Application of microbubbles to preparation of medicine for treating ischemic eye disease by combining ultrasonic to generate small-amplitude resonance or steady-state cavitation

Abstract

The invention discloses an application of microbubbles in preparing a medicine for treating ischemic eye diseases by combining ultrasonic to generate small-amplitude resonance or steady-state cavitation, namely under the excitation of ultrasonic pulses with ultrasonic peak negative pressure lower than 300kPa (kPa) or ultrasonic mechanical index (MI) lower than 0.2, the microbubbles in blood circulation generate small-amplitude resonance or steady-state cavitation; the cavitation mechanical effect stimulates eyeball blood perfusion to be increased, and then the treatment effect of improving the visual function is achieved. The novel treatment application of the microbubbles is characterized in that after the microbubbles enter human blood circulation through intravenous injection, under the condition that pulse type ultrasonic energy directional irradiation is conducted, the emission frequency is 500 KHz to 10.0 MHz, the peak value negative pressure is 10 kPa to 300 kPa, and the pulse width is 1 to 20 cycles, the microbubbles in an eyeball blood vessel cavity are stimulated to generate small-amplitude resonance or steady-state cavitation; and then the treatment effects of eyeball blood perfusion increase and vision improvement are achieved. The new medicine application of the microvesicles is suitable for treating various ischemic eye diseases, and is a brand-new new treatment application with application prospects.

Description

Use of microbubbles in the preparation of drugs for treating ischemic eye diseases by combining ultrasound to generate small-amplitude resonance or steady-state cavitation Technical Field The invention relates to a new use of microbubbles in treating eye diseases under ultrasonic stimulation, which is mainly used in treating ischemic eye diseases and belongs to the technical field of non-invasive ultrasonic treatment. Background Art Ischemic eye disease is a common type of eye disease caused by obstruction of the blood supply pathway to the eye due to various reasons, leading to ischemia and hypoxia of the eye tissue. The disease has a high incidence rate and complex etiology, and is often prone to cause serious visual damage. It is one of the acute and severe ophthalmic diseases. The causative factors of the disease include primary, secondary or systemic diseases, and often multiple factors exist at the same time, which increases the difficulty of diagnosis and treatment. If patients with this type of disease do not have timely and effective diagnosis and treatment, the prognosis is poor, and severe cases will suffer from permanent loss of visual function. Therefore, improving the ischemic state of the eye is of great clinical significance for saving and improving the patient's visual function. The diagnosis and treatment of ischemic eye disease has always been a hot spot and difficulty in the field of ophthalmology research. There is currently no clinically recognized effective treatment for ischemic eye disease. 95% of central retinal artery occlusions in acute ischemic eye disease are caused by thromboembolic diseases, while the other 5% are caused by arteritis-induced central retinal artery occlusion. [1] Previous studies have found that in elderly rhesus monkeys with atherosclerosis and hypertension, no optic nerve or retinal damage was observed when the central retinal artery occlusion occurred within 97 minutes; however, severe and irreversible optic nerve or retinal damage occurred 240 minutes after the occlusion. [2] . Therefore, it is crucial to restore blood perfusion during the golden period of treatment. The onset of central retinal vein thrombosis is relatively slow, and the site of blockage is mostly located at the cribriform plate. The optic nerve is significantly narrowed across the cribriform plate area, and the nerve fibers are crowded, which puts pressure on the central retinal vein. Here, the central retinal artery and central vein are located closest to each other, and the two are wrapped in the same outer membrane sheath, and the lumens of the two are separated only by the vascular endothelium and matrix. When arteries are sclerotic, the veins are compressed and the endothelial cells in the wall are stimulated to proliferate due to the restrictions of the outer membrane sheath, the lumen becomes narrow, and the blood flow slows down, leading to the deposition of platelets, red blood cells and fibrinogen and the formation of thrombi. [3] At present, clinical treatment mainly involves vasodilation and lowering intraocular pressure within a limited treatment time window. The methods used are mainly conventional conservative non-specific treatment methods, including eye massage, anterior chamber puncture, acetazolamide, mannitol, acupoint injection of anisodine, local anti-glaucoma and vasodilators, steroids, etc. Treatment options include alcohol and hyperbaric oxygen, but there are no data to support any single specific treatment. Intra-arterial and intravenous thrombolytic agents are under investigation, and the best management strategy has not yet been determined. [4]. The etiology and pathogenesis of ischemic eye disease are complex. It is currently believed that multiple factors such as local anatomical factors and systemic vascular risk factors are involved. Systemic basic diseases such as hypertension, hyperglycemia, and hyperlipidemia are positively correlated with this. These basic diseases cause atherosclerosis and even stenosis of blood vessels, leading to an increased risk of ischemic eye disease. In addition, many factors such as optic nerve ischemia caused by vasomotor regulation disorders, intraocular inflammation promotes the release of vasoactive peptides and proinflammatory factors, ocular tissue oxygen disorders, and optic nerve and blood vessel compression will increase the risk of disease. The focus of treating ischemic eye disease is to protect visual function, but there is no clear, unified, and recognized treatment plan or expert consensus on treatment. For example, the commonly used drug in the treatment of ischemic optic neuropathy is steroid hormones, but their effect on improving the vision of ischemic optic neuropathy is not significant and has many side effects, so they are no longer recommended. The efficacy and safety of autonomic nerve modulators and nerve cell protectors are not certain. Although anticoagulants can prevent thrombosis and vascular congestion, their limited time window and systemic or local bleeding risks may aggravate ischemic eye diseases and even endanger life. Therefore, although the basic methods for the clinical treatment of ischemic eye diseases currently include drug vasodilation, hormone shock, laser therapy, minimally invasive intervention and other therapies, these treatments do not have ideal therapeutic effects, which brings great challenges to clinical work. Therefore, it is very necessary to find a non-invasive and effective treatment method. In recent years, ultrasound contrast agent microbubbles have been actively used in basic research in the field of non-invasive ultrasound therapy for the stable cavitation and inertial cavitation effects in the blood vessel lumen. Ultrasound-induced microbubble cavitation resonance in blood vessels can effectively stimulate the increase of blood flow in the irradiated area, including in ischemic muscle tissue. [5] Foreign literature also reported that by appropriately adjusting the mechanical index (MI, a parameter similar to peak negative pressure), ultrasound contrast agents can be used in conjunction with clinical trials in patients with acute myocardial infarction, stroke, and peripheral arterial disease. The results showed that endothelial-dependent perfusion in atherosclerotic cardiovascular disease was enhanced, and multiple diseases were significantly improved. [6] In addition, blood flow to ischemic limb tissues increased by 3 to 4 times. [7] The mechanism of the so-called "sonoreperfusion" produced by ultrasound combined with microbubbles may be related to mechanical effects such as acoustic microflow, microjet and shear stress generated by ultrasonic cavitation of different intensities. These effects stimulate vascular endothelial cells and red blood cells to lead to the synthesis and release of a variety of vasodilators, including adenosine triphosphate (ATP), nitric oxide (NO), prostaglandins and adenosine, producing local blood flow. Tube dilation [7-9]This suggests that we can try to use this method to improve the ischemia and hypoxia of the target area. This treatment method just corresponds to the ischemia and hypoxia factors of ischemic eye diseases. It is known that ultrasound-stimulated microbubble cavitation can cause endothelial cells and erythrocytes in the irradiated target area to release ATP, which is directly converted into adenosine or the endothelium produces NO and prostaglandins through purinergic receptor signal transduction (P2Y and A2b), which not only increases the blood supply to the target area, but also causes relaxation of cells downstream of the target area. [8] In some preclinical models, it can acutely increase downstream lung perfusion

[0010] , transient cavitation may even produce a durable reversal of limb ischemia via shear-mediated activation of ATP channels [9 , 11] This provides a strong theoretical basis for improving retrobulbar blood supply and improving local optic nerve ischemia in patients with ischemic eye diseases. In the prior art, although US20080262512A1 uses ultrasound to treat eye diseases, it is an invasive needle-type ultrasound effect, which is an invasive method. WO2009020994A2 discloses a non-invasive treatment method, but the ultrasound energy required for drug-carrying microbubbles and microbubble explosions is relatively large, generally reaching the transient cavitation range, which can easily cause the rupture of tiny blood vessels in the eyes, causing local red blood cell overflow, increasing the risk of bleeding in the target area and the area outside the target, and safety cannot be guaranteed. In addition, the microjets, microradiation, and microexplosions generated by ultrasonic cavitation can cause bleeding in retinal blood vessels and may increase the degree or range of embolism, which is not conducive to the treatment of eye diseases. Summary of the invention In view of the above deficiencies in the prior art, the present invention proposes a non-invasive, safe, convenient, highly repeatable and effective system for treating ischemic eye diseases, and a new use of microbubbles in the preparation of drugs for treating ischemic eye diseases by combining ultrasound to generate small-amplitude resonance or steady-state cavitation. The present invention mainly relates to the effect or new use of microbubbles (i.e., ultrasound contrast agents) in the blood vessel cavity under the action of a pulsed, low-peak negative pressure ultrasonic energy, which produces a small-amplitude resonance or steady-state cavitation, stimulating the ocular microvessels to cause ocular blood perfusion and improvement of ocular ischemia. Microbubbles refer to various conventional commercialized or soon-to-be-commercialized ultrasound contrast agent microbubbles, and the ultrasound contrast enhancement effect of microbubbles has been approved and widely used in clinical diagnosis. Under the action of the ultrasonic energy designed by the present invention, the microbubbles in the blood circulation undergo cavitation resonance in the lumen, and the resonance intensity ranges from small and medium amplitudes to steady-state cavitation, avoiding transient cavitation or inertial cavitation of higher intensity. The small-amplitude resonance of the microbubbles that occurs is a resonant motion with a resonance intensity lower than that of steady-state cavitation, characterized by high-order harmonics; the steady-state cavitation effect of microbubbles appears as subharmonics and superharmonics. The ultrasonic energy of the present invention refers to a pulsed or intermittent pulsed ultrasonic pulse energy form with low peak sound pressure and extremely low emission duty cycle ( FIG. 1 ). The slight stimulation of the microvessels in the eye, especially the soft tissue behind the eye, caused by the small amplitude resonance or steady-state cavitation in the microbubble can enhance the blood perfusion and improve the local microcirculation. On this basis, the microenvironment of the lesion site changes and the ischemia of the eye is alleviated. In view of this, the technical solution adopted by the present invention is: the use of microbubbles in the preparation of a drug for treating ischemic eye diseases by combining ultrasound to generate small-amplitude resonance or steady-state cavitation, wherein the microbubbles generate small-amplitude resonance under ultrasonic energy, and the ultrasonic energy is in the form of: an ultrasonic emission frequency of 500kHz-10.0MHz, an ultrasonic peak negative pressure of 10-300kPa, a single ultrasonic pulse width of 1-20 cycles, and a pulse repetition frequency of 1-1000Hz. Furthermore, the ultrasound is emitted continuously or intermittently, the intermittent time of the intermittent ultrasound emission is 0-20 seconds, and the working duty cycle is less than 10%. Furthermore, the microbubbles refer to various commercialized or uncommercialized ultrasound contrast agent microbubbles or therapeutic microbubbles, such as SonoVue Show Zhuo'an Octafluoropropane lipid microsphere injection OptisonTM, and perfluoropropane human albumin microspheres, etc. Furthermore, the microbubbles are injected into the human body via peripheral vein, and the dosage of the microbubble injection is 0.01-1.0 mL. More specifically, the microbubbles are injected by bolus or slow injection via the median cubital vein, with a dosage of 0.01-1.0 mL. Furthermore, the ischemic eye disease refers to primary, secondary and ischemia-related diseases caused by various reasons in which the blood supply to the eye cannot meet the metabolic needs of tissues such as the retina, choroid and optic nerve. These diseases include but are not limited to: ischemic retinopathy: ophthalmic artery occlusion, central retinal artery occlusion, central retinal vein occlusion, branch retinal artery occlusion, ciliary retinal artery occlusion, traumatic retinopathy, and ocular ischemic syndrome; ischemic choroidopathy: traumatic choroidal ischemia, choroidal degenerative ischemia; ischemic optic neuropathy: anterior ischemic optic neuropathy, posterior ischemic optic neuropathy; other related eye diseases that may cause ischemia: diabetic retinopathy, age-related macular degeneration, hypertensive retinopathy, fundus lesions of large arteritis, and various blood diseases including leukemia. The ultrasonic instrument for emitting the ultrasound is an ultrasonic diagnostic instrument or an ultrasonic therapeutic instrument. The transducer is a planar or focused transducer in a multi-element or single-element form. The present invention also provides a system for treating ischemic eye diseases, comprising microbubbles and an ultrasound instrument, wherein the microbubbles generate small-amplitude resonance or steady-state cavitation under the action of ultrasonic energy emitted by the ultrasound instrument, wherein the ultrasonic energy is in the form of: ultrasonic emission frequency of 500kHz-10.0MHz, ultrasonic peak negative pressure of 10-300kPa, single ultrasonic pulse width of 1-20 cycles, and pulse repetition frequency of 1-1000Hz. The ultrasound is emitted continuously or intermittently, wherein the intermittent (pause) time of the intermittently emitted ultrasound is 0-20 seconds, and the working duty cycle is less than 10%. There are many factors that affect the occurrence and intensity of the acoustic cavitation effect in the body, but the most important factors are the peak negative pressure intensity of ultrasound and the concentration of microbubbles. The FDA stipulates that the clinical safety range of ultrasound contrast diagnosis is MI ≤ 0.23

[0012] The "Guidelines for Clinical Application of Ultrasound Contrast Imaging in China" states that the tolerance MI of ultrasound contrast agents used in China does not exceed 0.2. The MI used in the present invention is ≤ 0.12, which is within the safe range of ocular ultrasound examination. There has never been a research report in the literature on the use of ultrasound energy excitation contrast agent microbubbles with the above acoustic parameters for the treatment of ischemic eye diseases. The ultrasonic energy and microbubbles of the present invention can be used to construct a non-invasive, safe, convenient, highly repeatable and effective system for treating ischemic eye diseases. Microbubbles in the blood circulation, under the excitation of the ultrasonic pulse of the energy of the present invention, produce small and medium amplitude resonance or steady-state cavitation, which can mechanically stimulate the microvessels of the eyeball. The vascular effect produced by the resonance of microbubbles is utilized to release active substances such as NO and ATPase to dilate blood vessels, which not only increases blood perfusion, but also has a very significant and safe effect on ischemic eye diseases caused by spasm of microvasculature. BRIEF DESCRIPTION OF THE DRAWINGS FIG1 is a schematic diagram of ultrasound-stimulated microbubbles irradiating ocular blood vessels according to the present invention; Figure 2 is a time-intensity (AUC) curve of ultrasound angiography before and after treatment, A is fundus ultrasound angiography before treatment, and B is fundus ultrasound angiography immediately after treatment; it shows that blood supply increases after treatment; Figure 3 is a comparison of the visual field before and after treatment. The left picture shows the visual field of the patient before treatment, and the right picture shows the visual field of the patient after treatment. It shows that the visual field is improved after treatment. Figure 4 is a comparison of patients with central retinal artery occlusion before treatment, A is before treatment, B is 1 week after the first treatment, C is 2 weeks after the first treatment, and D is 1 month after the first treatment; follow-up observation of patients with central retinal artery occlusion after the first treatment showed that the flow velocity of the central retinal artery gradually increased and the resistance decreased after treatment; Figure 5 is a comparison of optic disc OCT images. The upper image shows that the optic disc nerve fiber layer was obviously swollen before treatment, and the lower image shows that the edema of the nerve fiber layer subsided after treatment. The edema subsided; Figure 6 is a comparison of macular OCT images. The upper image shows that the neuroepithelial layer in the macular area was significantly thickened before treatment, and the lower image shows that the edema of the neuroepithelial layer in the macular area was reduced after treatment, indicating that the thickness and edema of the neuroepithelial layer in the macular area were reduced after treatment. DETAILED DESCRIPTION (1) Acoustic measurement The acoustic parameters of the ultrasonic therapeutic instrument include ultrasonic frequency, peak negative pressure, pulse width and duty cycle, etc., all of which are measured by the hydrophone method. After the ultrasonic therapeutic instrument signal is sent out, the received signal is received by a capsule hydrophone (HGL-0085, ONDA) 3.4 cm away from the transmitting transducer, amplified by a preamplifier (NTR, Agilent), and then sampled and analyzed by a digital oscilloscope (DS05012A, Agilent) computer. (2) A brief description of conventional methods for ischemic eye disease treatment trials First, patients who were initially diagnosed with ischemic eye disease were given relevant ophthalmic examinations (examination items included visual acuity, visual field, fundus photography, optical coherence tomography (OCT), retinal fluorescein angiography (FFA) and grayscale ultrasound, color Doppler ultrasound, fundus blood vessel ultra-micro blood flow imaging and ultrasound angiography examinations. Then, the dose of microbubbles was intravenously injected, and the fundus was irradiated with multi-section pulsed ultrasound, and the treatment began at this time. Ultrasonic excitation of microbubbles with extremely low energy causes small to medium degrees of resonance in the tiny blood vessels of the eye, and the microbubbles expand, contract, stretch, and even produce energy forms such as steady-state cavitation. According to the patient's condition, three consecutive treatments can be performed with an interval of one week each time. According to different diseases, the treatment effect is judged by ophthalmic visual function and fundus-related examinations, conventional ophthalmic ultrasound examinations, ultra-micro blood flow imaging and other technologies at different time points (the first day of treatment or 1 day, 1 week or 2 weeks, 1 month, 3 months or 6 months). (3) Experiment on ultrasound-stimulated microbubbles for the treatment of ischemic eye diseases The present invention currently uses EPIQ 5 (Philips Ultrasound. Inc) ultrasonic diagnostic instrument, using eL18-4 transducer, and ULTIMUS 9E ultrasonic diagnostic instrument, using U5-15LE transducer. During the ultrasonic examination and treatment process, the ultrasonic transducer uses a spatial peak pulse average sound intensity Isppa <17mW / cm 2 The ultrasonographic contrast agent microbubble is the commercialized SonoVue Contrast agent, the core gas is sulfur hexafluoride, the concentration is about 1~5×108 / ml, in the present invention, the injection dose is <1ml / time. The specific experimental process is as follows: The design type of the present invention belongs to an asynchronous control experiment. A total of 20 patients with ischemic eye disease initially diagnosed in ophthalmology were selected as the experimental group, and 14 patients with ischemic eye disease in the non-same period (January 1, 2021-March 31, 2022) were selected as the historical control group. All subjects in the experimental and control groups underwent routine ocular ultrasound angiography. Routine ocular ultrasound angiography process: 0.8-1.0mL of contrast agent was injected through the median cubital vein. The MI was maintained between 0.06-0.08 during the first ultrasound angiography, and dynamic ocular angiography images were collected for 40 seconds. The experimental group used diagnostic ultrasound combined with microbubbles to irradiate the retrobulbar blood vessels of the eye, moderately increasing the MI of the diagnostic ultrasound to 0.09-0.12 for 60s-60s, with an interval of 10s. The control group only performed ultrasound angiography but did not increase the MI for ultrasound irradiation. Finally, both groups of patients underwent ultrasound angiography and ultramicro blood flow imaging fusion imaging again to observe blood perfusion. The results showed that in the experimental group, i.e., patients who underwent ultrasound-stimulated microbubble treatment, an increase in retrobulbar blood perfusion was observed immediately after treatment, and the quantitative indicator, the area under the ultrasound contrast curve (AUC), increased significantly (Figure 2). Ophthalmological examination showed that the visual acuity on the day or the next day after treatment was significantly improved, and the best corrected visual acuity (the Early Treatment Diabetic Retinopathy Study charts, ETDRS) Log MAR conversion value decreased from 2.67±0.72 to 2.25±0.89, with a significant statistical difference (P<0.05); the mean visual field mean deviation (MD) difference of patients with visual field loss was ≥3.0dB, which was clinically recognized as effective treatment. [13,14] This treatment method can enhance ocular blood perfusion, improve visual dysfunction caused by target tissue cell damage due to ocular ischemia and hypoxia, and effectively improve the patient's visual function. It is worth noting that fundus photography examination showed no adverse events such as rupture of fundus microvessels and bleeding in either the control group or the experimental group before and after treatment. Such results provide a scientific and reliable basis for the safety of this treatment method. (4) Continuous treatment and efficacy evaluation of ischemic eye diseases Consolidation treatment procedure: All patients received three or more consecutive treatments, with a one-week interval between each treatment. The specific treatment process was the same as above (3); The efficacy evaluation procedure, the efficacy observation period is initially set at 6 months, and the observation time points are divided into immediate or 1 day after the first treatment, 1 week or 2 weeks, 1 month, 3 or 6 months after the first treatment according to the different diseases suffered by the patients. The specific evaluation methods and indicators are as follows: routine ultrasound and ultramicroscopic blood flow imaging observations are performed before and after each review and treatment to measure the changes in the flow velocity and resistance index of the target blood vessels; visual acuity, visual field, and OCT examinations are performed before and after each review and treatment, and the changes in visual acuity, visual field (as shown in Figure 3) and fundus ultrastructure are compared in the three review results. The results of the current experiment indicate that the flow velocity of the target blood vessels in the experimental group increased, the resistance index decreased (see Figure 4), and the ocular blood perfusion was significantly improved; the patients' vision and visual field were improved or unchanged after improvement, with no short-term decline or deterioration trend. OCT showed that for patients with macular edema, the optic disc nerve fiber layer became thinner after treatment, and the edema in the macular area was reduced (see Figures 5 and 6). References [1] Shao Yi, Tan Siwen, Xiao Ang. Diagnosis and treatment of central retinal artery occlusion: Interpretation of the 2021 American Heart Association guidelines. Advances in Ophthalmology, 41 (2021) 901-904. [2] Hayreh, SS, JB Jonas, Optic disk and retinal nerve fiber layer damage after transient central retinal artery occlusion: an experimental study in rhesus monkeys, Am J Ophthalmol, 129 (2000) 786-795. [3] Terao, R., R. Fujino, T. Ahmed, Risk Factors and Treatment Strategy for Retinal Vascular Occlusive Diseases, J Clin Med, 11 (2022). [4] Lee, KE, C.Tschoe, SACoffman, C.Kittel, PABrown, Q.Vu, KMFargen, BHHayes, SQWolfe, Management of Acute Central Retinal Artery Occlusion, a "Retinal Stroke": An Institutional Series and Literature Review, J Stroke Cerebrovasc Dis, 30 (2021) 105531. [5] Tang Najiao, Experimental study on ultrasound microbubble enhancement of blood perfusion in hypovascular tumors and increase of doxorubicin release, Army Medical University of the Chinese People's Liberation Army, 2021. [6] El Kadi, S., TR Porter, NJ W Verouden, AC van Rossum, O. Kamp, Contrast Ultrasound, Sonothrombolysis and Sonoperfusion in Cardiovascular Disease: Shifting to Theragnostic Clinical Trials, JACC Cardiovasc Imaging, 15 (2022) 345-360. [7] Mason, OR, BP Davidson, P. Sheeran, M. Muller, JM Hodovan, J. Sutton, J. Powers, JRLindner, Augmentation of Tissue Perfusion in Patients With Peripheral Artery Disease Using Microbubble Cavitation, JACC Cardiovasc Imaging, 13 (2020) 641-651. [8]Atar,S.,R.J.Siegel,R.Akel,Y.Ye,Y.Lin,S.A.Modi,A.Sewani,E.Tuero,Y.Birnbaum,Ultrasound at 27kHz increases tissue expression and activity of nitric oxide synthases in acute limb ischemia in rabbits,Ultrasound Med Biol,33(2007)1483-1488. [9]Belcik,J.T.,B.P.Davidson,A.Xie,M.D.Wu,M.Yadava,Y.Qi,S.Liang,C.R.Chon,A.Y.Ammi,J.Field,L.Harmann,W.M.Chilian,J.Linden,J.R.Lindner,Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling,Circulation,135(2017)1240-1252.

[0010] Muller,M.A.,J.Hodovan,K.Ozawa,M.W.Hagen,T.R.Hobbs,J.Templon,Y.Zhao,J.A.Kaufman,J.R.Lindner,Augmentation of Pulmonary Perfusion by Conducted Effects of a Pulmonary Artery Ultrasound Catheter,Ultrasound Med Biol,48(2022)2146-2153.

[0011] Belcik,J.T.,B.P.Davidson,T.Foster,Y.Qi,Y.Zhao,D.Peters,J.R.Lindner,Contrast-enhanced ultrasound assessment of impaired adipose tissue and muscle perfusion in insulin-resistant mice,Circ Cardiovasc Imaging,8(2015).

[0012] Hirokawa T,Nishikage T,Moroe T,Kaijima M,Hayashi M,Naito T,et al.Visualization of uveal perfusion by contrast-enhanced harmonic ultrasonography at a low mechanical index:apilot animal study[J].J Utrasound Med,2002,21(2):299-307.

[0013] Lange C,Feltgen N,Junker B,Schulze-Bonsel K,Bach M:Resolving the clinical acuity categories"hand motion"and"counting fingers"using the Freiburg Visual Acuity Test(FrACT).Graefes Arch Clin Exp Ophthalmol 2009,247(1):137-142.

[0014] Abri Aghdam K,Aghajani A,Ashraf Khorasani M,Soltan Sanjari M,Chaibakhsh S,Habibi A,Falavarjani KG:Intravitreal Injection Of The Granulocyte-Colony Stimulating Factor For The Treatment Of Non-Arteritic Anterior Ischemic Optic Neuropathy:APilot Study.Semin Ophthalmol 2021,36(8):649-657.

Claims

1. Use of microbubbles in the preparation of a drug for treating ischemic eye diseases by combining ultrasound to generate small-amplitude resonance or steady-state cavitation, characterized in that: The microbubbles generate small-amplitude resonance or steady-state cavitation under ultrasonic energy, and the ultrasonic energy is in the form of: ultrasonic emission frequency of 500kHz-10.0MHz, ultrasonic peak negative pressure of 10-300kPa, single ultrasonic pulse width of 1-20 cycles, and pulse repetition frequency of 1-1000Hz.

2. The use according to claim 1, characterized in that: The ultrasound is emitted continuously or intermittently. The intermittent ultrasound emission has an intermittent time of 0-20 seconds and a working duty cycle of less than 10%.

3. The use according to claim 1 or 2, characterized in that: The microbubbles are ultrasound contrast agent microbubbles or therapeutic microbubbles, including SonoVue, Shizhuoan, octafluoropropane lipid microsphere injection, Optison TM and perfluoropropane human albumin microspheres.

4. The use according to claim 1 or 2, characterized in that: The microbubbles are injected into the human body via peripheral veins, and the dosage of the microbubble injection is 0.01 to 1.0 mL.

5. The use according to claim 4, characterized in that: The microbubbles are administered by bolus injection or slow injection via the median cubital vein, with a dosage of 0.01-1.0 mL.

6. The use according to claim 1, 2 or 5, characterized in that: The ischemic eye diseases include ischemic retinopathy, ischemic choroidopathy, ischemic optic neuropathy and other related eye diseases that may cause ischemia.

7. The use according to claim 6, characterized in that: The ischemic retinopathy includes ophthalmic artery occlusion, central retinal artery occlusion, central retinal vein occlusion, branch retinal artery occlusion, ciliary retinal artery occlusion, traumatic retinopathy, and ocular ischemic syndrome; the ischemic choroidopathy includes traumatic choroidal ischemia and choroidal degenerative ischemia; the ischemic optic neuropathy includes anterior ischemic optic neuropathy and posterior ischemic optic neuropathy; the other related eye diseases that may cause ischemia include diabetic retinopathy, age-related macular degeneration, hypertensive retinopathy, fundus lesions caused by large-scale arteritis, and various blood diseases including leukemia.

8. The use according to claim 1 or 2, characterized in that: The ultrasonic instrument for emitting the ultrasound is an ultrasonic diagnostic instrument or an ultrasonic therapeutic instrument, and the ultrasonic transducer is a planar or focused transducer in a multi-element or single-element form.

9. A system for treating ischemic eye disease, characterized in that: The invention comprises microbubbles and an ultrasonic instrument. The microbubbles generate small-amplitude resonance or steady-state cavitation under the action of ultrasonic energy emitted by the ultrasonic instrument. The ultrasonic energy is in the form of: ultrasonic emission frequency of 500kHz-10.0MHz, ultrasonic peak negative pressure of 10-300kPa, single ultrasonic pulse width of 1-20 cycles, and pulse repetition frequency of 1-1000Hz.

10. The system for treating ischemic eye disease according to claim 9, characterized in that: The ultrasound is emitted continuously or intermittently. The intermittent ultrasound emission has an intermittent time of 0-20 seconds and a working duty cycle of less than 10%.

Images