CN112426529A - Use of I1 imidazoline receptor antagonists for relieving alpha 2-adrenoreceptor agonist-mediated anesthesia - Google Patents
Use of I1 imidazoline receptor antagonists for relieving alpha 2-adrenoreceptor agonist-mediated anesthesia Download PDFInfo
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- 206010002091 Anaesthesia Diseases 0.000 title claims abstract description 33
- 230000037005 anaesthesia Effects 0.000 title claims abstract description 33
- 229940096915 Imidazoline receptor antagonist Drugs 0.000 title claims abstract description 17
- 230000001404 mediated effect Effects 0.000 title claims abstract description 14
- 229940121947 Alpha 2 adrenoreceptor agonist Drugs 0.000 title claims description 3
- 230000003444 anaesthetic effect Effects 0.000 claims abstract description 29
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 claims abstract description 26
- 239000005557 antagonist Substances 0.000 claims abstract description 23
- 239000000729 antidote Substances 0.000 claims abstract description 11
- HRLIOXLXPOHXTA-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CN=C[N]1 HRLIOXLXPOHXTA-NSHDSACASA-N 0.000 claims description 19
- 229960004253 dexmedetomidine Drugs 0.000 claims description 19
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- 238000001949 anaesthesia Methods 0.000 claims description 5
- 229940002612 prodrug Drugs 0.000 claims description 4
- 239000000651 prodrug Substances 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 238000007918 intramuscular administration Methods 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 239000003855 balanced salt solution Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 238000007912 intraperitoneal administration Methods 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- 230000002688 persistence Effects 0.000 claims 1
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- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 2
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- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 2
- 229960003804 efavirenz Drugs 0.000 description 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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Abstract
The present invention provides the use of an antagonist of the I1 imidazoline receptor for the preparation of an antidote for the relief of an anaesthetic effect mediated by an alpha 2-adrenoceptor agonist and an anaesthetic-wake-up kit comprising an alpha 2-adrenoceptor agonist mediating an anaesthetic effect and an antagonist of the I1 imidazoline receptor for the relief of the anaesthetic effect. The I1 imidazoline receptor antagonist plays the role of an anesthesia antidote by antagonizing the imidazoline receptor, can completely, thoroughly, quickly and efficiently relieve the anesthesia effect mediated by the alpha 2-adrenoceptor agonist, and has stronger awakening effect.
Description
Technical Field
The present invention is in the field of biomedicine and relates to the use of antagonists of the I1 imidazoline receptor (I1R) as antidotes for anesthesia, and in particular to the use as antidotes for α 2-adrenoceptor agonist-mediated anesthesia.
Background
Dexmedetomidine (DEX) is a selective central alpha 2-adrenoceptor agonist approved by the U.S. Food and Drug Administration (FDA) for use in intensive care and medical emergency sedation, anesthesia and analgesia. In china, dexmedetomidine was approved by the national food and drug administration at 6 months 2009 for use in clinical anesthesia and sedation of ICU.
Clinically, if a patient needs to be awakened in time after an operation such as anesthesia or sedation is required, an effective anesthetic antidote that can be used in conjunction with dexmedetomidine is needed.
Disclosure of Invention
In a first aspect of the invention, there is provided the use of an antagonist of the I1 imidazoline receptor for the manufacture of an antidote for the relief of anaesthetic effect mediated by an alpha 2-adrenoceptor agonist, wherein, after anaesthesia with an alpha 2-adrenoceptor agonist and entering a state of anaesthesia, the antagonist of the I1 imidazoline receptor is administered at a time when arousal is required, and wherein the ratio of the dose of administration of the antagonist of the I1 imidazoline receptor to the dose of administration of the alpha 2-adrenoceptor agonist is from 5:6 to 10:3, and the anaesthetic effect mediated by the alpha 2-adrenoceptor agonist is relieved from 10 minutes to 50 minutes after the administration of the antagonist of the I1 imidazoline receptor. The I1 imidazoline receptor antagonist may be efaracter or a prodrug thereof. The alpha 2-adrenoceptor agonist may be dexmedetomidine.
In some embodiments of the first aspect of the present invention, the α 2-adrenoceptor agonist and the I1 imidazoline receptor antagonist are administered by the same administration or by different administrations. The administration mode is selected from: oral administration, intravenous administration, intramuscular administration, intraperitoneal administration and intracavity administration. For example, dexmedetomidine may be administered intramuscularly and efavirulent if arousal is desired.
In a second aspect of the invention, provided herein is a narcotic-wake-up kit comprising an alpha 2-adrenoceptor agonist mediating a narcotic effect and an I1 imidazoline receptor antagonist to relieve the narcotic effect; wherein the antagonist of the I1 imidazoline receptor is efaraxan or a prodrug thereof, and the alpha 2-adrenoceptor agonist is dexmedetomidine.
In some embodiments of the second aspect of the invention, the kit further comprises a pharmaceutically acceptable diluent selected from the group consisting of: normal saline, balanced salt solution, glucose solution and sterile pyrogen-free water.
In some embodiments of the second aspect of the invention, the anesthetic kit further comprises instructions for administration and dosage of an α 2-adrenoceptor agonist and an I1 imidazoline receptor antagonist. For example, the instructions describe administering an α 2-adrenoceptor agonist intramuscularly to a subject in need of anesthesia and, after the subject enters a state of continuous anesthesia, awakening by administering an I1 imidazoline receptor antagonist intravenously when awakening is desired (e.g., after 40 minutes of anesthesia duration), the ratio of the dose of the I1 imidazoline receptor antagonist to the dose of the α 2-adrenoceptor agonist being 5:6 to 10: 3. For example, the instructions describe administering an α 2-adrenoceptor agonist intramuscularly to a subject in need of anesthesia and, after the subject enters a state of continuous anesthesia, awakening by administering an antagonist of the I1 imidazoline receptor intramuscularly when awakening is desired (e.g., after 40 minutes of anesthesia duration), the ratio of the dose of the antagonist of the I1 imidazoline receptor to the dose of the α 2-adrenoceptor agonist being 10: 3. When using this wake-up-anaesthetic kit, the α 2-adrenoceptor agonist-mediated anaesthetic effect is relieved at the time of wake-up upon administration of an I1 imidazoline receptor antagonist, typically 10 to 20 minutes after administration.
Drawings
FIG. 1A shows the spontaneous locomotor distance observed and recorded in mice awakened (i.e., anesthetized) by intravenous injection of 0.5mg/kg efacrigen 10 minutes after the I1 imidazoline receptor knockout mice and wild mice received dexmedetomidine into anesthesia.
Fig. 1B shows the rate of reduction in spontaneous motility distance of I1 imidazoline receptor knockout mice and wild mice.
Fig. 2A shows the wake-up time of the non-administered control group, the administered group, and the positive control group administered with altimezole.
Fig. 2B shows the spontaneous movement distances after arousal of the control group without administration, the group with administration, and the positive control group with administration of altimezole.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following detailed description of various aspects of the present invention is provided with specific examples, which are only used for illustrating the present invention and do not limit the scope and spirit of the present invention.
In the present examples, the use of antagonists of imidazoline receptors as antidotes for anesthesia was demonstrated by observing the spontaneous activity of mice anesthetized with dexmedetomidine after awakening from administration of efaclon as an exemplary example of an imidazoline receptor antagonist, and dexmedetomidine as an exemplary example of a drug mediating anesthetic effects.
The "wake-up time" in the present invention means: the time required for the release of the anesthetic effect, for example, in the case of using only the anesthetic without using an antagonist for an imidazoline receptor, the wake-up time refers to the time required for the anesthetic effect to return to normal activities after the anesthetic effect is naturally metabolized in the subject, i.e., the time required for the release of the anesthetic effect. For example, in the case of a combination of an anesthetic and an imidazoline receptor antagonist, the wake-up time refers to the time required for the subject to resume normal activities following administration of the imidazoline receptor antagonist after the subject has been placed in an anesthetic-sustained state using the anesthetic.
1. Experimental animals:
1.1: c57 mouse, SPF grade, male, initial weight 18-22 g, purchased from sbefu (beijing) biotechnology limited, license number: SCXK (Jing) 2016-0002. Feeding environment (temperature: 22 +/-2 ℃, humidity (40 +/-20)%, 12-hour light and shade cycle (fluorescent lamp illumination is 8: 00-20: 00), freely taking food and drinking water, and feeding with growth maintenance pellet feed.
1.2: i1 Imidazoline receptor (imidazoline receptor) knockout mouse, which is homozygote mouse obtained by using C57BL/6J mouse as background and adopting gene targeting technology. Animals were kept in SPF-rated animal houses with ambient temperature of 22 + -2 deg.C and humidity of (40 + -20)% and were fed water for 12 hours of circadian rhythm and freedom.
Mice with age of about 8-12 months and weight of about 20-40 g were selected for all experiments. The experimental scheme is approved by the ethical committee of experimental animals of the military medical research institute of the national academy of people's liberation military.
The I1 imidacloprid receptor knockout mice and littermate-contrast wild mice are constructed and bred by military medical research institute of military science institute of the people's liberation military sciences of China.
2. Experimental reagent:
dexmedetomidine, purchased from Shandong Bolode Biotech, Inc., diluted to the desired concentration with normal saline when used; efavirenz is purchased from abcam (abcam, usa) and is diluted to the desired concentration with physiological saline at the time of use; atimezole (ATI) is available from haizheng pharmaceutical company, zhejiang.
3. The experimental instrument:
the spontaneous activity case: anlai software technologies ltd (ningbo); LOC-V01 spontaneous activity video trajectory analysis instrument: anlai software technologies ltd (Ningbo).
4. The experimental method comprises the following steps:
spontaneous activity experiments: before the formal experiment, all experimental mice need to adapt to the environment of the spontaneous activity box two days in advance. The mice were placed in an activity box and allowed to move freely for 15min, and the movement time and movement trajectory were recorded. In the official experiment, mice were dosed and recorded for 15min, with experimental times ranging from 9-13 am.
5. The data statistical analysis method comprises the following steps:
the spontaneous locomotor distance of the mice is expressed as Mean ± s.e.m, statistical analysis is performed with GraphPad Prism 6.0 software, and the comparison of spontaneous locomotor distance of locomotor activity between groups is performed by one-way anova combined with Bonferroni post-hoc test. P <0.05 indicates a statistical difference.
Example 1 antagonists of imidazoline receptors relieve dexmedetomidine-mediated anesthetic effects
A panel of I1 imidazoline receptor knock-out mice (KO) and a panel of wild control mice (WT) (9 mice per group) were used. Each mouse was anesthetized by administering 150 μ g/kg dexmedetomidine intramuscularly, 10 minutes after the mouse entered the anesthetized state, the mouse was awakened (i.e., anesthetized) by intravenous injection of 0.5mg/kg efacryn, and the spontaneous activity of the mouse was observed and recorded. As shown in fig. 1A, the spontaneous movement distance of the wild control mouse group is far greater than that of the I1 imidazoline receptor knockout mouse group, which indicates that efacrine exerts the effect of an anesthetic antidote by antagonizing imidazoline receptors, and that efacrine not only relieves the anesthetic effect but also completely relieves the anesthetic effect, and the mice can immediately recover normal movement after awakening, thereby having a strong awakening effect.
Meanwhile, the rate of decrease in spontaneous motility distance of mice was calculated by the following formula:
spontaneous motility distance reduction rate (basal motility-spontaneous motility after administration of efakson to relieve anesthesia)/basal motility 100%
As shown in fig. 1B, the rate of decrease in spontaneous motility distance was greater in the group of I1 imidazoline receptor knock-out mice than in the group of wild mice, which also indicates that efacrine exerts an anesthetic antidote effect by antagonizing imidazoline receptors, and that the anesthetic effect can be completely and completely removed using efacrine, so that mice can immediately recover normal spontaneous motility with strong arousal effect.
Example 3 Wake-Up time for anesthesia relief with antagonists of I1 imidazoline receptors
Wild-type mice were used, each mouse was anesthetized by intramuscular administration of 150 μ g/kg dexmedetomidine, and 10 minutes after the mice entered the anesthetized state, the mice were divided into 5 groups (9 mice per group) as follows:
a. control group: if the efacrigen is not administered, recording the awakening time of the efacrigen;
b. the group was administered with 0.125mg/kg Efaakson (EFA), 0.125mg/kg efaakson was administered by intravenous injection, the time of awakening was recorded, and the spontaneous activity of the mouse was observed after awakening and the distance of activity was recorded;
c. the group is administrated with 0.5mg/kg Efaakson (EFA), 0.5mg/kg efaakson is administrated by intravenous injection, the awakening time is recorded, the spontaneous activity of the mouse is observed after awakening, and the activity distance is recorded;
d. a positive control group administered with 0.125mg/kg Altemezole (ATI), 0.125mg/kg of a commercially available altemezole as an α 2 adrenoreceptor specific antagonist administered by intravenous injection, the time of awakening was recorded, and spontaneous activity of the mice was observed after awakening, and the distance of activity was recorded;
e. a positive control group administered with 0.5mg/kg Altemezole (ATI), 0.5mg/kg of commercial altemezole as an α 2 adrenoreceptor specific antagonist administered by intravenous injection, the time of awakening was recorded, and the spontaneous activity of the mice after awakening was observed and the distance of activity was recorded.
Fig. 2A shows the wake-up time of the non-administered control group, the administered group, and the positive control group. As can be seen from FIG. 2A, the control group, which was not administered, took as long as 300 minutes to release the anesthetic effect and awaken the mice, whereas the administration group and the positive control group, which received the administration of 0.125mg/kg and 0.5mg/kg of efacrigen, took as long as several tens of minutes to rapidly release the anesthetic effect and awaken the mice. It follows that efavirenz is able to rapidly and efficiently relieve dexmedetomidine-mediated anaesthesia, can be used as an antidote for the anaesthetic dexmedetomidine and is comparable in terms of wake-up time to the existing art-known awetozole with a wake-up effect.
Fig. 2B shows the spontaneous movement distance of mice in the dosing group and the positive control group after awakening at different doses. As can be seen from fig. 2B, the spontaneous movement distance of the administration group after awakening is dose-dependent, and the spontaneous movement distance increases with increasing administration dose, which indicates that not only the anesthesia effect can be relieved but also the anesthesia effect can be completely and completely relieved with increasing administration dose of efacrine, and the mice can return to normal movement. The spontaneous motility distance in the positive control group was also dose-dependent, and increased with increasing administered dose, and the spontaneous motility distance of mice administered with efaxotrophy group was higher than that of the positive control group under the condition of administration of the same 0.5mg/kg dose, which indicates that efaxotrophy had a superior arousal effect in view of arousal effect to that of altemezole having an arousal effect known in the art at present.
The experiments show that the antagonist of the I1 imidazoline receptor can quickly and efficiently relieve the anesthetic effect mediated by dexmedetomidine, and can immediately recover normal activities after awakening, so that the antagonist has a strong awakening effect. The antagonist of the I1 imidazoline receptor has important application value in clinic for relieving the anesthesia effect mediated by the alpha 2-adrenergic receptor agonist, after the patient needs to be subjected to surgical treatment in the anesthesia state, medical staff can select the appropriate time after the operation to relieve the anesthesia effect by administering the antagonist of the I1 imidazoline receptor, and observe the state of the patient after awakening in time without waiting for the spontaneous metabolic relief of the anesthesia effect in the body, so that the risk possibly generated by the long time of the anesthesia state and the risk of difficult awakening due to the long time of the anesthesia can be reduced to a certain extent.
The present invention has been described in conjunction with specific embodiments which are intended to be exemplary only and are not intended to limit the scope of the invention, which is to be given the full breadth of the appended claims and any and all modifications, variations or alterations that may occur to those skilled in the art without departing from the spirit of the invention. Therefore, various equivalent changes made according to the present invention still fall within the scope covered by the present invention.
Claims (10)
- Use of an I1 imidazoline receptor antagonist for the preparation of an antidote for the relief of anaesthetic effects mediated by an alpha 2-adrenoreceptor agonist.
- 2. The use of claim 1, wherein the antagonist of the I1 imidazoline receptor is efaracter or a prodrug thereof.
- 3. Use according to claim 1 or 2, wherein the alpha 2-adrenoceptor agonist is dexmedetomidine.
- 4. The use according to any one of claims 1 to 3, wherein the antagonist of the I1 imidazoline receptor is administered when arousal is required after anaesthesia with an alpha 2-adrenoceptor agonist and entering a state of persistence of anaesthesia.
- 5. The use of claim 4 wherein the α 2-adrenoceptor agonist-mediated anesthesia is relieved 10 to 20 minutes after the administration of the I1 imidazoline receptor antagonist.
- 6. The use of claim 4 wherein the α 2-adrenoceptor agonist and the I1 imidazoline receptor antagonist are administered by the same administration or by different administrations.
- 7. The use of claim 6, wherein the administration is selected from the group consisting of: oral administration, intravenous administration, intramuscular administration, intraperitoneal administration and intracavity administration.
- 8. A narcotic-wake kit comprising an alpha 2-adrenoceptor agonist mediating an anaesthetic effect and an I1 imidazoline receptor antagonist to abrogate the anaesthetic effect.
- 9. The kit of claim 8 wherein said antagonist of the I1 imidazoline receptor is efaractene or a prodrug thereof and said α 2-adrenoceptor agonist is dexmedetomidine.
- 10. The kit of claim 8 or 9, further comprising a pharmaceutically acceptable diluent selected from the group consisting of: normal saline, balanced salt solution, glucose solution and sterile pyrogen-free water.
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| CN114984223A (en) * | 2022-05-31 | 2022-09-02 | 中国人民解放军陆军军医大学第二附属医院 | Application of growth hormone secretagogue receptor antagonist in preparation of inhalation anesthetic resuscitation preparation |
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| US20200261422A1 (en) * | 2019-02-15 | 2020-08-20 | Massachusetts Institute Of Technology | Methods for evaluating treatments and physiology in human patients using intravenous alpha-2 adrenergic antagonist agents |
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|---|---|---|---|---|
| US20200261422A1 (en) * | 2019-02-15 | 2020-08-20 | Massachusetts Institute Of Technology | Methods for evaluating treatments and physiology in human patients using intravenous alpha-2 adrenergic antagonist agents |
Non-Patent Citations (2)
| Title |
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| NANA SATO 等: "Imidazoline 1 receptor activation preserves respiratory drive in spontaneously breathing newborn rats during dexmedetomidine administration", 《PEDIATRIC ANESTHESIA》 * |
| 杨志芳: "I1咪唑啉受体对α2A肾上腺素受体功能的影响及其机制研究", 《中国优秀博硕士学位论文全文数据库(硕士) 医药卫生科技辑》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114984223A (en) * | 2022-05-31 | 2022-09-02 | 中国人民解放军陆军军医大学第二附属医院 | Application of growth hormone secretagogue receptor antagonist in preparation of inhalation anesthetic resuscitation preparation |
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