Application of ferritin in preparation of anesthetic antagonist
By using whole ferroferrin to specifically interact with inhaled anesthetics, the problem of lack of effective antagonists in the prior art is solved, and rapid awakening and safety improvement after anesthesia is achieved.
Patent Information
- Application Number
- CN202510216678.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-26
- Publication Date
- 2025-04-08
AI Technical Summary
The prior art lacks effective inhaled antagonists, resulting in serious side effects after anesthesia and long wake-up time, which increases the patient's medical expenses and surgical turnover time.
Total ferroferrin is used as an antagonist of anesthetics, and the antagonism effect on anesthetics is achieved by specifically interacting with inhaled anesthetics such as isoflurane and heptaflurane.
It significantly shortens the awakening time of mice after anesthesia, improves the safety and comfort of anesthesia, and reduces the patient's stay time and medical expenses.
Smart Images
Figure CN119770623A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of anesthetic antagonists, and particularly relates to the application of ferritin in the preparation of anesthetic antagonists. Background Art
[0002] Inhalation anesthetics are a type of volatile liquid / gas that is inhaled into the lungs through the respiratory tract, absorbed into the blood circulation through the alveolar capillaries, and reaches the central nervous system, producing sedation, loss of consciousness, immobilization, and a certain smooth muscle and skeletal muscle relaxation effect. It has the characteristics of strong anesthetic efficacy, high controllability, and easy use. It is widely used in the induction of general anesthesia, especially in the maintenance of anesthesia.
[0003] Although inhalation anesthetics are becoming more and more common, their side effects cannot be ignored. The main side effects of inhalation anesthetics include: postoperative nausea and vomiting, agitation / delirium during recovery, chills after anesthesia, arrhythmia, malignant hyperthermia and neurotoxicity. In order to improve the safety and comfort of inhalation general anesthesia, these side effects must be faced and overcome in the clinical use of inhalation anesthetics, but there is still no antagonist for inhalation anesthetics.
[0004] Although inhaled anesthetics have been used and developed for more than 170 years, the exact molecular mechanism of action of general anesthetics is still unclear, which is one of the 125 most important and urgent basic scientific problems in the 21st century. At present, studies have reported that multiple sites such as TASK channels, HCN channels, and GABAA receptors are the targets of inhaled anesthetics, but no single theory can fully explain the overall pharmacological phenomena of inhaled anesthetics. Nevertheless, with the development of anesthesiology, the mortality rate of general anesthesia in developed countries has dropped to one in 200,000-300,000. On the other hand, the toxic and side effects of general anesthetics are still a problem that cannot be ignored, especially for patients with serious conditions, very young or elderly patients. Because the targets and mechanisms of action of inhaled anesthetics are unclear, target-based antagonist design cannot be achieved. At present, there is still a lack of effective antagonists for inhaled anesthetics commonly used in clinical practice. Summary of the invention
[0005] In view of the defects of the prior art, the purpose of the present invention is to provide a protein that can specifically bind to inhaled anesthetics and have an antagonistic effect on inhaled general anesthesia, so as to improve the safety of implementing inhaled general anesthesia, reduce the side effects of drugs, shorten the patient's stay in the operating room and post-anesthesia recovery room, increase the patient's comfort, reduce the patient's medical expenses, and further improve the work efficiency of surgical and anesthesia medical staff.
[0006] In order to achieve the above object, the present invention provides the use of ferritin in the preparation of anesthetic antagonist products.
[0007] Furthermore, the ferritin is holoferritin.
[0008] Furthermore, the anesthetic comprises an inhaled anesthetic.
[0009] Furthermore, the inhalation anesthetic comprises a fluorinated inhalation anesthetic.
[0010] Furthermore, the fluorinated inhalation anesthetic includes isoflurane or sevoflurane.
[0011] As shown in the embodiments of the present invention, ferritin can antagonize fluorinated inhaled anesthetics in mice and shorten the recovery time of mice under general anesthesia. Specifically, the present invention found that holoferritin can significantly shorten the recovery time of mice that inhaled 1.69% isoflurane for 3 hours, and the higher the dose of ferritin, the shorter the recovery time. When the dose of ferritin is 540 μg / g, the recovery time is shortened by half.
[0012] Studies have shown that the time for adult patients to recover from sevoflurane anesthesia is 6-17.8 minutes, and the time they stay in the post-anesthesia care unit (PACU) is 56-166 minutes. The time for adult patients to recover from desflurane anesthesia is 4.7-11.3 minutes, and the time they stay in the PACU is 56-143 minutes. The time for adult patients to recover from desflurane anesthesia is relatively long, at 7-20.5 minutes, and the time they stay in the PACU is 157-184 minutes. The data show a certain range of fluctuations due to the different patients included in different studies, the length of surgery and anesthesia time.
[0013] Delayed recovery after general anesthesia is considered when consciousness is not restored for more than 90 minutes after the cessation of general anesthesia. A large number of studies have confirmed that delayed recovery is closely related to postoperative pain, postoperative nausea and vomiting, wound healing, and length of hospital stay. The new generation of fluorinated inhalation anesthetics can help patients recover faster after discontinuation of the drug, but the recovery time will be prolonged in cases of long-term inhalation, low ventilation, and low cardiac output. In addition, the residual inhalation anesthetics during the recovery period will also produce a synergistic effect with the residual opioids and muscle relaxants, promoting the residual effects of these anesthetics and prolonging the patient's recovery time. Delayed recovery after general anesthesia will increase the risk of recovery, prolong the patient's stay in the operating room and PACU, and increase the toxic effects of residual anesthetics, thereby delaying surgical turnover and increasing patients' medical expenses.
[0014] Therefore, the contribution of the present invention to the art is at least to provide an antagonist drug for inhaled anesthetics to solve the above-mentioned problems.
[0015] Beneficial effects of the present invention:
[0016] The present invention finds that ferritin can produce an antagonistic effect on anesthetics, and the present invention realizes the application of ferritin in the preparation of anesthetic antagonist products. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 Results of an ITC experiment of isoflurane titration of ferritin.
[0018] Figure 2 The results of the ITC experiment of sevoflurane titration of ferritin.
[0019] Figure 3 The figure is a crystal of holoferritin and a structural diagram of its complex with isoflurane and sevoflurane, wherein, Part A: the crystal of holoferritin; Part B: the 24-mer nanocage structure of holoferritin; Part C: the binding site of isoflurane and holoferritin, wherein the binding site is located between two ferritin molecules and is displayed as a rod; Part D: the electron density map of isoflurane, in which the circles indicate the electron density of the isoflurane molecules; Part E: the electron density map of sevoflurane, in which the circles indicate the electron density of the sevoflurane molecules.
[0020] Figure 4 This figure shows the effect of ferritin on the recovery time of mice from isoflurane inhalation anesthesia. DETAILED DESCRIPTION
[0021] The present invention is described in detail below through examples. It is necessary to point out that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by technical personnel in this field based on the above invention content still fall within the scope of protection of the present invention.
[0022] Example 1
[0023] An isoflurane inhalation general anesthesia model was established in mice. Different doses of candidate proteins were injected during anesthesia. The recovery time of the righting reflex of mice was recorded and compared with that of mice that were not injected with the initial screening candidate proteins.
[0024] a. Model establishment: Adult male C57BL / 6 mice were selected. On the day of the experiment, the mice were given 1.69% (1.3 MAC, the concentration was selected according to the pre-experimental awakening time) isoflurane + 50% oxygen. The gas flow rate during induction was 2 L / min. When the exhaled isoflurane concentration reached 1.69% and was balanced for 15 minutes, the timing was started. The inhalation continued for 3 hours, and the gas flow rate was maintained at 1 L / min. During the experiment, the animals were kept warm with electric blankets.
[0025] b. Grouping: The mice were randomly divided into a control group and an experimental group. The mice in the experimental group were given tail vein injection of different doses of the primary screening candidate protein at the end of anesthesia, while the mice in the control group were given tail vein injection of an equal volume of normal saline at the end of anesthesia.
[0026] c. Observe the righting reflex (awakening) recovery time of mice after inhalation anesthesia, and make statistical comparison between the two groups.
[0027] like Figure 1 As shown, the inventors used isothermal titration microcalorimetry (ITC) experiments to preliminarily confirm that there is a relatively strong specific interaction between holoferritin and fluorinated inhaled anesthetics (isoflurane and sevoflurane) (see Figure 1 and Figure 2 shown).
[0028] Through crystal screening experiments, the inventors obtained the crystals of all-ferritin (see Figure 3 The crystal structure of the holoferritin-isoflurane complex was also obtained by the immersion method. Holoferritin is a 24-mer cage structure (see Figure 3 B), an isoflurane molecule binds in the binding pocket between two ferritins (see Figure 3 The electron density of isoflurane is shown in Figure 3 As shown in part D of FIG. , we have also solved the crystal structure of the complex of holoferritin and sevoflurane, as shown in FIG. Figure 3 As shown in the middle part E, sevoflurane and isoflurane bind to the same site, which indicates that the coordination number between holoferritin and isoflurane / sevoflurane is 0.5, that is, 2 ferritin molecules bind to 1 isoflurane / sevoflurane molecule.
[0029] Based on the discovery that holoferritin can bind to isoflurane, in order to test whether holoferritin can play an antagonistic effect on fluorinated inhaled anesthetics, the inventors conducted a mouse general anesthesia recovery experiment using mice. The results showed that holoferritin can significantly shorten the recovery time of mice that inhaled 1.69% (1.3MAC) isoflurane for 3 hours, and the higher the dose of ferritin, the shorter the recovery time. When the dose of ferritin was 540μg / g, the recovery time was shortened by half (52.5%) (see Figure 4 ). This result suggests that ferritin may bind to free anesthetic molecules in plasma and show an antagonistic effect on inhaled anesthetics. Therefore, this protein molecule that can bind to anesthetics has the potential to become an antagonist of systemic inhaled anesthetics.
Claims
1. Application of ferritin in the preparation of anesthetic antagonists.
2. The use according to claim 1, characterized in that: The ferritin is holoferritin.
3. The use according to claim 1 or 2, characterized in that: The anesthetics include inhaled anesthetics.
4. The use according to claim 3, characterized in that: The inhalation anesthetics include fluorinated inhalation anesthetics.
5. The use according to claim 4, characterized in that: The fluorinated inhalation anesthetic includes isoflurane or sevoflurane.