0.01～10mg/kg body weight/day for mammal for pharmaceutical composition of the present invention.In the present invention, the single dosage of M cholinergic receptor-blocking agent is 0.8～7.2mg/kg, preferred 2.0～7.2mg/kg, more preferably 2.0～2.5mg/kg; α
1The single dosage of receptor blocking agent is 0.07～27.5mg/kg, preferred 0.6～27.5mg/kg, more preferably 0.6～1.2mg/kg.
In the present invention, described cold damage refers under certain condition because cold acts on human body, causes local and even damage whole body.The generation of cold damage is except relevant with intensity, wind speed, humidity, the time of enduring cold of cold, also with moist, local blood circulation is bad descends relevant with cold tolerance.
In the present invention, described cold injury refers to that the body local organization that causes is freezed under cold environment, microcirculation disturbance and blood coagulation system are unusual, develops into the disease of tissue local necrosis then.
In the present invention, described thrombosis also can be described as thrombosis, refer in the cardiovascular of live body, blood solidify or blood in some visible component is separated out, coagulation forms solid matter piece process, formed solid matter piece is called thrombosis.Described pre-preventing thrombosis refers to prevent thrombosis, reduces incidence of thrombus; Described treatment thrombosis refers to shorten thrombosis length, and anti-tampon comes off or removes thrombosis, thrombus.
The beneficial effect of the invention
The present invention confirms by experiment, with M cholinergic receptor-blocking agent and α
1The receptor blocking agent coupling can effectively prevent or treat cold damage, and its effect is better than single medicine greatly, shows that two class drug combinations have synergism; Can reduce dosage by drug combination, reduce drug side effect.Simultaneously, the present invention also confirms, with M cholinergic receptor-blocking agent and α
1The receptor blocking agent coupling can effectively reduce thrombosis and take place, and shortens thrombosis length, and has the function of protection vascular endothelial cell, can be used for prevention or the treatment of thrombosis.
The specific embodiment
Be described in detail below in conjunction with the embodiment of the present invention of embodiment, but it will be understood to those of skill in the art that the following example only is used for explanation the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person among the embodiment carries out according to the condition of normal condition or manufacturer's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
(terazosin Ter) purchases the emerging milky way chemical industry company limited in Hubei to terazosin; (doxazosin Dox) purchases in Chinese pharmaceutical biological product and identifies institute doxazosin; (tolazoline Tol) purchases the Fine Chemical Co., Ltd in Hubei Kang Baotai to tolazoline; Anisodamine is purchased the pharmaceutical Co. Ltd in Henan Pu Rui; Prazosin is that Japanese TCI company produces; Type I type carrageenin (carrageenin type I) is U.S. Sigma company product.
The influence of the mouse tail thrombosis length that embodiment 1 Anisodamine, prazosin and compositions thereof are induced carrageenin under the cold environment.
Experimental technique: SPF level body weight 18～22g male mouse of kunming (purchasing the Experimental Animal Center in Military Medical Science Institute) gives I type carrageenin 5mg.kg
-1(be mixed with 0.05% solution with normal saline, according to every 10g body weight 0.1ml volume lumbar injection), be subjected to reagent thing group mice 30min before the injection carrageenin to be subjected to reagent thing (equally with normal saline preparation) (Anisodamine concentration is respectively 0.008%, 0.024%, 0.072%, prazosin concentration is respectively 0.0007%, 0.002%, 0.006%(concentration unit g/ml), two medicine combination group to be about to two medicines according to the preventative filling stomach of 0.1ml/10g body weight and merge and be configured in the normal saline.The model group normal saline is irritated stomach).Behind the injection carrageenin in the cold environment that is exposed to 18 ± 1 ℃ of temperature and 30-50% humidity of mice, the drinking-water and keep illumination 12 hours every days of freely ingesting, close observation afterbody thrombosis situation is measured afterbody thrombosis length after 48 hours simultaneously.
Experimental result: compare with model group, Anisodamine, prazosin and Anisodamine and prazosin compositions can significantly shorten thrombosis length (P＜0.05); Compare respectively with prazosin 0.07 dosage group with Anisodamine 0.8, Anisodamine 0.8+ prazosin 0.07 dosage group can significantly shorten thrombosis length (P＜0.05); Compare respectively with prazosin 0.6 dosage group with Anisodamine 7.2, Anisodamine 7.2+ prazosin 0.6 dosage group can significantly shorten thrombosis length (P＜0.05), sees Table 1.
The result shows that Anisodamine and prazosin coupling have synergism to the length that shortens thrombosis under the prevention mice cold environment.
The compatibility of table 1. various dose Anisodamine, prazosin and Anisodamine and prazosin brings out thrombotic influence to carrageenin under the cold environment
| Medicine and dosage (mg/kg) | n | Thrombosis length (mm) | Thrombosis length suppression ratio (%) |
| Model | 10 | 46.4±8.8 | -- |
| Anisodamine 0.8 | 10 | 38.2±8.8 * | 17.7 |
| Anisodamine 2.4 | 10 | 32.9±12.7 * | 29.0 |
| Anisodamine 7.2 | 10 | 20.5±10.2 * | 55.8 |
| Prazosin 0.07 | 10 | 36.3±7.0 * | 21.7 |
| Prazosin 0.2 | 10 | 26.8±3.7 * | 42.2 |
| Prazosin 0.6 | 10 | 20.9±4.7 * | 54.9 |
| Anisodamine 0.8+ prazosin 0.07 | 10 | 20.5±8.0 *▲△ | 55.8 |
| Anisodamine 7.2+ prazosin 0.6 | 10 | 3.5±1.8 *▲△ | 92.4 |
*P＜0.05 is compared with model group;
▲P＜0.05, with Isodose Anisodamine list use than;
△P＜0.05, with Isodose prazosin list use than.
The influence of the mouse tail thrombosis length that embodiment 2 Anisodamine and prazosin compositions are induced carrageenin under the cold environment.
Experimental model: SPF level body weight 18～22g male mouse of kunming gives I type carrageenin 2.5mg.kg
-1(be mixed with 0.025% solution with normal saline, according to every 10g body weight 0.1ml volume lumbar injection), be subjected to reagent thing group mice before the injection carrageenin 30min preventative filling stomach is subjected to reagent thing (with normal saline preparation) (in each dosage group according to the 0.1ml/10g body weight, Anisodamine concentration is respectively 0.025%, 0.02%, 0.016%, 0.012%, 0.008%, prazosin concentration is respectively 0.275%, 0.021%, 0.002%, 0.006%(concentration unit g/ml), the blank group is respectively with volume normal saline lumbar injection with irritate stomach, model group only gives I type carrageenin, do not give and be subjected to the reagent thing, mice is raised in the environment of 18 ± 1 ℃ temperature and 30-50% humidity subsequently, freely ingest and drink water and maintenance illumination 12 hours every days, close observation afterbody thrombosis situation is simultaneously measured afterbody and is become bolt rate and thrombosis length (be criterion so that thrombosis not to take place fully) after 48 hours.
Experimental result: compare with model group, Anisodamine+tolazoline group thrombosis length significantly shortens (P＜0.05); Anisodamine+prazosin compatibility (1)-(9) group all can significantly shorten thrombosis length (P＜0.05); Compare with Anisodamine+tolazoline group, Anisodamine+prazosin compatibility (1)-(9) group all can significantly shorten thrombosis length (P＜0.05), see Table 3.
Compare with model group, Anisodamine+tolazoline group does not have significant difference to incidence of thrombus; Anisodamine+prazosin compatibility (1), (5), (6) group incidence of thrombus significantly descend (P＜0.05); Compare with Anisodamine+tolazoline group, Anisodamine+prazosin compatibility (1), (5), (6) group incidence of thrombus significantly descend (P＜0.05), see Table 2.
Table 2 Anisodamine, tolazoline and prazosin coupling are to 2.5mg.kg under the cold environment
-1Carrageenin brings out the influence of mouse tail thrombosis
| Medicine and dosage (mg/kg) | n | Thrombosis length (mm) | Become bolt rate (%) |
| Model | 30 | 24.6±4.6 | 86.6 |
| Anisodamine 2.5+ tolazoline 12.5 | 30 | 19.3±6.2 * | 76.6 |
| (1) Anisodamine 2.5+ prazosin 27.5 | 20 | 7.0±2.1 *▲ | 55.0 ▲ |
| (2) Anisodamine 2.5+ prazosin 2.17 | 23 | 7.6±2.5 *▲ | 60.8 |
| (3) Anisodamine 2.5+ prazosin 0.07 | 30 | 15.3±5.0 *▲ | 86.6 |
| (4) Anisodamine 2.5+ prazosin 0.2 | 30 | 11.7±3.2 *▲ | 70.0 |
| (5) Anisodamine 2.5+ prazosin 0.6 | 31 | 7.8±3.0 *▲ | 54.8 *▲ |
| (6) Anisodamine 2.0+ prazosin 0.6 | 26 | 6.9±2.7 *▲ | 50.0 *▲ |
| (7) Anisodamine 1.6+ prazosin 0.6 | 25 | 9.4±3.5 *▲ | 60.0 |
| (8) Anisodamine 1.2+ prazosin 0.6 | 25 | 13.7±2.9 *▲ | 72.0 |
| (9) Anisodamine 0.8+ prazosin 0.6 | 30 | 12.8±3.3 *▲ | 80.0 |
*P＜0.05, with the model group ratio,
▲P＜0.05 is with 12.5 groups of ratios of Anisodamine 2.5+ tolazoline.
Above result of the test shows that Anisodamine and prazosin associating compatibility are used, and have antithrombotic effect, and its effect are better than Anisodamine and tolazoline coupling.
Embodiment 3 Anisodamine bring out the influence of the blood coagulation of thrombosis mice and fibrinolytic function with prazosin and tolazoline use in conjunction respectively to carrageenin under the cold environment.
Present embodiment is identical with modeling and the experimental technique of embodiment 2, detects the content of plasma prothrombin time (PT), activated partial thromboplastin time (APTT), blood plasma tissue plasminogen activator (t-PA) content and activator of plasminogen mortifier-1(PAI-1).(use platelet aggregation thrombin analyser to measure the test kit description according to PT, APTT and require further operation; Require operation detection according to the enzyme linked immunological kit description when t-PA and PAI-1 assay).
Experimental result: compare with the blank group, model group PT significantly shortens, Plasma t-PA content significantly reduces, PAI-1 content significantly raises (P＜0.05).Compare with model group, Anisodamine+tolazoline group PT does not have significance and prolongs, Anisodamine+prazosin group PT significant prolongation (P＜0.05), Anisodamine+prazosin group Plasma t-PA content significantly raises, PAI-1 content significantly reduces (P＜0.05), sees Table 3.
The influence of the blood coagulation of thrombosis mice and fibrinolytic function is brought out in table 3 Anisodamine and prazosin coupling to carrageenin under the cold environment
(n=8-10)
| Medicine and dosage (mg/kg) | PT(s) | APTT(s) | t-PA(ng/ml) | PAI-1(ng/ml) |
| Blank | 9.0±0.6 | 21.5±2.6 | 2.8±0.4 | 5.7±0.5 |
| Model | 8.0±0.4 * | 20.5±1.3 | 1.6±0.2 * | 9.2±0.8 * |
| Anisodamine 2.5+ tolazoline 12.5 | 8.4±1.0 | 20.6±2.9 | 1.8±0.2 * | 9.8±0.7 * |
| Anisodamine 2.0+ prazosin 0.6 | 8.8±0.4 ▲ | 20.3±1.9 | 2.3±0.3 *▲ | 7.8±0.4 *▲ |
*P＜0.05, with blank group ratio,
▲P＜0.05 is with the model group ratio.
Above experimental result shows that Anisodamine and prazosin use in conjunction have the parafunctional effect of blood coagulation system under the cold environment of improvement.
Embodiment 4 Anisodamine respectively with prazosin and tolazoline use in conjunction to the protective effect of endotheliocyte under the cold environment and and the influence of platelet function.
Present embodiment is identical with modeling and the experimental technique of embodiment 2, detects 6-ketone-prostaglandin F in the blood plasma
1α (6-ketone-PGF
1α) the plain B of content and thromboxane
2(TXB
2) content (pressing TXB2,6-Keto-PGF1 α radioimmunology analysis medicine box description mensuration respectively).
Experimental result: compare 6-ketone-PGF in the model group blood plasma with the blank group
1Alpha content significantly reduces (P＜0.05), TXB
2Content significantly increases (P＜0.05).Compare 6-ketone-PGF in Anisodamine+tolazoline group blood plasma with model group
1Alpha content presents rising trend, TXB
2Content presents reduction trend, the two there are no significant difference; Anisodamine+prazosin group blood plasma 6-ketone-PGF
1Alpha content significantly raise (P＜0.05), blood plasma TXB
2Content significantly reduces (P＜0.05), sees Table 4.
Table 4 Anisodamine and prazosin coupling are brought out thrombosis mice plasma 6-Keto-PGF to carrageenin under the cold environment
1α and TXB
2The influence of level
(n=7-10)
| Medicine and dosage (mg/kg) | 6-Keto-PGF 1α(pg/ml) | TXB 2(pg/ml) |
| Blank | 152.1±33.3 | 283.4±48.2 |
| Model | 106.8±12.9 * | 372.9±25.5 * |
| Anisodamine 2.5+ tolazoline 12.5 | 126.8±27.8 | 331.3±61.4 |
| Anisodamine 2.0+ prazosin 0.6 | 144.4±26.6 ▲ | 292.7±40.2 ▲ |
*P＜0.05, with blank group ratio,
▲P＜0.05 is with the model group ratio.
Above experimental result shows that Anisodamine and prazosin use in conjunction have the effect of protection blood vessel inner skin cell function.
Embodiment 5 different α
1Receptor antagonist and Anisodamine are to the dilating effect of rat arteria caudalis
Experimental model: the male Wistar rat vertebra dislocation method of SPF level body weight 180～220g is put to death, along root of the tail portion with knife blade ring cutting cortex and peel off, cut the veutro vagina vasorum subsequently, the careful separation arteria caudalis is rapidly as in the plate that contains 4 ℃ of Krebs-ringer nutritional solutions.Blood vessel is fixed with pin, careful rejecting blood vessel surrounding tissue under the anatomical lens, and be cut into 2mm left and right sides vascular ring.2 one metal wires of diameter 40 μ m, long 2.2mm are penetrated vascular ring, be individually fixed in lifting arm one end and sensor one end of myograph (Denmark DMT company, model 610M) bath (containing 5ml Krebs-ringer nutritional solution), continue to feed 95%O
2And 5%CO
2Mist, body lotion keeps 37 ℃.Spiral micrometer by the moving recording instrument stiff end of rotation flesh changes the tinsel spacing, adjusts vascular ring transmural pressure power (the basic tension force that bears when being equivalent to normal physiological conditions 100mmHg), and balance begins experiment after 30 minutes.Bath is interior with 10 μ molL
-1Noradrenaline bitartrate (norepinephrine, NE) preshrinking vascular ring, its maximum stable shrinkage amplitude (tension force) is 100%, be subjected to the reagent thing with the concentration method of cumulative scale again, the ratio that the diastole amplitude of drug-induced vascular ring and NE bring out between the maximum stable shrinkage amplitude is the diastolic rate of blood vessel.
Experimental result: with final concentration 10 μ molL
-1N E preshrinking vascular ring, after shrinkage amplitude reached maximum and stablizes, cumulative bad adding concentration was 0.01～10 μ molL successively
-1Tolazoline, prazosin, terazosin, doxazosin and Anisodamine, obtain vascular ring to each medicine stretching reaction (seeing Table 5).
Table 5 Anisodamine, tolazoline, terazosin, prazosin and doxazosin are to the diastole effect of Mus arteria caudalis ring
*P＜0.05 is with 0.01 μ molL of each medicine
-1Group is compared,
▲P＜0.05 is with 10 μ molL
-1Anisodamine is compared, n=8.
The result shows that with the increase of administration concentration, the vascular ring diastolic rate progressively increases, at 0.01～10 μ molL
-1Has concentration dependent in the scope.What maximum diastolic rate was the highest in the said medicine is prazosin 82.6 ± 8.9%.Pass through EC
50The comparison (seeing Table 6) of (calculating with the bliss method), prazosin are respectively tolazoline, terazosin, doxazosin 12.45,3.88,12.0 times to the dilating effect of Mus arteria caudalis ring.
Table 6Bliss method is calculated medicine EC
50, slope and correlation coefficient (n=8)
In sum, α
1Receptor antagonist is to being that the periphery acra tiny blood vessels of representative has significant dilating effect with the arteria caudalis, and wherein the effect of prazosin is the strongest.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (10)
1. pharmaceutical composition, it comprises the M cholinergic receptor-blocking agent of prevention or treatment effective dose, and the α of prevention or treatment effective dose
1Receptor blocking agent.
2. the pharmaceutical composition of claim 1, wherein said M cholinergic receptor-blocking agent is selected from atropine, Anisodamine, scopolamine or their pharmaceutically acceptable salt.
3. claim 1 or 2 pharmaceutical composition, wherein said α
1Receptor blocking agent is selected from tolazoline, prazosin, terazosin, doxazosin or their pharmaceutically acceptable salt.
4. each pharmaceutical composition of claim 1-3, wherein said M cholinergic receptor-blocking agent and α
1The weight ratio of receptor blocking agent is 1:11～36:1, is preferably 2～10:1,3～8:1 more preferably, 3～5:1 more preferably again.
5. each pharmaceutical composition of claim 1-4, it also comprises pharmaceutically acceptable carrier or excipient.
6. medicine box product, it comprises at least one first pharmaceutical preparation unit and at least one second pharmaceutical preparation unit, the described first medication preparation unit and the second pharmaceutical preparation unit are optional to be present in this medicine box product independently of each other; The described first pharmaceutical preparation unit comprises M cholinergic receptor-blocking agent and optional pharmaceutically acceptable carrier or the excipient of prevention or treatment effective dose, and the described second pharmaceutical preparation unit comprises the α of prevention or treatment effective dose
1Receptor blocking agent and optional pharmaceutically acceptable carrier or excipient.
7. the medicine box product of claim 6, wherein said M cholinergic receptor-blocking agent is selected from atropine, Anisodamine, scopolamine or their pharmaceutically acceptable salt.
8. claim 6 or 7 medicine box product, wherein said α
1Receptor blocking agent is selected from tolazoline, prazosin, terazosin, doxazosin or their pharmaceutically acceptable salt.
9. each medicine box product of claim 6-8, wherein said M cholinergic receptor-blocking agent and α
1The weight ratio of receptor blocking agent is 1:11～36:1, is preferably 2～10:1,3～8:1 more preferably, 3～5:1 more preferably again.
Claim 1-5 each pharmaceutical composition or the medicine box product of claim 6-9 in the preparation prevention or treat purposes in the medicine of cold damage, cold injury, thrombosis or protection vascular endothelial cell.
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| CN201310187477.0A CN103272235B (en) | 2013-05-21 | 2013-05-21 | For preventing or treat the pharmaceutical composition of Cold water stress and thrombosis |
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| CN201310187477.0A CN103272235B (en) | 2013-05-21 | 2013-05-21 | For preventing or treat the pharmaceutical composition of Cold water stress and thrombosis |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110698531A (en) * | 2019-11-01 | 2020-01-17 | 首都医科大学附属北京中医医院 | Novel compound for improving microcirculation disturbance and preparation method thereof |
Citations (2)
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| CN1200267A (en) * | 1997-03-30 | 1998-12-02 | 刘卫东 | Compound ointment for preventing and treating cold injury and chilblain |
| CN1706381A (en) * | 2005-04-29 | 2005-12-14 | 李爱华 | Frostbite and chilblain treating ointment |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1200267A (en) * | 1997-03-30 | 1998-12-02 | 刘卫东 | Compound ointment for preventing and treating cold injury and chilblain |
| CN1706381A (en) * | 2005-04-29 | 2005-12-14 | 李爱华 | Frostbite and chilblain treating ointment |
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| Title |
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| 张是敬: "口服冻伤预防药25号及38号方的效用", 《中国人民解放军军事医学科学院院刊》, no. 3, 31 December 1979 (1979-12-31), pages 371 - 374 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110698531A (en) * | 2019-11-01 | 2020-01-17 | 首都医科大学附属北京中医医院 | Novel compound for improving microcirculation disturbance and preparation method thereof |
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| CN103272235B (en) | 2015-08-19 |
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