CN103272235B - For preventing or treat the pharmaceutical composition of Cold water stress and thrombosis - Google Patents
For preventing or treat the pharmaceutical composition of Cold water stress and thrombosis Download PDFInfo
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Abstract
The invention belongs to medical art; relate to the pharmaceutical composition for preventing or treat Cold water stress; particularly comprise the pharmaceutical composition of M cholinoceptor blocking agent and α 1 receptor antagonist, and described pharmaceutical composition is for the preparation of the purposes of medicine of prevention or treatment Cold water stress, cold injury, thrombosis or protection vascular endothelial cell.The present invention confirms; by by M cholinoceptor blocking agent and the coupling of α 1 receptor antagonist; can effectively prevent or treat Cold water stress; and effectively can reduce thrombosis to occur; shorten thrombosis length; and there is the function of protection vascular endothelial cell, its effect is better than single medicine greatly, shows that two class drug combinations have synergism.
Description
Technical field
The invention belongs to medical art; relate to the pharmaceutical composition for preventing or treat Cold water stress; particularly comprise the pharmaceutical composition of M cholinoceptor blocking agent and α 1 receptor antagonist, and described pharmaceutical composition is for the preparation of the purposes of medicine of prevention or treatment Cold water stress, cold injury, thrombosis or protection vascular endothelial cell.
Background technology
Cold water stress is the damage that body causes by cold stimulation, is divided into general Cold water stress and locality Cold water stress clinically.General Cold water stress comprises " hypothermia " (numb with cold), and locality Cold water stress comprises the property freezed damage and non-freezing damage.The property freezed is damaged, and is called for short cold injury; Non-freezing 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 water stress.After human body is caught a cold, be first that the temperature of baring skin declines, along with cold expoure time lengthening, skin occur flushing, cold, swollen, bitterly, the symptom such as fiber crops, after this dermal sensation weakens gradually and even disappears, and occurs cold injury time serious.The cold environment being in varying strength for a long time can cause the generation of body microcirculation disturbance and the Cold water stress phenomenon such as blood coagulation system is abnormal in various degree.As long as ambient temperature is lower than 35 DEG C, long-time exposure can cause hypothermia, is down to less than 20 DEG C can causes freezing dying when core temperature; The optimum ambient temperature of human body is 27-29 DEG C, and the natural environment therefore residing for human body is relatively cold environment mostly.When human body mean skin temperature is 22 DEG C, be then human body cold resistance lower limit (see Wang Hai chief editor, Occupational High Altitude Disease pharmacotherapeutics, p180, p185-186,2010).
Cold injury be a kind of cause tissue to freeze by cold expoure, microcirculation disturbance and blood coagulation system abnormal, then develop into the disease of tissue local necrosis.Cold injury be a complicated process, pathophysiological mechanism about cold injury also imperfectly understands at present, the pathophysiological mechanism progress that relevant cold injury occurs finds, the generation of cold injury along with the change etc. of the change of the damage of vascular endothelial cell, inner skin cell function, the change of blood coagulation system, hemorheological change and tissue metabolism's function (see liberation army prevention medicine magazine, the pathogenetic research of cold injury, 15(5): 416-418,1995).
Research confirms, cold injury forms point two stages.First stage is that tissue freezes, and causes histiocyte coup injury, and the scope of tissue injury and the degree of depth depend primarily on degree and the persistent period of cold expoure.After second stage mainly betides the thawing of frozen tissue rewarming, tissue blood recovers, and then occur the development of gradual microcirculation disturbance, pathological change rapidly, causing histiocyte ischemic necrosis, is indirect injury.Current therapeutic scheme clinically mainly comprises rewarming treatment, infection, improvement is endured cold locally and systemic blood circulation, antioxidant and whole body supporting treatment (see Wang Hai chief editor, Occupational High Altitude Disease pharmacotherapeutics, p172-180,2010).
Be not specifically designed to the medicine of prevention and therapy Cold water stress at present clinically, therefore, the medicine that research has prevention or treatment Cold water stress has important clinical meaning.
Summary of the invention
The present inventor, by making great efforts untiringly, is surprisingly found out that M cholinergic receptor-blocking agent and α
1receptor blocking agent coupling, can effectively prevent or treat Cold water stress, this completes the present invention.
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.
The pharmaceutical composition of any one according to a first aspect of the 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 can be such as hydrogen salt hydrochlorate, hydrobromate, hydriodate, sulfate or phosphate etc., preferred hydrobromate.
The pharmaceutical composition of any one according to a first aspect of the 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 can be such as tartrate, hydrochlorate, sulfate, citrate etc., preferred salt hydrochlorate or tartrate.
The pharmaceutical composition of any one according to a first aspect of the 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, is more preferably 3 ~ 8:1, then is more preferably 3 ~ 5:1.
The pharmaceutical composition of any one 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 kit product, and it comprises at least one first pharmaceutical preparation unit and at least one second pharmaceutical preparation unit, and unit prepared by described first medicine and the second pharmaceutical preparation unit is optionally present in this kit product independently of each other; Described first pharmaceutical preparation unit comprises the M cholinergic receptor-blocking agent and optional pharmaceutically acceptable carrier or excipient that prevent or treat effective dose, and described second pharmaceutical preparation unit comprises the α of prevention or treatment effective dose
1receptor blocking agent and optional pharmaceutically acceptable carrier or excipient.
The kit product of any one according to a second aspect of the 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 can be such as hydrogen salt hydrochlorate, hydrobromate, hydriodate, sulfate or phosphate etc., preferred hydrobromate.
The kit product of any one according to a second aspect of the 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 can be such as tartrate, hydrochlorate, sulfate, citrate etc., preferred salt hydrochlorate or tartrate.
The kit product of any one according to a second aspect of the 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, is more preferably 3 ~ 8:1, then is more preferably 3 ~ 5:1.
Fourth aspect present invention relates to the pharmaceutical composition of any one of first aspect present invention or the kit product of any one of the second aspect purposes in the medicine of preparation prevention or treatment Cold water stress or cold injury, thrombosis, protection vascular endothelial cell.
In the present invention, can by M cholinergic receptor-blocking agent and α
1receptor blocking agent makes preparation respectively, and description to specifications simultaneously or take in order in use, also said medicine can be combined and make clinically or pharmaceutically acceptable any one dosage form.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.The peroral dosage forms such as preferred tablet, capsule and powder.
Pharmaceutical composition of the present invention or kit product can in solid dosage formss for oral administration, oral solid formulation of the present invention, can 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 lubricant etc.If a) filler or extender are as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) binding agent is as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and Radix Acaciae senegalis; C) wetting agent is as glycerol; D) disintegrating agent is as agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some silicate and sodium carbonate; E) solution retarding agents is as paraffin; F) accelerator is absorbed as quaternary ammonium compound; G) wetting agent is as spermol and glyceryl monostearate; H) adsorbent as Kaolin and bentonite and i) lubricant as Pulvis Talci, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.When capsule, tablet and pill, in described dosage form, also buffer agent can be comprised.
Pharmaceutical composition of the present invention or kit product can in liquid dosage forms 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 is except the inert diluent also can commonly used containing this area containing active ingredient beyond the region of objective existence, such as water or other solvents, the fatty acid ester of solubilizing agent and emulsifying agent such as 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 sorbitan and their mixture.
Term used herein " prevention or treatment effective dose " causes research worker, veterinary, doctor or the tissue sought by other people, system, biology of animal or human or the medicine of medical science response or the amount of pharmaceutical preparation.
When for above-mentioned treating and/or preventing, total consumption per day of pharmaceutical composition of the present invention must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the order of severity of this obstacle; The activity of the particular compound adopted; The concrete compositions adopted; Age of patient, body weight, general health situation, sex and diet; The administration time of the particular compound adopted, route of administration and excretion rate; The treatment persistent period; The medicine combinationally using with adopted particular compound or use simultaneously; Ratio between medicine; And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from lower than for obtaining level that required therapeutic effect requires, increases dosage, gradually until obtain required effect.In general, pharmaceutical composition of the present invention is used for the dosage of mammal particularly people can between 0.001 ~ 1000mg/kg body weight/day, such as, between 0.01 ~ 100mg/kg body weight/day, such as, between 0.01 ~ 10mg/kg body weight/day.In the present invention, the single dosage of M cholinergic receptor-blocking agent is 0.8 ~ 7.2mg/kg, preferably 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, preferably 0.6 ~ 27.5mg/kg, more preferably 0.6 ~ 1.2mg/kg.
In the present invention, described Cold water stress refers under certain condition because cold acts on human body, cause local and even the damage of whole body.The generation of Cold water stress except relevant with the intensity of cold, wind speed, humidity, time of enduring cold, also with moist, local blood circulation is bad and cold tolerance declines relevant.
In the present invention, described cold injury refers to that the body local organization caused in cold environments is freezed, microcirculation disturbance and blood coagulation system abnormal, then develop into the disease of tissue local necrosis.
In the present invention, described thrombosis also can be described as thrombosis, refers in the cardiovascular of live body, and the process that blood solidifies or in blood, some visible component is separated out, coagulation forms solid matter block, the solid matter block formed is called thrombosis.Described pre-preventing thrombosis refers to and prevents thrombosis, reduces incidence of thrombus; Described treatment thrombosis refers to and shortens thrombosis length, prevents thrombus breaks loose or removes thrombosis, thrombus.
The beneficial effect of the invention
The present invention confirms by experiment, by M cholinergic receptor-blocking agent and α
1receptor blocking agent coupling, can effectively prevent or treat Cold water stress, its effect be better than single medicine greatly, shows that two class drug combinations have synergism; Can dosage be reduced by drug combination, reduce drug side effect.Meanwhile, the present invention also confirms, by M cholinergic receptor-blocking agent and α
1receptor blocking agent coupling, effectively can reduce thrombosis and occur, shorten thrombosis length, and have the function of protection vascular endothelial cell, can be used for prevention or the treatment of thrombosis.
Detailed description of the invention
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturer suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
Terazosin (terazosin, Ter) is purchased from the emerging milky way Chemical Co., Ltd. in Hubei; Doxazosin (doxazosin, Dox) is purchased from Chinese pharmaceutical biological product qualification institute; Tolazoline (tolazoline, Tol) is purchased from Hubei Kang Baotai Fine Chemical Co., Ltd; Anisodamine is purchased from Henan Pu Rui pharmaceutical Co. Ltd; Prazosin is that Japanese TCI company produces; Type I type carrageenin (carrageenin type I) is Sigma Co., USA's product.
Embodiment 1 Anisodamine, prazosin and compositions thereof are on the impact of the mouse tail thrombosis length of carrageenin induction under cold environment.
Experimental technique: SPF level body weight 18 ~ 22g male mouse of kunming (being purchased from Military Medical Science Institute's Experimental Animal Center) gives I type carrageenin 5mg.kg
-1(become the solution of 0.05% with normal saline, according to every 10g body weight 0.1ml volume lumbar injection), test medicine group mice before injection carrageenin 30min according to the preventative gavage of 0.1ml/10g body weight give test medicine (equally with normal saline) (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 are about to two medicines and merge and be configured in normal saline.Model group normal saline gavage).After injection carrageenin, mice cold expoure is in the environment of 18 ± 1 DEG C of temperature and 30-50% humidity, freely ingests and drinks water and keep h light every day 12, while close observation afterbody thrombosis situation, measure afterbody thrombosis length after 48 hours.
Experimental result: compared with model group, Anisodamine, prazosin and Anisodamine and prazosin compositions significantly can shorten thrombosis length (P < 0.05); Do not compare with prazosin 0.07 dosage component with Anisodamine 0.8, Anisodamine 0.8+ prazosin 0.07 dosage group significantly can shorten thrombosis length (P < 0.05); Do not compare with prazosin 0.6 dosage component with Anisodamine 7.2, Anisodamine 7.2+ prazosin 0.6 dosage group significantly can shorten thrombosis length (P < 0.05), in table 1.
Result shows, Anisodamine and prazosin coupling have synergism to the length shortening thrombosis under prevention mice cold environment.
The compatibility of table 1. various dose Anisodamine, prazosin and Anisodamine and prazosin brings out thrombotic impact to carrageenin under 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, compared with model group;
▲p < 0.05, ratio alone with Isodose Anisodamine;
△p < 0.05, ratio alone with Isodose prazosin.
Embodiment 2 Anisodamine and prazosin compositions are on the impact of the mouse tail thrombosis length of carrageenin induction under cold environment.
Experimental model: SPF level body weight 18 ~ 22g male mouse of kunming, gives I type carrageenin 2.5mg.kg
-1(become the solution of 0.025% with normal saline, according to every 10g body weight 0.1ml volume lumbar injection), test medicine group mice 30min before injection carrageenin give test medicine (with normal saline) (in each dosage group according to the preventative gavage of 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), blank group is respectively with same volume normal saline lumbar injection and gavage, model group only gives I type carrageenin, do not give test medicine, Mouse feeder is in the environment of the temperature of 18 ± 1 DEG C and 30-50% humidity subsequently, freely ingest and drink water and keep h light every day 12, close observation afterbody thrombosis situation simultaneously, measure afterbody after 48 hours and become bolt rate and thrombosis length (thrombosis not to occur completely for criterion).
Experimental result: compared with model group, Anisodamine+tolazoline group thrombosis length significantly shortens (P < 0.05); Anisodamine+prazosin compatibility (1)-(9) group all significantly can shorten thrombosis length (P < 0.05); Compared with Anisodamine+tolazoline group, Anisodamine+prazosin compatibility (1)-(9) group all significantly can shorten thrombosis length (P < 0.05), in table 3.
Compared with model group, Anisodamine+tolazoline group to incidence of thrombus without significant difference; Anisodamine+prazosin compatibility (1), (5), (6) group incidence of thrombus significantly decline (P < 0.05); Compared with Anisodamine+tolazoline group, Anisodamine+prazosin compatibility (1), (5), (6) group incidence of thrombus significantly decline (P < 0.05), in table 2.
Table 2 Anisodamine, tolazoline and prazosin coupling are to 2.5mg.kg under cold environment
-1carrageenin brings out the impact 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 model group ratio,
▲p < 0.05, with Anisodamine 2.5+ tolazoline 12.5 groups of ratios.
Above result of the test shows, Anisodamine and the application of prazosin associating compatibility, have antithrombotic effect, and its effect is better than Anisodamine and tolazoline coupling.
Embodiment 3 Anisodamine brings out the impact of the blood coagulation of thrombosis mice and fibrinolytic function with prazosin and tolazoline use in conjunction to carrageenin under cold environment respectively.
The present embodiment is identical with experimental technique with the modeling of embodiment 2, detects plasma prothrombin time (PT), activated partial thromboplastin time (APTT), plasma tissue type activator of plasminogen (t-PA) content and plasminogen activator inhibitor-1(PAI-1) content.(use platelet aggregation thrombin analyser to measure test kit description according to PT, APTT and require operation further; Operation detection is required according to enzyme linked immunological kit description) during t-PA and PAI-1 assay.
Experimental result: compared with blank group, model group PT significantly shortens, Plasma t-PA content significantly reduces, PAI-1 content significantly raises (P < 0.05).Compared with model group, Anisodamine+tolazoline group PT extends without significance, 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), in table 3.
Table 3 Anisodamine and prazosin coupling bring out the impact of the blood coagulation of thrombosis mice and fibrinolytic function to carrageenin under 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, with model group ratio.
Above experimental result shows, Anisodamine and prazosin use in conjunction have improves the parafunctional effect of blood coagulation system under cold environment.
Embodiment 4 Anisodamine respectively with prazosin and tolazoline use in conjunction on the protective effect of endotheliocyte under cold environment and and the impact of platelet function.
The present embodiment is identical with experimental technique with the modeling of embodiment 2, detects 6-ketone-prostaglandin F in blood plasma
1α (6-ketone-PGF
1α) content and thromboxane element B
2(TXB
2) content (pressing TXB2,6-Keto-PGF1 α radioimmunology analysis medicine box description respectively to measure).
Experimental result: compared with blank group, 6-ketone-PGF in model group blood plasma
1alpha content significantly reduces (P < 0.05), TXB
2content significantly increases (P < 0.05).Compared with model group, 6-ketone-PGF in Anisodamine+tolazoline group blood plasma
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 raises (P < 0.05), blood plasma TXB
2content significantly reduces (P < 0.05), in table 4.
Table 4 Anisodamine and prazosin coupling bring out thrombosis mice plasma 6-Keto-PGF to carrageenin under cold environment
1α and TXB
2the impact 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, with model group ratio.
Above experimental result shows, Anisodamine and prazosin use in conjunction have the effect of protection blood vessel inner skin cell function.
The different α of embodiment 5
1the dilating effect of receptor antagonist and anisodamine on rat arteria caudalis
Experimental model: the male Wistar rat vertebra dislocation method of SPF level body weight 180 ~ 220g is put to death, peel off with knife blade ring cutting cortex along root of the tail portion, cut ventral blood vessels sheath subsequently, careful separation arteria caudalis, rapidly as containing in the plate of 4 DEG C of Krebs-ringer nutritional solutions.Blood vessel pin is fixed, and carefully rejects tissues surrounding vascular under anatomical lens, and is cut into about 2mm vascular ring.2 one metal wires of diameter 40 μm, long 2.2mm are penetrated vascular ring, is individually fixed in lifting arm one end and sensor one end of myograph (DMT company of Denmark, model 610M) bath (containing 5ml Krebs-ringer nutritional solution), continues to pass into 95%O
2and 5%CO
2mist, body lotion keeps 37 DEG C.The spiral micrometer moving recording instrument stiff end by rotating flesh changes tinsel spacing, adjustment vascular ring transmural pressure power (basal tension born when being equivalent to normal physiological conditions 100mmHg), balances after 30 minutes and starts experiment.With 10 μm of olL in bath
-1noradrenaline bitartrate (norepinephrine, NE) preshrinking vascular ring, its maximum stable shrinkage amplitude (tension force) is 100%, give test medicine with concentration method of cumulative scale again, the diastole amplitude of drug-induced vascular ring and the NE ratio brought out between maximum stable shrinkage amplitude is the diastolic rate of blood vessel.
Experimental result: with final concentration 10 μm of olL
-1n E preshrinking vascular ring, when shrinkage amplitude reach maximum and stable after, cumulative bad adds concentration is successively 0.01 ~ 10 μm of olL
-1tolazoline, prazosin, terazosin, doxazosin and Anisodamine, obtain vascular ring to each medicine stretching reaction (see table 5).
Table 5 Anisodamine, tolazoline, terazosin, prazosin and doxazosin are to the diastole effect of Mus arteria caudalis ring
*p < 0.05, with 0.01 μm of olL of each medicine
-1group is compared,
▲p < 0.05, with 10 μm of olL
-1anisodamine is compared, n=8.
Result shows, with the increase of administration concentration, vascular ring diastolic rate progressively increases, at 0.01 ~ 10 μm of olL
-1in scope, there is concentration dependent.What in said medicine, maximum diastolic rate was the highest is prazosin 82.6 ± 8.9%.Pass through EC
50the comparison (see table 6) of (calculating by bliss method), the dilating effect of prazosin to Mus arteria caudalis ring be respectively tolazoline, terazosin, 12.45,3.88,12.0 times of doxazosin.
Table 6Bliss method calculates medicine EC
50, slope and correlation coefficient (n=8)
In sum, α
1receptor antagonist has significant dilating effect to the periphery acra tiny blood vessels taking arteria caudalis as representative, 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 amendment 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, its active component is by preventing or treat the M cholinergic receptor-blocking agent of effective dose and the α of prevention or treatment effective dose
1receptor blocking agent forms, and wherein said M cholinergic receptor-blocking agent is selected from atropine, Anisodamine, scopolamine or their pharmaceutically acceptable salt, wherein said α
1receptor blocking agent is selected from tolazoline, prazosin, terazosin, doxazosin or their pharmaceutically acceptable salt, and described M cholinergic receptor-blocking agent and α
1the weight ratio of receptor blocking agent is 1:11 ~ 36:1.
2. the pharmaceutical composition of claim 1, wherein said M cholinergic receptor-blocking agent and α
1the weight ratio of receptor blocking agent is for being 2 ~ 10:1.
3. the pharmaceutical composition of claim 1, wherein said M cholinergic receptor-blocking agent and α
1the weight ratio of receptor blocking agent is 3 ~ 8:1.
4. the pharmaceutical composition of claim 1, wherein said M cholinergic receptor-blocking agent and α
1the weight ratio of receptor blocking agent is 3 ~ 5:1.
5. the pharmaceutical composition of any one of claim 1-4, it also comprises pharmaceutically acceptable carrier or excipient.
6. kit product, be made up of at least one first pharmaceutical preparation unit and at least one second pharmaceutical preparation unit, unit prepared by described first medicine and the second pharmaceutical preparation unit is present in this kit product independently of each other; Described first pharmaceutical preparation unit comprises the active component and optional pharmaceutically acceptable carrier or excipient that are made up of the M cholinergic receptor-blocking agent prevented or treat effective dose, and described second pharmaceutical preparation unit comprises by the α preventing or treat effective dose
1the active component of receptor blocking agent composition and optional pharmaceutically acceptable carrier or excipient, wherein said M cholinergic receptor-blocking agent is selected from atropine, Anisodamine, scopolamine or their pharmaceutically acceptable salt, wherein said α
1receptor blocking agent is selected from tolazoline, prazosin, terazosin, doxazosin or their pharmaceutically acceptable salt, and described M cholinergic receptor-blocking agent and α
1the weight ratio of receptor blocking agent is 1:11 ~ 36:1.
7. the kit product of claim 6, wherein said M cholinergic receptor-blocking agent and α
1the weight ratio of receptor blocking agent is for being 2 ~ 10:1.
8. the kit product of claim 6, wherein said M cholinergic receptor-blocking agent and α
1the weight ratio of receptor blocking agent is 3 ~ 8:1.
9. the kit product of claim 6, wherein said M cholinergic receptor-blocking agent and α
1the weight ratio of receptor blocking agent is 3 ~ 5:1.
10. the pharmaceutical composition of any one of claim 1-5 or the kit product of claim 6-9 prevent or treat the purposes in the medicine of Cold water stress, cold injury, thrombosis or protection vascular endothelial cell in preparation.
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Citations (2)
| 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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2013
- 2013-05-21 CN CN201310187477.0A patent/CN103272235B/en active Active
Patent Citations (2)
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 口服冻伤预防药25号及38号方的效用;张是敬;《中国人民解放军军事医学科学院院刊》;19791231(第3期);第371-374页 * |
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