CN105796554A - Application of imidafenacin in preparation of drugs for pre-anesthetic medication - Google Patents
Application of imidafenacin in preparation of drugs for pre-anesthetic medication Download PDFInfo
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- CN105796554A CN105796554A CN201410845056.7A CN201410845056A CN105796554A CN 105796554 A CN105796554 A CN 105796554A CN 201410845056 A CN201410845056 A CN 201410845056A CN 105796554 A CN105796554 A CN 105796554A
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Abstract
The invention discloses application of imidafenacin in preparation of drugs for pre-anesthetic medication. Preclinical pharmacological tests prove that imidafenacin not only can be used for pre-anesthetic medication, but also has effects superior to those of atropine, thus opening up a new path for clinical pre-anesthetic medication.
Description
Technical field
Technical solution of the present invention relates to the new application of imidafenacin, belongs to pharmaceutical technology field.
Background technology
Premedication in order that release the uneasy psychology such as the anxiety of patient, fear, anxiety, reduce the secretion of saliva and respiratory tract during anesthesia, thus keeping respiratory passage unblocked, being beneficial in art management of respiratory and reducing postoperative pulmonary complications, simultaneously prevented also from because of art moderate stimulation, bring out vagus reflex or other visceral reflexs cause the complication such as bradycardia, laryngospasm.Classical premedication is atropine, owing to it is nonselective, antagonism M cholinoceptor medicine, often causes increased heart rate and the untoward reaction such as postoperative urine retention and enteroparalysis；Simultaneously can excited high-order brain centres, the Agitations such as agitation, hallucination occur, these unfavorable factors are especially dangerous for the gerontal patient being easier to generation cardiovascular and cerebrovascular vessel accident and mind consciousness changing.
Desirable general anesthesia premedicate should meet abundant calmness, improves the threshold of pain, reduce oxygen consumption and stress, suppression glandular secretion, minimizing anaesthetic consumption, does not bring again untoward reaction, there is no any medicine at present and can reach above-mentioned whole requirement.Conventional anticholinergic agent is to reduce oral cavity and respiratory secretions clinically, and prevents from art moderate stimulation from bringing out vagus reflex causing the complication such as laryngospasm.The anticholinergic agent that tradition uses is atropine and scopolamine, they are all non-selective muscarinic (M) receptor blocking agents, maincenter sedation after existing M1 receptor block and the bronchus after Ms receptor block and visceral smooth muscle relexation, also M2 receptor block is had to cause increased heart rate, the effects such as blood pressure rising, therefore, both medicines disable in the patient of hyperthyroidism, cardiac insufficiency, mitral stenosis and tachyarrhythmia, and are cautious use of children's Yu and old people.
Imidafenacin, chemical name is 4-(2-methyl isophthalic acid-imidazole radicals)-2,2-diphenyl butanamides, shown in its structure such as formula (I):
Formula (I) imidafenacin structural formula
Molecular formula: C20H21N3O
Molecular weight: 319.4
Imidafenacin is the novel diphenyl butanamide class anticholinergic agent developed jointly with Fructus Pruni woods pharmacy by ONO Pharmaceutical Co., Ltd. of Japan, it it is a kind of novel anticholinergic agent, it is characterized in heart M2 receptor without obvious effect, and Selective depression M1 and M3 receptor, adding imidafenacin relatively low for cholinoceptor affinity in cerebral tissue, therefore maincenter and periphery untoward reaction also can be less.
Imidafenacin has height bladder selectivity, now for the treatment of overactive bladder, lists in Japan in June, 2007.Have no at present and be used as the report in premedication about imidafenacin.
Summary of the invention
The goal of the invention of the present invention is to provide the new opplication of a kind of imidafenacin, i.e. imidafenacin application in the medicine of preparation premedication.We are confirmed by pharmacological evaluation in process of experimental, and imidafenacin as premedication, and can be better than the anticholinergic agent atropine commonly used clinically.Imidafenacin and pharmaceutically acceptable adjuvant can be made the regular dosage forms such as tablet, capsule, injection.
Specific embodiment
In order to further illustrate the beneficial effect of technical solution of the present invention, we are verified by effect experiment, and effect experiment is as follows:
Test the impact on isolated rat submaxillary gland of 1 imidafenacin
1 experiment material
1.1 experimental animals: SPF level adult male SD rats, are provided by Chengdu University of Traditional Chinese Medicine's Animal Experimental Study center, weight 220～280g, totally 30, often group 6, pre-raising 1 week, rat feed is full price Mus particulate material, plant of laboratory animal special commission of Sichuan Province provide.
1.2 experimental drugs:
Imidafenacin, atropine sulfate, CCh(carbachol).
1.3 experiment equipments:
Superclean bench, electronic balance, first fluorine fiber pipe, BF-41 type constant water bath box, peristaltic pump.
2. experimental technique
2.1 test packets: experiment is divided into 5 groups, model group, imidafenacin high dose group (6.0 μm of ol/ml), dosage group (3.0 μm of ol/ml) in imidafenacin, imidafenacin low dose group (1.0 μm of ol/ml), atropine sulfate group (2.9 μm of ol/ml).
2.2 submaxillary gland separate and perfusion system
Adaptability is raised 1 week.After sodium phenobarbital (45mg/kg intraperitoneal injection) anesthesia, separating bilateral submaxillary gland (120～180mg), the sublingual gland of attachment is extractd after Ligation of artery, vein, walther's canal.Cutting off submaxillary gland vein, transfer to thermostatic bath (37 DEG C), the extralobular main pipeline of submaxillary gland inserts the fluorofibre pipe (O.3ram × 0.5ram external diameter) of hollow and samples；The far-end of submaxillary gland arterial branch inserts the stainless steel pipe (26G) of hollow and is connected to perfusion device.Connect of Vein catheter drainage saliva.Peristaltic pump (Cole-Palmer) is used to carry out submaxillary gland perfusion with the speed of 2ml/min.Perfusion buffer solution (mM) composed as follows: Na+, 145；K+, 4.3；Ca2+, 1.0；Mg2+, 1.0；cl-, 148.3；Glucose, 5.0.It is simultaneously introduced 10mmol/IHEPES (4-hydroxyethyl piperazine ethanesulfonic acid) and regulates pH value to 7.4.And it is placed on 37 DEG C of reservoir inner equilibriums to 100 oxygen content.
2.3 perfusions
First carry out the buffer perfusion of at least 20min with peristaltic pump, after baseline is steady, each group all adds 0.2mol/LCCh perfusate perfusion 5min, now starts to measure salivation amount.Add relative medicine dosage after 5min and enter perfusion 5min in perfusate.
2.4 experimental index: glandular secretion amount；In order to measure secretory volume, being full of perfusion buffers in venous duct, tip is placed in electronic balance (minimum registration is 0.1mg), it is to avoid contact with beaker bottom.
3. statistical procedures
Each group secretory volume mean ± standard deviation (X ± S) represents, adopts SPSS11.0 software to be analyzed, and adopts t to check P < O.05 to have significance statistical significance for difference.
4. experimental result and analysis
The impact (X ± S) on rat submandibular gland of table 1 imidafenacin
| Group | Quantity | Dosage (μm ol/ml) | Saliva amount (ml) |
| Model group | 6 | 62.67±4.58 | |
| Imidafenacin high dose group | 6 | 6.0 | 52.14 ± 5.76 ● |
| Dosage group in imidafenacin | 6 | 3.0 | 56.36 ± 8.16 |
| Imidafenacin low dose group | 6 | 1.0 | 59.52±9.13● |
| Atropine sulfate group | 6 | 2.9 | 57.21 ± 6.83 |
Note: compare P < 0.05 with model group；< 0.01, compares with atropine sulfate group ● P < 0.05.
Shown by table 1 result: in imidafenacin, high dose group and atropine sulfate group are variant with model group, show this model modeling success (P < 0.05, P < 0.01), and high dose group and atropine sulfate group all can suppress the choline effect to carbachol in imidafenacin, play cholinolytic effect, the secretion (P < 0.05) of rat submandibular gland can be reduced；Comparing with atropine sulfate group, imidafenacin high dose is better than atropine sulfate (P < 0.05) in suppressing glandular secretion.
Test the effect of the 2 anti-rabbit salivations of imidafenacin
1. experiment material
1.1. animal: large ear rabbit 40, male and female half and half, body weight 1.8-2.4kg, one-level, is purchased from Sichuan University's Experimental Animal Center.
1.2. experimental drug:
Imidafenacin, atropine sulfate, pilocarpine.
1.3. instrument: electronic balance METTLERAE260 Swiss
2. experimental technique
2.1 test packets: by sex, body weight, rabbit is randomly divided into 5 groups, model group, imidafenacin high dose group, dosage group in imidafenacin, imidafenacin low dose group, atropine sulfate group, often group given low is 3ml/kg.
null2.2 processs of the test: rabbit is raised 1 day，Within second day, test respectively，Rabbit is put into rabbit hutch fix，Model group gives the gavage pure water containing 0.5%CMC-Na，Imidafenacin high dose group dosage is: 0.01mg/kg，In imidafenacin, dosage group dosage is: 0.005mg/kg，Imidafenacin low dose group dosage is: 0.0025mg/kg，Atropine sulfate group dosage is: 0.15mg/kg,After each group gavage, 30min gives injection pilocarpine 5mg/kg，Close dry cotton ball (is put into rabbit oral cavity with mosquito forceps by the saliva amount of rabbit secretion in collecting 1 hour subsequently，Wipe one time up and down，Wipe in the same way at interval of 5min one time，Finally adding up to weighs is calculated as rabbit saliva amount).
2.3 experimental index: saliva is measured
2.4 interpretations and process: saliva is measured, adopt SPSS11.0 software to be analyzed, and collection capacity compares with (X ± S) standard, adopts t inspection to carry out P value and analyzes.
3. experimental result and analysis
The effect (X ± S) of the anti-rabbit salivation of table 2-imidafenacin
| Group Not | Quantity | Dosage (mg/kg) | Collection capacity (mg) |
| Model group | 8 | 710.05±50.43 | |
| Imidafenacin high dose group | 8 | 0.01 | 398.75±33.44★★★▲ |
| Dosage group in imidafenacin | 8 | 0.005 | 451.58±37.56★★ |
| Imidafenacin low dose group | 8 | 0.0025 | 613.50±18.42★▲ |
| Atropine sulfate group | 8 | 0.15 | 435.63±22.86★★ |
Note: compare ★ P < 0.05 with model group；★ ★ < 0.01, compares ▲ P < 0.05 with atropine sulfate group.
Shown by the result of table 2: atropine sulfate group and model group have significant difference, show this test modeling success (P < 0.05, P < 0.01), imidafenacin each dosage group is all variant with model group, it was shown that the secretion of imidafenacin energy antagonism rabbit saliva.Atropine sulfate group is variant with imidafenacin low dose group and high dose group, difference is not had with middle dosage group, show that atropine sulfate has equivalent action in the effect of anti-rabbit salivation with dosage group in imidafenacin, but imidafenacin high dose group is better than atropine sulfate group (P < 0.05), it shows that imidafenacin functionally has a better effect at anti-salivation, and imidafenacin antagonism salivation demonstrates dose-dependence.
Shown by above inside and outside effect experiment, imidafenacin has the function suppressing saliva glandular secretion, this suppresses function for atropine, the advantageous effect having taking dose low (is converted by dose,equivalent, imidafenacin referrer's dosage is 0.1mg/ day, atropine sulfate people's dosage is oral: 0.3～0.6mg/ time, every day 3 times, the each 1mg of maximum dose, every day 3mg), therefore in imidafenacin exploitation for having a good application prospect in this new indication of premedication.
Claims (2)
1. the compound application in the medicine of preparation premedication, it is characterised in that this compound is imidafenacin.
2. a kind of compound as claimed in claim 1 application in the medicine of preparation premedication, it is characterised in that people's consumption of imidafenacin is 0.1mg/d.
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| Application Number | Priority Date | Filing Date | Title |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107213151A (en) * | 2017-05-16 | 2017-09-29 | 牡丹江医学院 | A kind of medical composition and its use for being used to nurse before surgery anesthesia |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107213151A (en) * | 2017-05-16 | 2017-09-29 | 牡丹江医学院 | A kind of medical composition and its use for being used to nurse before surgery anesthesia |
| CN107213151B (en) * | 2017-05-16 | 2020-05-12 | 牡丹江医学院 | Pharmaceutical composition for reducing salivary secretion in surgical anesthesia process and application thereof |
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Application publication date: 20160727 |
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| WD01 | Invention patent application deemed withdrawn after publication |