Contrast agent for enhancing the effect of elca volume reduction

Abstract

The application discloses a contrast agent for enhancing the effect of ELCA volume reduction, and belongs to the field of medical reagents, and particularly relates to a contrast agent which comprises a heparin-based compound and a contrast agent, wherein the heparin-based compound comprises heparin, and the content of the heparin-based compound in the contrast agent is 2-64 mu g / mL. The contrast agent comprises at least one of iopromide and iodixanol. The heparin-based compound further comprises a heparin derivative, and the heparin derivative is prepared by subjecting heparin to oxidation and then to reaction with a derivatizing agent. The derivatizing agent comprises L-alanyl-L-proline methyl ester hydrochloride. The application is a contrast agent which can be combined with ELCA, enhances the effect of ELCA volume reduction, has a good effect on blood vessel plaque erosion, and has high shock wave pressure when combined with excimer laser.

Description

Technical Field

[0001] This invention belongs to the field of medical reagents, specifically relating to a contrast agent for enhancing the volume reduction effect of ELCA. Background Technology

[0002] With continuous advancements in equipment and technology, excimer laser coronary atherectomy (ELCA) has garnered significant attention in the treatment of coronary heart disease. Currently, the excimer laser used clinically is a xenon chloride pulsed laser with a wavelength of 308 nm. This technique primarily utilizes the synergistic effects of photochemical, photothermal, and photomechanical processes to ablate atherosclerotic plaques within the coronary arteries, thereby reducing plaque volume and facilitating subsequent balloon dilation and stent placement, ultimately optimizing surgical outcomes.

[0003] The erosive effect of ELCA on intravascular plaques is affected by different fluid media. Early ELCA in coronary artery disease treatment was performed directly in the bloodstream, often using large-diameter laser fiber catheters, which increased the risk of dissection and perforation. Although saline injection significantly reduced the occurrence of serious complications such as dissection and perforation, it also reduced the therapeutic efficacy of ELCA. Summary of the Invention

[0004] The purpose of this invention is to provide a contrast agent that can be used in combination with ELCA to enhance the volume reduction effect of ELCA, has a good effect on vascular plaque ablation, and has high shock wave pressure when used with excimer laser.

[0005] The technical solution adopted by the present invention to achieve the above objectives is as follows:

[0006] A contrast agent comprises a heparin-based compound and a contrast agent, wherein the heparin-based compound includes heparin, and the concentration of the heparin-based compound in the contrast agent is 2-64 μg / mL. When ELCA combined with contrast agent injection is used to treat ISR, the no-reflow rate is as high as 17.9%. This invention improves the ablation effect on vascular plaques by using a heparin-based compound, verapamil, nitroglycerin, and / or a contrast agent together as a contrast agent in conjunction with an excimer laser, and the contrast agent interacts with the excimer laser to generate high shock wave pressure.

[0007] Preferably, the contrast agent also includes physiological saline.

[0008] Preferably, the heparin-based compound includes a heparin derivative, which is prepared by first oxidizing heparin and then reacting it with a derivatizing agent, including L-alanyl-L-proline methyl ester hydrochloride. In this invention, L-alanyl-L-proline methyl ester hydrochloride can also be used to derivatize heparin derivatives obtained from oxidized heparin. The heparin derivative needs to be used in conjunction with verapamil, nitroglycerin, and / or a contrast agent. The heparin derivative, verapamil, and nitroglycerin need to be used within a certain dosage range; the dosage does not need to be too high to achieve excellent plaque ablation effects on blood vessels and high shock wave pressure when the contrast agent containing the heparin derivative interacts with the excimer laser.

[0009] Preferably, the contrast agent includes at least one of iopromide and iodixanol.

[0010] Preferably, the contrast agent also includes verapamil and / or nitroglycerin.

[0011] Preferably, the content of verapamil in the contrast agent is 0.2-6.4 μg / mL.

[0012] Preferably, the content of nitroglycerin in the contrast agent is 0.02-0.64 μg / mL.

[0013] This invention discloses a method for preparing a contrast agent, wherein a mixture is mixed with a contrast agent injection solution to obtain a contrast agent. The mixture contains a heparin-based compound, and the contrast agent injection solution contains at least one of iopromide and iodixanol. The content of the heparin-based compound in the contrast agent is 2-64 μg / mL.

[0014] Preferably, the mixture and the contrast agent injection solution are mixed at a volume ratio of 1:0.25-4.

[0015] Preferably, the mixture is obtained by adding heparin-based compounds, verapamil, and nitroglycerin to physiological saline.

[0016] Preferably, the contrast agent injection solution is obtained by adding contrast agent to physiological saline.

[0017] Preferably, in the preparation of the contrast agent, heparin-based compound, verapamil and nitroglycerin are added to physiological saline to obtain a mixture, and then contrast agent injection solution is added and mixed to obtain the contrast agent.

[0018] More preferably, in the preparation of the contrast agent, the heparin-based compound is heparin, and the content of heparin in the mixture is 10-80 μg / mL.

[0019] More preferably, in the preparation of the contrast agent, the content of verapamil in the mixture is 1-8 μg / mL.

[0020] More preferably, in the preparation of the contrast agent, the content of nitroglycerin in the mixture is 0.1-0.8 μg / mL.

[0021] More preferably, in the preparation of the contrast agent, the contrast agent injection solution is iopromide injection solution, which is obtained by mixing iopromide with physiological saline, and the content of iopromide in the iopromide injection solution is 20-80 wt%.

[0022] More preferably, in the preparation of the contrast agent, the contrast agent injection solution is iodixanol injection solution, which is obtained by mixing iodixanol with physiological saline, and the content of iodixanol in the iodixanol injection solution is 20-80 wt%.

[0023] More preferably, in the preparation of the contrast agent, the mixture and the contrast agent injection solution are mixed in a volume ratio of 1:0.25-4.

[0024] Preferably, the heparin-based compound includes a heparin derivative, and the preparation of the heparin derivative includes the preparation of oxidized heparin.

[0025] Preferably, in the preparation of heparin oxidase, sodium heparin is added to deionized water to obtain a sodium heparin solution, then a mixed acid salt is added, and the reaction is carried out at 20-40℃ for 10-30 min. After the reaction is completed, the pH is adjusted to 8-9, dialyzed, and then freeze-dried to obtain heparin oxidase.

[0026] More preferably, in the preparation of oxidized heparin, the amount of sodium heparin used is 1-5 wt% of deionized water.

[0027] More preferably, in the preparation of heparin oxidase, the mixed acid salt is composed of sulfuric acid, sodium nitrite and water, wherein the sulfuric acid content in the mixed acid salt is 0.1-1M and the sodium nitrite content in the mixed acid salt is 3-10M.

[0028] More preferably, in the preparation of oxidized heparin, the amount of mixed acid salt used is 300-500 wt% of the heparin sodium solution.

[0029] Preferably, in the preparation of heparin derivatives, heparin oxide and a derivatizing agent are mixed in a dimethylene sulfoxide solution, then triethylamine is added, and the reaction is carried out at 40-80°C for 2-10 hours. After the reaction is completed, acetone is added to precipitate the product, which is then washed and dried to obtain the heparin derivative.

[0030] More preferably, in the preparation of heparin derivatives, the dimethylene sulfoxide solution is prepared by mixing dimethylene sulfoxide and deionized water, wherein the dimethylene sulfoxide and deionized water are mixed in a volume ratio of 1:0.1-10.

[0031] More preferably, in the preparation of heparin derivatives, the amount of heparin oxide used is 10-30 wt% of the dimethylene sulfoxide solution.

[0032] More preferably, in the preparation of heparin derivatives, the derivatizing agent is L-alanyl-L-proline methyl ester hydrochloride, and the amount of L-alanyl-L-proline methyl ester hydrochloride used is 10-30 wt% of oxidized heparin.

[0033] More preferably, in the preparation of heparin derivatives, the amount of triethylamine used is 1-10 wt% of heparin oxidase.

[0034] More preferably, in the preparation of heparin derivatives, an appropriate amount of acetone is used to precipitate the product.

[0035] More preferably, in the preparation of heparin derivatives, valine may also be added to the derivatizing agent, with the amount of valine used being 1-20 wt% of oxidized heparin. When the derivatizing agent derivatizes oxidized heparin, valine and L-alanyl-L-proline methyl ester hydrochloride may also be used together. After the heparin-based compound obtained by derivatizing oxidized heparin with valine and L-alanyl-L-proline methyl ester hydrochloride is used together with verapamil, nitroglycerin, and / or contrast agents, the ablation effect on vascular plaques can be further improved, and the contrast agent containing this heparin derivative exhibits higher shock wave pressure when interacting with excimer lasers.

[0036] This invention discloses the use of heparin-based compounds and contrast agents in the preparation of contrast agents used in conjunction with ELCA.

[0037] This invention utilizes a contrast agent prepared by mixing a heparin-based compound, verapamil, and nitroglycerin in physiological saline, followed by the addition of a contrast agent. The contrast agent includes iopromide or iodixanol, with at least one of iopromide and iodixanol. The heparin-based compound also includes a heparin derivative, prepared by oxidizing heparin followed by a derivatizing agent reaction, including L-alanyl-L-proline methyl ester hydrochloride. Therefore, it possesses the following beneficial effects: it can be used in ELCA (Elastic Endovascular Cataract Surgery), can ablate vascular plaques, and exhibits high shock wave pressure when interacting with excimer lasers. Thus, this invention provides a contrast agent that can be used in combination with ELCA, enhances the volume reduction effect of ELCA, has a good ablation effect on vascular plaques, and exhibits high shock wave pressure when interacting with excimer lasers. Attached Figure Description

[0038] Figure 1 This is a schematic diagram of a laser ablation experiment.

[0039] Figure 2 This is an infrared spectrum.

[0040] Figure 3 This is a map showing the area of ​​erosion removal in the plaque.

[0041] Figure 4This is a shock wave pressure diagram. Detailed Implementation

[0042] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0043] The concepts involved in this application will first be described with reference to the accompanying drawings. It should be noted that the following descriptions of various concepts are only for the purpose of making the content of this application easier to understand and do not constitute a limitation on the scope of protection of this application; furthermore, the embodiments and features in the embodiments of this application can be combined with each other unless otherwise specified. This application will now be described in detail with reference to the accompanying drawings and embodiments.

[0044] The research content of this invention is as follows:

[0045] 1.1 Excimer Laser System

[0046] This invention utilizes a CVX-300 excimer laser system (Spectranetics, Colorado Springs, CO, USA), which emits a xenon chloride excimer laser with an emission wavelength of 308 nm and a pulse duration of 135 ns. The concentrically designed laser guide used can deliver a maximum energy density of 80 mJ / mm². 2 The pulse frequency is 80 Hz. After the laser emitter has been powered on and warmed up for 5 minutes, the parameters are calibrated using a standard laser fiber optic conduit.

[0047] 1.2 Vascular plaque model

[0048] Given the scarcity of human specimens, this invention uses chicken sausage as a vascular plaque model. The main components of the vascular plaque model include 15.6 g of carbohydrates, 10.4 g of fat, 57 mg of cholesterol, 14 g of protein, and 9 mg of calcium per 100 g. The model measures 35 mm in length and 16 mm in diameter, and a lumen is formed using a 1.8 mm diameter puncture needle.

[0049] 1.3 Contrast Agent

[0050] The contrast agents used in this invention are iodixanol (GE Healthcare, Chicago, IL, USA) and iopromide (Ultravist, Bayer Healthcare Co., LTD).

[0051] 1.4 Optical coherence tomography (OCT)

[0052] This invention employs an OCT system (C7XR; ILUMIENTMOptis™; St. Abbott Medical, Chicago, IL, USA) to examine plaque models. During the OCT examination, a 2.7 F imaging catheter is introduced into the lumen along the sheath and exits distally. The automatic retraction speed is set to 18 mm / s, and the scanning frequency is 100 frames / s. Simultaneously, contrast agent is injected into the sheath to purge gas from the lumen, obtaining clear images to complete the OCT detection. In OCT image analysis, after obtaining a 35 mm long lumen image, 10 mm regions at the proximal and distal ends are removed. Quantitative analysis is performed on each frame of the middle 15 mm image to calculate the average lumen area.

[0053] 1.5 Shock wave pressure monitoring

[0054] A hydrophone is a device for measuring shock wave pressure. It employs a piezoelectric sensing element to detect and capture the shock wave pressure generated by an excimer laser in a liquid, converting it into a voltage output proportional to the corresponding pressure. This invention uses the RHSA-30 hydrophone, which operates in the range of 20 Hz to 20 kHz and has a receiving sensitivity of -172 dB. The hydrophone is non-directional in the horizontal plane but exhibits (±2) dB directivity in the vertical plane (50 Hz, 240°).

[0055] 1.6 Oscilloscope

[0056] An oscilloscope is an electronic measuring instrument used to visualize and quantify the waveform of electrical signals, converting them into observable waveforms while automatically calculating relevant voltage values. This invention uses a Tektronix TDS7104 digital oscilloscope with an analog bandwidth of 1 GHz and a sampling rate of 10 GS / s.

[0057] 1.7 Laser ablation experiment

[0058] A trimmed 6 Fr radial artery sheath was connected to the plaque model, such as Figure 1 As shown. The lumen of the plaque model was filled with physiological saline via a sheath, and OCT examination was performed to record the baseline mean lumen area. Subsequently, the model was ablated using a parameter-corrected 0.9 mm laser fiber catheter, with the laser emission flux set to 80 mJ / mm². 2The pulse repetition frequency was 80 Hz. The catheter was advanced at an average speed of 0.5 mm / s. Simultaneously with laser ablation, contrast agent was injected into the catheter through the radial artery sheath at a rate of 1 ml / s. The first ablation was completed when the laser fiber catheter had completely passed through the lumen. An OCT examination was immediately performed on the lumen, and the average lumen area after the first ablation was recorded. The second and third ablation processes were performed using the same procedure, and the lumen areas after the second and third ablation processes were recorded. One set of laser ablation experiments was completed.

[0059] 1.8 Statistical Analysis

[0060] Data were analyzed using SPSS 28.0 statistical software (IBM, Armonk, NY, USA). For continuous variables, the Kolmogorov-Smirnov normality test was performed, and normally distributed data were expressed as mean ± standard deviation. One-way ANOVA was used for comparisons among multiple groups, followed by post-hoc analysis using the LSD test. The correlation between variables was assessed using the Pearson correlation test, and correlation coefficients (r) were calculated. A p-value < 0.05 was considered statistically significant.

[0061] Example 1: A contrast agent for enhancing the volume reduction effect of ELCA

[0062] Preparation of contrast agent: Heparin, verapamil, and nitroglycerin were added to physiological saline to obtain a mixture, and then iopromide injection was added and mixed to obtain the contrast agent. The heparin content in the mixture was 40 μg / mL, the verapamil content was 4 μg / mL, and the nitroglycerin content was 0.4 μg / mL. Iopromide injection was obtained by mixing iopromide with physiological saline, and the iopromide content in the iopromide injection was 30 wt%. The mixture and iopromide injection were mixed at a volume ratio of 1:1.

[0063] Example 2: A contrast agent for enhancing the volume reduction effect of ELCA

[0064] Preparation of contrast agent: Heparin, verapamil, and nitroglycerin were added to physiological saline to obtain a mixture, and then iodixanol injection was added and mixed to obtain the contrast agent. The heparin content in the mixture was 40 μg / mL, the verapamil content was 4 μg / mL, and the nitroglycerin content was 0.4 μg / mL. Iodixanol injection was obtained by mixing iodixanol with physiological saline, and the iodixanol content in the iodixanol injection was 30 wt%. The mixture and iodixanol injection were mixed at a volume ratio of 1:1.

[0065] Example 3: A contrast agent for enhancing the volume reduction effect of ELCA

[0066] The difference between this embodiment and Embodiment 1 is that heparin is replaced with a heparin derivative.

[0067] Preparation of oxidized heparin: Sodium heparin was added to deionized water to obtain a sodium heparin solution. Then, a mixed acid salt was added, and the mixture was reacted at 30°C for 20 min. After the reaction was complete, the pH was adjusted to 8.5, dialyzed, and then lyophilized to obtain oxidized heparin. The amount of sodium heparin used was 3 wt% of the deionized water. The mixed acid salt was composed of sulfuric acid, sodium nitrite, and water. The sulfuric acid content in the mixed acid salt was 0.5 M, the sodium nitrite content was 5.5 M, and the amount of the mixed acid salt used was 400 wt% of the sodium heparin solution.

[0068] Preparation of heparin derivatives: Heparin oxidase and a derivatizing agent were mixed in a dimethylene sulfoxide solution, and then triethylamine was added. The reaction was carried out at 60°C for 6 hours. After the reaction was completed, acetone was added to precipitate the product, which was then washed and dried to obtain the heparin derivative. The dimethylene sulfoxide solution was prepared by mixing dimethylene sulfoxide and deionized water in a 1:1 volume ratio. The amount of heparin oxidase used was 20 wt% of the dimethylene sulfoxide solution. The derivatizing agent was L-alanyl-L-proline methyl ester hydrochloride, which was used in an amount equal to 20 wt% of the heparin oxidase. Triethylamine was used in an amount equal to 5 wt% of the heparin oxidase. A suitable amount of acetone was added to precipitate the product.

[0069] Example 4: A contrast agent for enhancing the volume reduction effect of ELCA

[0070] The difference between this embodiment and Embodiment 2 is that heparin is replaced with a heparin derivative.

[0071] Preparation of oxidized heparin: Sodium heparin was added to deionized water to obtain a sodium heparin solution. Then, a mixed acid salt was added, and the mixture was reacted at 30°C for 20 min. After the reaction was complete, the pH was adjusted to 8.5, dialyzed, and then lyophilized to obtain oxidized heparin. The amount of sodium heparin used was 3 wt% of the deionized water. The mixed acid salt was composed of sulfuric acid, sodium nitrite, and water. The sulfuric acid content in the mixed acid salt was 0.5 M, the sodium nitrite content was 5.5 M, and the amount of the mixed acid salt used was 400 wt% of the sodium heparin solution.

[0072] Preparation of heparin derivatives: Heparin oxidase and a derivatizing agent were mixed in a dimethylene sulfoxide solution, and then triethylamine was added. The reaction was carried out at 60°C for 6 hours. After the reaction was completed, acetone was added to precipitate the product, which was then washed and dried to obtain the heparin derivative. The dimethylene sulfoxide solution was prepared by mixing dimethylene sulfoxide and deionized water in a 1:1 volume ratio. The amount of heparin oxidase used was 20 wt% of the dimethylene sulfoxide solution. The derivatizing agent was L-alanyl-L-proline methyl ester hydrochloride, which was used in an amount equal to 20 wt% of the heparin oxidase. Triethylamine was used in an amount equal to 5 wt% of the heparin oxidase. A suitable amount of acetone was added to precipitate the product.

[0073] Example 5: A contrast agent for enhancing the volume reduction effect of ELCA

[0074] The difference between this embodiment and Embodiment 1 is that heparin is replaced with a heparin derivative.

[0075] Preparation of oxidized heparin: Sodium heparin was added to deionized water to obtain a sodium heparin solution. Then, a mixed acid salt was added, and the mixture was reacted at 30°C for 20 min. After the reaction was complete, the pH was adjusted to 8.5, dialyzed, and then lyophilized to obtain oxidized heparin. The amount of sodium heparin used was 3 wt% of the deionized water. The mixed acid salt was composed of sulfuric acid, sodium nitrite, and water. The sulfuric acid content in the mixed acid salt was 0.5 M, the sodium nitrite content was 5.5 M, and the amount of the mixed acid salt used was 400 wt% of the sodium heparin solution.

[0076] Preparation of heparin derivatives: Heparin oxidase and a derivatizing agent were mixed in a dimethylene sulfoxide solution, and then triethylamine was added. The reaction was carried out at 60°C for 6 hours. After the reaction was completed, acetone was added to precipitate the product, which was then washed and dried to obtain the heparin derivative. The dimethylene sulfoxide solution was prepared by mixing dimethylene sulfoxide and deionized water in a 1:1 volume ratio. The amount of heparin oxidase used was 20 wt% of the dimethylene sulfoxide solution. The derivatizing agents were L-alanyl-L-proline methyl ester hydrochloride and valine. The amount of L-alanyl-L-proline methyl ester hydrochloride was 20 wt% of the heparin oxidase, the amount of valine was 10 wt% of the heparin oxidase, and the amount of triethylamine was 5 wt% of the heparin oxidase. A suitable amount of acetone was added to precipitate the product.

[0077] Example 6: A contrast agent for enhancing the volume reduction effect of ELCA

[0078] The difference between this embodiment and Embodiment 2 is that heparin is replaced with a heparin derivative.

[0079] Preparation of oxidized heparin: Sodium heparin was added to deionized water to obtain a sodium heparin solution. Then, a mixed acid salt was added, and the mixture was reacted at 30°C for 20 min. After the reaction was complete, the pH was adjusted to 8.5, dialyzed, and then lyophilized to obtain oxidized heparin. The amount of sodium heparin used was 3 wt% of the deionized water. The mixed acid salt was composed of sulfuric acid, sodium nitrite, and water. The sulfuric acid content in the mixed acid salt was 0.5 M, the sodium nitrite content was 5.5 M, and the amount of the mixed acid salt used was 400 wt% of the sodium heparin solution.

[0080] Preparation of heparin derivatives: Heparin oxidase and a derivatizing agent were mixed in a dimethylene sulfoxide solution, and then triethylamine was added. The reaction was carried out at 60°C for 6 hours. After the reaction was completed, acetone was added to precipitate the product, which was then washed and dried to obtain the heparin derivative. The dimethylene sulfoxide solution was prepared by mixing dimethylene sulfoxide and deionized water in a 1:1 volume ratio. The amount of heparin oxidase used was 20 wt% of the dimethylene sulfoxide solution. The derivatizing agents were L-alanyl-L-proline methyl ester hydrochloride and valine. The amount of L-alanyl-L-proline methyl ester hydrochloride was 20 wt% of the heparin oxidase, the amount of valine was 10 wt% of the heparin oxidase, and the amount of triethylamine was 5 wt% of the heparin oxidase. A suitable amount of acetone was added to precipitate the product.

[0081] Comparative Example 1: A contrast agent for enhancing the volume reduction effect of ELCA

[0082] The difference between this embodiment and Embodiment 1 is that heparin is replaced with oxyheparin.

[0083] Preparation of oxidized heparin: Sodium heparin was added to deionized water to obtain a sodium heparin solution. Then, a mixed acid salt was added, and the mixture was reacted at 30°C for 20 min. After the reaction was complete, the pH was adjusted to 8.5, dialyzed, and then lyophilized to obtain oxidized heparin. The amount of sodium heparin used was 3 wt% of the deionized water. The mixed acid salt was composed of sulfuric acid, sodium nitrite, and water. The sulfuric acid content in the mixed acid salt was 0.5 M, the sodium nitrite content was 5.5 M, and the amount of the mixed acid salt used was 400 wt% of the sodium heparin solution.

[0084] Comparative Example 2: A contrast agent for enhancing the volume reduction effect of ELCA

[0085] The difference between this embodiment and Embodiment 2 is that heparin is replaced with oxyheparin.

[0086] Preparation of oxidized heparin: Sodium heparin was added to deionized water to obtain a sodium heparin solution. Then, a mixed acid salt was added, and the mixture was reacted at 30°C for 20 min. After the reaction was complete, the pH was adjusted to 8.5, dialyzed, and then lyophilized to obtain oxidized heparin. The amount of sodium heparin used was 3 wt% of the deionized water. The mixed acid salt was composed of sulfuric acid, sodium nitrite, and water. The sulfuric acid content in the mixed acid salt was 0.5 M, the sodium nitrite content was 5.5 M, and the amount of the mixed acid salt used was 400 wt% of the sodium heparin solution.

[0087] Comparative Example 3: A contrast agent for enhancing the volume reduction effect of ELCA

[0088] The difference between this embodiment and Embodiment 1 is that heparin is replaced with a heparin derivative.

[0089] Preparation of contrast agent: Heparin derivative, verapamil, and nitroglycerin were added to physiological saline to obtain a mixture, and then iopromide injection was added and mixed to obtain the contrast agent. The content of heparin derivative in the mixture was 5 μg / mL, the content of verapamil in the mixture was 4 μg / mL, and the content of nitroglycerin in the mixture was 0.4 μg / mL. Iopromide injection was obtained by mixing iopromide with physiological saline, and the content of iopromide in the iopromide injection was 20-80 wt%. The mixture and iopromide injection were mixed at a volume ratio of 1:1.

[0090] Comparative Example 4: A contrast agent for enhancing the volume reduction effect of ELCA

[0091] The difference between this embodiment and Embodiment 2 is that heparin is replaced with a heparin derivative.

[0092] Preparation of contrast agent: Heparin derivative, verapamil, and nitroglycerin were added to physiological saline to obtain a mixture, and then iodixanol injection was added and mixed to obtain the contrast agent. The content of heparin derivative in the mixture was 5 μg / mL, the content of verapamil in the mixture was 4 μg / mL, and the content of nitroglycerin in the mixture was 0.4 μg / mL. Iodixanol injection was obtained by mixing iodixanol with physiological saline, and the content of iodixanol injection was 20-80 wt%. The mixture and iodixanol injection were mixed at a volume ratio of 1:1.

[0093] Experimental example:

[0094] The heparin derivatives prepared in Example 3 were characterized by infrared spectroscopy, and the results are as follows: Figure 2 As shown, at 1682cm -1 The infrared absorption peak for the carbonyl group is at 1609 cm⁻¹. -1 The infrared absorption peak at the point where the carbon-nitrogen double bond is located indicates that a heparin derivative has been obtained.

[0095] This invention uses the vascular plaque model from the aforementioned study to conduct laser ablation experiments. The contrast agent used in the laser ablation experiments is the contrast agent prepared in the examples and comparative examples. A blank group is set up, consisting of physiological saline. The results of the plaque ablation area are as follows: Figure 3 As shown, S1 is Example 1, S2 is Example 2, S3 is Example 3, S4 is Example 4, S5 is Example 5, S6 is Example 6, D1 is Comparative Example 1, D2 is Comparative Example 2, D3 is Comparative Example 3, D4 is Comparative Example 4, and B is the blank group. This invention prepares a contrast agent by mixing heparin, verapamil, and nitroglycerin in physiological saline, and then adding a contrast agent, including iopromide or iodixanol. The contrast agent prepared by the above method can be used in ELCA. This invention uses a "chicken sausage" as a vascular plaque model, and then uses the contrast agent coupled with an excimer laser for laser ablation experiments, which can obtain a higher plaque ablation area, indicating better effect when used in ELCA. This invention then oxidizes heparin to obtain oxidized heparin, and then uses oxidized heparin and a derivatizing agent... A derivatization reaction yields a heparin derivative, with L-alanyl-L-proline methyl ester hydrochloride as the derivatizing agent. When used in combination with verapamil, nitroglycerin, and contrast agents, the heparin derivative increases the plaque ablation area of ​​vascular plaques. However, replacing heparin with oxyheparin does not significantly improve the plaque ablation area. Furthermore, if the amount of heparin derivative obtained using L-alanyl-L-proline methyl ester hydrochloride is too low, it also fails to significantly increase the plaque ablation area. This invention also reveals that L-alanyl-L-proline methyl ester hydrochloride and valine can be used together as derivatizing agents. When the resulting heparin derivative is used in combination with verapamil, nitroglycerin, and contrast agents, it further increases the plaque ablation area of ​​vascular plaques, indicating better efficacy for ELCA.

[0096] This invention monitors the shock wave pressure of excimer lasers in the contrast agents of the examples and comparative examples according to the methods described in the aforementioned studies. A blank group was set up, consisting of physiological saline. The shock wave pressure results are as follows: Figure 4As shown, S1 is Example 1, S2 is Example 2, S3 is Example 3, S4 is Example 4, S5 is Example 5, S6 is Example 6, D1 is Comparative Example 1, D2 is Comparative Example 2, D3 is Comparative Example 3, D4 is Comparative Example 4, and B is the blank group. This invention prepares a contrast agent by mixing heparin, verapamil, and nitroglycerin in physiological saline, and then adding a contrast agent, including iopromide or iodixanol. The contrast agent prepared by the above method can be used in ELCA. This invention uses a "chicken sausage" as a vascular plaque model, and then uses the contrast agent coupled with an excimer laser for laser ablation experiments, which can obtain higher shock wave pressure. This invention then oxidizes heparin to obtain oxidized heparin. Heparin derivatives are obtained by reacting oxidized heparin with a derivatizing agent, such as L-alanyl-L-proline methyl ester hydrochloride. When used in combination with verapamil, nitroglycerin, and contrast agents, the resulting heparin derivatives can increase shock wave pressure. However, if heparin is replaced with oxidized heparin, there is no significant increase in shock wave pressure. Furthermore, if the amount of heparin derivative obtained using L-alanyl-L-proline methyl ester hydrochloride is too low, it also cannot significantly increase shock wave pressure. This invention also discovers that L-alanyl-L-proline methyl ester hydrochloride and valine can be used together as derivatizing agents. When used in combination with verapamil, nitroglycerin, and contrast agents, the resulting heparin derivatives can further increase shock wave pressure.

[0097] The embodiments and / or implementation methods described above are merely preferred embodiments and / or implementation methods for implementing the technology of the present invention, and are not intended to limit the implementation methods of the technology of the present invention in any way. Any person skilled in the art can make some modifications or alterations to other equivalent embodiments without departing from the scope of the technical means disclosed in the content of the present invention, but they should still be regarded as the technology or embodiments that are substantially the same as the present invention.

[0098] This document uses specific examples to illustrate the principles and implementation methods of this application. The descriptions of the above embodiments are only for the purpose of helping to understand the methods and core ideas of this application. The above descriptions are only preferred embodiments of this application. It should be noted that due to the limitations of written expression, while there are objectively infinite specific structures, those skilled in the art can make several improvements, modifications, or changes without departing from the principles of this application, and can also combine the above technical features in an appropriate manner. These improvements, modifications, changes, or combinations, or the direct application of the inventive concept and technical solution to other situations without modification, should all be considered within the scope of protection of this application.

Claims

1. A contrast agent, comprising: The contrast agent comprises heparin-based compounds, including heparin derivatives, and the content of the heparin-based compounds in the contrast agent is 2-64 μg / mL; the heparin derivatives are prepared by first oxidizing heparin and then reacting it with a derivatizing agent, including L-alanyl-L-proline methyl ester hydrochloride and valine.

2. The contrast agent according to claim 1, characterized in that: The contrast agent also includes physiological saline.

3. The contrast agent according to claim 1, characterized in that: The contrast agent includes at least one of iopromide and iodixanol.

4. The contrast agent according to claim 1, characterized in that: The contrast agents also include verapamil and / or nitroglycerin.

5. A method for preparing a contrast agent, comprising mixing a mixture with a contrast agent injection solution to obtain a contrast agent, wherein the mixture contains a heparin-based compound, and the contrast agent injection solution contains at least one of iopromide and iodixanol; the content of the heparin-based compound in the contrast agent is 2-64 μg / mL; the heparin-based compound includes a heparin derivative, and the preparation of the heparin derivative includes the preparation of heparin oxidase; in the preparation of heparin oxidase, heparin sodium is added to deionized water to obtain a heparin sodium solution, then a mixed acid salt is added, and the mixture is reacted at 20-40℃ for 10-30 min; after the reaction is completed, the pH is adjusted to 8-9, dialyzed, and then lyophilized to obtain heparin oxidase; in the preparation of the heparin derivative, heparin oxidase and a derivatizing agent are mixed in a dimethylene sulfoxide solution, then triethylamine is added, and the mixture is reacted at 40-80℃ for 2-10 h; after the reaction is completed, acetone is added to precipitate the product, which is then washed and dried to obtain the heparin derivative, wherein the derivatizing agent includes L-alanyl-L-proline methyl ester hydrochloride and valine.

6. The method for preparing the contrast agent according to claim 5, characterized in that: The mixture and contrast agent injection solution are mixed at a volume ratio of 1:0.25-4.

7. The method for preparing the contrast agent according to claim 5, characterized in that: The mixture was obtained by adding heparin-based compounds, verapamil, and nitroglycerin to physiological saline.

8. The method for preparing the contrast agent according to claim 5, characterized in that: The contrast agent injection solution is obtained by adding contrast agent to physiological saline.

9. The use of heparin-based compounds and contrast agents in the preparation of contrast agents for use in combination with ELCA, characterized by: The heparin-based compounds include heparin derivatives, which are prepared by first oxidizing heparin and then reacting it with a derivatizing agent, including L-alanyl-L-proline methyl ester hydrochloride and valine.

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