CN102008473B - Application of nicotine and medical composition - Google Patents
Application of nicotine and medical composition Download PDFInfo
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- CN102008473B CN102008473B CN201010556623.9A CN201010556623A CN102008473B CN 102008473 B CN102008473 B CN 102008473B CN 201010556623 A CN201010556623 A CN 201010556623A CN 102008473 B CN102008473 B CN 102008473B
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- nicotine
- blood vessel
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Abstract
The invention discloses application of nicotine to the preparation of an agent for reinforcing the medicament effect of a nitro blood vessel dilatation medicament and the application of the nicotine serving as a component for reinforcing the medicament effect of the nitro blood vessel dilatation medicament to the preparation of a vasodilator, wherein the vasodilator contains the nitro blood vessel dilatation medicament. The invention also discloses a medical composition which contains the nicotine and pharmaceutically acceptable auxiliaries. In the invention, better effect of the nicotine on the reinforcement of the medicament effect of the nitro blood vessel dilatation medicament is discovered for the first time, thus the application arrange of the nicotine is broadened.
Description
Technical field
The present invention relates to the application of nicotine in field of medicaments, and a kind of pharmaceutical composition.
Background technology
It is that a class can change into nitric oxide production donor in vivo that nitro expands blood vessel medicine, and release Effect of Nitric Oxide is vasodilatory medicine in vascular smooth muscle, as sodium nitroprusside, nitroglycerine tablets etc.It is of many uses, is usually used in hypertensive emergency and operating room control blood pressure, also for the treatment of the diseases such as angina pectoris, heart failure, high altitude pulmonary edema.But nitro expands blood vessel medicine and easily produces tachyphylaxis when using, showing as needs to continue to increase dosage and just can reach original effect, therefore for avoiding tachyphylaxis, needs interval to use clinically.In addition, when Dose Requirment of Sodium Nitroprusside is large, can cyanide poisoning be caused, also limit clinical use amount and time.Therefore, searching makes the method for such medicine enhanced sensitivity very necessary.
Nicotine is a kind of alkaloid be present in plant of Solanaceae, is also the important component of Nicotiana tabacum L..It is a kind of unpleasant, bitter in the mouth, water white oily liquids, and high volatility, is very easily oxidized to lead in atmosphere, water soluble, ethanol, chloroform, ether equal solvent.The effect of nicotine to human body is extensive, complicated, plays a role mainly through nicotine receptor.Research report was how relevant to the cardiovascular adverse effect of smoking in the past.
But not yet have in prior art any about nicotine for strengthening the bibliographical information of nitro medicament for expanding vascellum drug effect.
Summary of the invention
Technical problem to be solved by this invention be for nitro medicament for expanding vascellum easily produce toleration and consumption large time can produce the defect of the untoward reaction such as poisoning, and provide the new opplication of a kind of nicotine in vasodilation field and a kind of pharmaceutical composition.
The present inventor, surprisingly finds in the influence process of vascular function at research nicotine: nicotine has significantly enhancing nitro and expands the effect of blood vessel medicine drug effect.Thus, the present invention is solved the problems of the technologies described above by following technical proposals:
The present invention relates to nicotine and prepare the application in nitro expansion blood vessel medicine drug effect reinforcing agent.
The invention still further relates to nicotine and preparing the application in vasodilator medicine as nitro expansion blood vessel medicine drug effect enhancing ingredients, wherein said vasodilator medicine contains nitro and expands blood vessel medicine.
The invention further relates to a kind of pharmaceutical composition, it contains nicotine and pharmaceutically acceptable adjuvant.This pharmaceutical composition can only contain nicotine as sole active agent, uses to expand blood vessel medicine drug effect reinforcing agent as nitro.This pharmaceutical composition also can also containing other active component except nicotine.Other described active component is expand the drug action of blood vessel medicine to the enhancing nitro of nicotine not have harmful effect can the active component of conbined usage, as nitro expands blood vessel medicine.
In the present invention, described nitro expands the various nitros expansion blood vessel medicines that blood vessel medicine is known in the art, and namely by changing into nitric oxide production donor in vivo, release Effect of Nitric Oxide is vasodilatory class medicine, such as a sodium nitroprusside in vascular smooth muscle.
As required, vasodilator medicine of the present invention or pharmaceutical composition can be the various regular dosage forms be made up of active component and the acceptable adjuvant of pharmaceutical field, as tablet, pill and injection etc.Obvious, according to this area general knowledge, the form of described vasodilator medicine can be and expands primarily of nicotine and nitro the pharmaceutical compositions that blood vessel medicine is mixed, or is that the nitro containing nicotine comprised independently expands blood vessel medicine drug effect reinforcing agent and expands the kit form of pharmaceutical composition of blood vessel medicine containing nitro.Equally, when pharmaceutical composition of the present invention is simultaneously containing nicotine and other active component (as nitro expands blood vessel medicine), the form of pharmaceutical composition also can be above-mentioned two kinds of forms.
In described vasodilator medicine or pharmaceutical composition, the content of nicotine expands more than blood vessel medicine effective dose at enhancing nitro, can determine, specifically can select as required according to this area conventional method, usual rat 0.8mg/kg/ days ~ 3mg/kg/ days, people's consumption can convert by this area conventional method.The content of nitro expansion blood vessel medicine can be the known consumption of these medicines.But because nicotine expands the potentiation of blood vessel medicine drug effect to nitro, nitro expands the content of blood vessel medicine can suitably lower than known consumption, as long as treating more than effective dose.More specifically, suitably dosage can be selected according to method of administration, patient age, sex and other condition and symptom.In general, vasodilator medicine of the present invention or pharmaceutical composition apply more than two weeks, can produce the effect that obvious nitro expands the enhancing of blood vessel medicine drug effect.
On the basis meeting this area general knowledge, each preferred feature above-mentioned in the present invention can combination in any, obtains the preferred embodiments of the invention.
Except specified otherwise, the raw material that the present invention relates to and reagent are all commercially.
Positive progressive effect of the present invention is: Late Cambrian nicotine of the present invention significantly can strengthen the drug effect that nitro class expands blood vessel medicine.This discovery has widened the range of application of nicotine on the one hand, expands blood vessel prescription medicine and uses and easily produce toleration on the other hand for improving nitro, and reduces its use amount and avoid poisoningly having important and positive medical significance.
Accompanying drawing explanation
Fig. 1 is the curve chart (modeling 2 weeks) that in embodiment 1, nicotine strengthens the vasorelaxation action of sodium nitroprusside.
Fig. 2 is the curve chart (modeling 3 weeks) that in embodiment 1, nicotine strengthens the vasorelaxation action of sodium nitroprusside.
Fig. 3 is the curve chart (modeling 6 weeks) that in embodiment 1, nicotine strengthens the vasorelaxation action of sodium nitroprusside.
Fig. 4 is the curve chart (modeling 6 weeks) that in embodiment 1, nicotine strengthens the vasorelaxation action of acetylcholine.
Detailed description of the invention
Further illustrate the present invention by embodiment below, but the present invention is not limited.Raw material described in embodiment or reagent except special instruction, all commercially.
Embodiment 1 nicotine strengthens the drug effect of nitro vasodilator drug
First set up animal model, process is as follows: male Sprague Dawley (SD) rat in 10 ~ 11 week age is divided into normal saline group and nicotine group at random.Normal saline group is to normal saline (0.5mlkg
-1d
-1) 6 weeks; Nicotine group is to nicotine (3mgkg
-1d
-1) 6 weeks.Each group of route of administration is subcutaneous injection, every day 1 time, and administration volume is 0.5ml/kg, records the change of the weight weekly of rat in two groups simultaneously, and adjusts dosage accordingly.
Get nicotine group and normal saline group withdrawal model thoracic aorta, be cut into the vascular strip that 5mm is wide, preparation does not contain the vascular strip (F-E+) of endothelium containing tunica adventitia fat and does not contain tunica adventitia fat not containing the vascular strip (F-E-) of endothelium.(composition of Krebs liquid is (unit: mM): NaCl 118.4, KCl 14.7, CaCl vascular strip to be put into the bath filling 20ml Krebs liquid
22.5, MgSO
47H
2o 1.2, KH
2pO
41.2, NaHCO
325.0, glucose 11.1, CaNa2-EDTA 0.026), pass to containing 95%O simultaneously
2and 5%CO
2gas.French EMKA in vitro tissue perfusion system is used to carry out antiotasis experiment.
(1) nicotine strengthens the vasorelaxation action of sodium nitroprusside
Respectively antiotasis experiment is carried out to the rat of modeling 2 weeks, 3 weeks and 6 weeks.Preparation F-E-vascular strip is stabilized in Krebs liquid, and rest tension 2g, with 3 × 10
-7the neophryn solution of M makes it shrink, and after maximum collapse amount to be achieved, adding cumulative concentration is respectively: 1 × 10
-10, 3 × 10
-10, 1 × 10
-9, 3 × 10
-9, 1 × 10
-8, 3 × 10
-8, 1 × 10
-7, 3 × 10
-7, 1 × 10
-6, 3 × 10
-6, 1 × 10
-5, 3 × 10
-5with 1 × 10
-4the sodium nitroprusside solution of M, observe the stretching reaction of vascular strip, with the negative logarithm (-1gM) mapping of the diastolic dimension of vascular strip to sodium nitroprusside solution cumulative concentration, the results are shown in Figure 1 ~ 3, in figure, * * represents that nicotine group is compared with normal saline group, have significant significant difference (P < 0.01), * represents that nicotine group is compared with normal saline group, has obvious significant difference (P < 0.05).
Table 1. nicotine treatment strengthens the vasorelaxation action of sodium nitroprusside
*p < 0.05 relative physiologic saline 2 weeks groups;
#p < 0.05,
##p < 0.01 relative physiologic saline 3 weeks groups;
relative physiologic saline 6 weeks groups.
As can be seen from table 1 and Fig. 1 ~ 3, nicotine treatment 2 weeks, 3 weeks and all significantly can strengthen the vasorelaxation action of sodium nitroprusside for 6 weeks.
(2) nicotine strengthens the vasorelaxation action of acetylcholine
Acetylcholine is a kind of endogenous messenger existed in human body, known it blood vessel endothelium can be stimulated to generate nitric oxide, Effect of Nitric Oxide causes vasodilation in vascular smooth muscle.Therefore to expand blood vessel medicine similar for the vasodilatory mechanism of acetylcholine and nitro, is all played a role by nitric oxide.
Carry out antiotasis experiment to the modeling rat of 6 weeks, preparation F-E+ vascular strip is stabilized in Krebs liquid, and rest tension 2g, adds 3 × 10 subsequently
-7the neophryn solution of M makes it shrink.After maximum collapse amount to be achieved, add cumulative concentration and be respectively: 1 × 10
-8, 3 × 10
-8, 1 × 10
-7, 3 × 10
-7, 1 × 10
-6, 3 × 10
-6, 1 × 10
-5, 3 × 10
-5, 1 × 10
-4with 3 × 10
-4the acetylcholine of M, observes its stretching reaction to vascular strip.With the negative logarithm (-lgM) mapping of the diastolic dimension of vascular strip to acetylcholine cumulative concentration, the results are shown in Figure 4, in figure, * represents that nicotine group is compared with normal saline group, has significant significant difference (P < 0.05).
Table 2. nicotine treatment strengthens the vasorelaxation action of acetylcholine
*p < 0.05 relative physiologic saline group
As can be seen from table 2 and Fig. 4, nicotine significantly can strengthen the vasorelaxation action of acetylcholine.
By expanding experiment (1) and (2) of blood vessel medicine sodium nitroprusside and the enhancing of acetylcholine drug effect to nitro, namely provable nicotine is to the potentiation of nitro medicament for expanding vascellum.
Embodiment 2 nicotine strengthens the Acute Hypotensive Effect of sodium nitroprusside
First set up animal model, process is as follows: male Sprague Dawley (SD) rat in 10 ~ 11 week age is divided into normal saline group and nicotine group at random.Normal saline group is to normal saline (0.5mlkg
-1d
-1) 6 weeks; Nicotine group is to nicotine (3mgkg
-1d
-1) 6 weeks.Each group of route of administration is subcutaneous injection, every day 1 time, and administration volume is 0.5ml/kg, records the change of the weight weekly of rat in two groups simultaneously, and adjusts dosage accordingly.
Rat after completing modeling carries out clear-headed pressure measurement.First with ketalar 50mg/kg and diazepam 5mg/kg, intraperitoneal injection of anesthesia is carried out to rat, then carry out tremulous pulse, venous cannulation.The postoperative recovery rat of 24 hours is placed in (drum diameter 30cm, high 24cm in homemade plexiglass cylinder, the circular hole of a diameter 15cm is had in the middle of cover, there is the long and narrow breach of a wide 8cm between hole and lid edge, walk for artery and vein conduit).Laboratory environment is constant temperature (20 ~ 25 DEG C), constant humidity (60%), sound insulation.Take out the metal needle on ductus arteriosus, release heparinization polyvinylpyrrolidonesolution solution (by 10g polyvinylpyrrolidone (polyvinyl pynolidone, PVP) 20ml is dissolved in containing formulated in the normal saline of heparin 200IU/ml), then push back the blood in conduit with the heparinized saline of a small amount of 200IU/ml, then conduit is connected with pressure transducer with perfusion tee T through tumbler.Inject pump by the constant speed be connected on perfusion tee T again, inject the isotonic glucose solution of heparinization of 20IU/ml with the speed of 0.6ml/h.Note the bubble in the whole tubing of emptying, in order to avoid affect blood pressure waveform.Blood pressure signal of often fighting is converted to bioelectrical signals through pressure transducer, and through sampling plate, often to be fought systolic pressure (systolic blood pressure, SBP), diastolic pressure (diastolic blood pressure, DBP) etc. by computer real time record.After adaptation in 3 hours is stable, starts to record blood pressure signal of often fighting, first record 1 hour basic blood pressure, give the sodium nitroprusside of various dose subsequently respectively, off-line analysis hemodynamic index.Sodium nitroprusside is that nitro expands blood vessel medicine, and blood vessel dilating directly can cause the decline of blood pressure, and the changing value that blood pressure reduces is in table 3.
More responsive to sodium nitroprusside Acute Hypotensive Effect after table 3. nicotine treatment
*p < 0.05 relative physiologic saline group sodium nitroprusside 3 μ g/kg;
#p < 0.05,
##p < 0.01 relative physiologic saline group sodium nitroprusside 10 μ g/kg.
As can be seen from Table 3, nicotine significantly can strengthen the Acute Hypotensive Effect of sodium nitroprusside.
Claims (5)
1. nicotine is preparing the application in nitro expansion blood vessel medicine drug effect reinforcing agent, it is characterized in that: it is sodium nitroprusside that described nitro expands blood vessel medicine.
2. nicotine is preparing the application in vasodilator medicine as nitro expansion blood vessel medicine drug effect enhancing ingredients, and wherein said vasodilator medicine is that nitro expands blood vessel medicine, it is characterized in that: it is sodium nitroprusside that described nitro expands blood vessel medicine.
3. apply as claimed in claim 2, it is characterized in that: the form of described vasodilator medicine is expand by nicotine and described nitro the pharmaceutical compositions that blood vessel medicine is mixed, or is the kit form being expanded blood vessel medicine drug effect reinforcing agent by the nitro containing nicotine independently and formed containing the pharmaceutical composition that described nitro expands blood vessel medicine.
4. a pharmaceutical composition, is characterized in that: it expands blood vessel medicine by nicotine and pharmaceutically acceptable adjuvant and nitro and forms, and it is sodium nitroprusside that described nitro expands blood vessel medicine.
5. pharmaceutical composition as claimed in claim 4, it is characterized in that: the form of described pharmaceutical composition is expand by nicotine and described nitro the pharmaceutical compositions that blood vessel medicine is mixed, or is the kit form being expanded blood vessel medicine drug effect reinforcing agent by the nitro containing nicotine independently and formed containing the pharmaceutical composition that described nitro expands blood vessel medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010556623.9A CN102008473B (en) | 2010-11-23 | 2010-11-23 | Application of nicotine and medical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010556623.9A CN102008473B (en) | 2010-11-23 | 2010-11-23 | Application of nicotine and medical composition |
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| Publication Number | Publication Date |
|---|---|
| CN102008473A CN102008473A (en) | 2011-04-13 |
| CN102008473B true CN102008473B (en) | 2014-12-17 |
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|---|---|---|---|
| CN201010556623.9A Active CN102008473B (en) | 2010-11-23 | 2010-11-23 | Application of nicotine and medical composition |
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|---|---|
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005046661A2 (en) * | 2003-11-07 | 2005-05-26 | University Of Sheffield | Use of nitric oxide donors for the treatment of drug addiction |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU765999B2 (en) * | 1998-12-15 | 2003-10-09 | Wm. Wrigley Jr. Company | Improved release of medicament active agents from a chewing gum coating |
| WO2004017896A2 (en) * | 2002-08-21 | 2004-03-04 | Merck & Co., Inc. | Combination therapy using a dual ppar alpha/gamma agonist and an angiotensin ii type i receptor antagonist |
-
2010
- 2010-11-23 CN CN201010556623.9A patent/CN102008473B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005046661A2 (en) * | 2003-11-07 | 2005-05-26 | University Of Sheffield | Use of nitric oxide donors for the treatment of drug addiction |
Non-Patent Citations (2)
| Title |
|---|
| Gerzanich V等.Chronic nicotine alters NO signaling of Ca2+ channels in cerebral arterioles.《Circulation research》.2001,第88卷(第3期),全文. * |
| SI ML 等.Presynaptic alpha(7)-nicotinic acetylcholine receptors mediate nicotine-induced nitric oxidergic neurogenic vasodilation in porcine basilar arteries.《Journal of pharmacology and experimental therapeutics》.2001,第298卷(第1期),全文. * |
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|---|---|
| CN102008473A (en) | 2011-04-13 |
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