WO2022056736A1 - Application de lévofloxacine ou de sels pharmaceutiquement acceptables de cette dernière dans la préparation de médicaments contre les lésions cérébrales d'ischémie-reperfusion ou de produits de soins de santé - Google Patents

Application de lévofloxacine ou de sels pharmaceutiquement acceptables de cette dernière dans la préparation de médicaments contre les lésions cérébrales d'ischémie-reperfusion ou de produits de soins de santé Download PDF

Info

Publication number
WO2022056736A1
WO2022056736A1 PCT/CN2020/115620 CN2020115620W WO2022056736A1 WO 2022056736 A1 WO2022056736 A1 WO 2022056736A1 CN 2020115620 W CN2020115620 W CN 2020115620W WO 2022056736 A1 WO2022056736 A1 WO 2022056736A1
Authority
WO
WIPO (PCT)
Prior art keywords
levofloxacin
reperfusion injury
cerebral ischemia
pharmaceutically acceptable
health care
Prior art date
Application number
PCT/CN2020/115620
Other languages
English (en)
Chinese (zh)
Inventor
畅君雷
杨时伦
马寅仲
朱亚东
Original Assignee
中国科学院深圳先进技术研究院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国科学院深圳先进技术研究院 filed Critical 中国科学院深圳先进技术研究院
Priority to PCT/CN2020/115620 priority Critical patent/WO2022056736A1/fr
Publication of WO2022056736A1 publication Critical patent/WO2022056736A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to the technical field of medicaments for the treatment of cardiovascular and cerebrovascular diseases, in particular to the application of levofloxacin or a pharmaceutically acceptable salt thereof in the preparation of medicaments or health-care products against cerebral ischemia-reperfusion injury.
  • Stroke also known as stroke or cerebrovascular accident, is a disease that damages brain tissue due to blockage or rupture of blood vessels in the brain, which prevents blood from flowing into the brain.
  • stroke has become the first cause of death and disability among adults in my country, and it is also one of the main causes of death and disability in the world.
  • an average of 2.7 million new stroke cases occur every year, of which 50% of stroke patients have different degrees of hemiplegia, 30% of patients cannot walk independently, and 15%-30% of patients have permanent disability. Therefore, stroke brings a huge economic and mental burden to the patient's family and social stability.
  • ischemic stroke mainly due to the occurrence of atherosclerotic lesions or thrombosis in the arteries supplying blood to the brain, stenosis or even occlusion of the vascular lumen, resulting in focal cerebral insufficiency. and sickness.
  • the main treatment method in the acute phase of ischemic stroke (within 3.5 to 8 hours) is to dredge the blood vessels, so that the damaged brain tissue can restore blood flow in time.
  • Recombinant tissue plasminogen activator (rtPA) and mechanical thrombectomy are the main methods of recanalization in clinical practice.
  • vascular recanalization therapy can significantly reduce brain tissue damage, improve patient prognosis and reduce disability and mortality, but it also brings a series of side effects, which can affect the formation of brain tissue.
  • Secondary injury namely ischemia-reperfusion injury (I/R injury).
  • I/R injury ischemia-reperfusion injury
  • mitochondria When an occluded vessel is reperfused, mitochondria are no longer able to effectively neutralize reactive species in the blood, causing increased release of reactive oxygen species.
  • necrotic cellular debris can trigger cerebral ischemia cascades that typically occur hours to days later (subacute phase).
  • the pathological process in the subacute phase is secondary to the initial ischemic injury, such as delayed apoptosis of cells in the less damaged infarct border area. If the above-mentioned side effects after vascular recanalization therapy can be controlled or alleviated, the benefits of vascular recanalization therapy can be maximized and the prognosis of ischemic stroke patients can be improved.
  • Levofloxacin is a third-generation fluoroquinolone broad-spectrum antibacterial drug, which has been used for many years and is one of the "essential drugs list" drugs of the World Health Organization. Chronic infections and refractory infections caused by sensitive bacteria such as infections. Its mechanism of action is to directly inhibit the synthesis of bacterial DNA, and it has the strongest activity against Gram-negative bacteria, penicillin-sensitive or insensitive bacteria. Levofloxacin was patented in 1987 and approved for clinical use by the US FDA in 1996 (the patent expired in 2011). Its chemical structure is as follows: But its role in the preparation of anti-cerebral ischemia-reperfusion injury drugs or health products has not been reported yet.
  • the purpose of the present invention is to provide a medicine or health care product for resisting cerebral ischemia-reperfusion injury.
  • One aspect of the present invention provides an application of levofloxacin or a pharmaceutically acceptable salt thereof in the preparation of a medicine or a health care product against cerebral ischemia-reperfusion injury.
  • Another aspect of the present invention provides an application of levofloxacin or a pharmaceutically acceptable salt thereof in the preparation of a medicine or health care product for improving neurological dysfunction, preferably, the neurological dysfunction is neurological function caused by cerebral ischemia-reperfusion injury obstacle.
  • Another aspect of the present invention provides an application of levofloxacin or a pharmaceutically acceptable salt thereof in the preparation of a medicine or health care product for reducing cerebral infarction volume, preferably, the cerebral infarction volume is cerebral infarction caused by cerebral ischemia-reperfusion injury volume.
  • Another aspect of the present invention provides an application of levofloxacin or a pharmaceutically acceptable salt thereof in the preparation of a medicine or health product for protecting blood-brain barrier damage, preferably, the blood-brain barrier damage is caused by cerebral ischemia-reperfusion injury Blood-brain barrier damage.
  • Another aspect of the present invention provides a pharmaceutical composition or health care product against cerebral ischemia-reperfusion injury, which contains levofloxacin or a pharmaceutically acceptable salt thereof as an active substance.
  • the pharmaceutical composition is in the form of intravenous injection and oral administration.
  • the dosage of the intravenous injection dosage form is 20-60 mg/kg/day; the dosage of the oral dosage form is 20-60 mg/kg/day.
  • the administration time of the pharmaceutical composition is simultaneous administration during reperfusion, and thereafter every 24 hours for 3-7 consecutive days.
  • the present invention discovers for the first time the application of levofloxacin or its pharmaceutically acceptable salt in the preparation of medicines or health products for anti-cerebral ischemia-reperfusion injury, and the levofloxacin or its pharmaceutically acceptable salt is used for anti-cerebral ischemia-reperfusion injury.
  • Blood reperfusion injury can reduce the volume of cerebral infarction, improve neurological dysfunction, and protect the blood-brain barrier function. It is a drug suitable for the recovery period of stroke prognosis.
  • Figure 1 shows the effects of levofloxacin on neurobehavioral function (A) and forelimb gripping ability (B) in mice in Example 1 of the present invention.
  • Figure 2 shows the effect of levofloxacin on the volume of cerebral infarction in mice in Example 2 of the present invention, wherein (A) is the TTC staining photo of the mouse brain slice, and (B) is the statistics of the volume of cerebral infarction.
  • Figure 3 shows the effect of levofloxacin on the integrity of the blood-brain barrier in mice in Example 3 of the present invention, wherein (A) is a photo of Evans blue leakage staining of mouse brain slices, and (B) is Evans blue on the side of mouse cerebral infarction leakage concentration.
  • the present invention provides an example of the efficacy of the mouse model of cerebral ischemia-reperfusion injury, including:
  • mice C57BL/6 male mice aged 8-10 weeks and weighing 20-30g were randomly divided into three groups, namely the solvent control group, the levofloxacin 20 mg/kg administration group, and the levofloxacin 60 mg/kg administration group.
  • Transient middle cerebral artery embolization-reperfusion models were established in the above three groups by suture method. Mice were first anesthetized using isoflurane gas anesthesia (2.5 vol% induction, 1.5 vol% maintenance). After 5 min of anesthesia, the mice were fixed on the surgical board in a supine position. The mouse neck was then trimmed with curved scissors, and the mouse neck was sterilized with sufficient iodophor.
  • the 20 mg/kg administration group was intravenously injected with levofloxacin 20 mg/kg/day, the levofloxacin 60 mg/kg administration group was intravenously injected with levofloxacin 60 mg/kg/day, and the solvent control group was intravenously injected with an equal volume of 0.9% normal saline). Then, the neck wound was sutured and povidone-iodine was disinfected, after which the mice were returned to their cages.
  • the neurological function score refers to the observation method of Bederson and Belvyev, etc., the tail of the rat is lifted, and the two forelimbs of normal mice are stretched forward symmetrically. If internal rotation of the shoulder and adduction of the forelimb occur, they are scored according to their severity.
  • the normal extension of the bilateral forelimbs was rated as 0; only the contralateral forelimb was adducted, and there was no other symptoms, the score was 1; the rat tail was pulled flat, and the grasping power of the contralateral forelimb was significantly decreased, and the grasping strength of the contralateral forelimb was significantly decreased, and the score was 2; The rat can move freely, and the limb tilts to the opposite side when the rat's tail is flattened as 3 points; when placed on a flat surface, the mouse can only rotate or roll to the opposite side as 4 points; when placed on a flat surface, there is no voluntary movement, and Death within 24 hours was rated 5. The results are shown in Figure 1A.
  • Forelimb grasping ability detection The mouse forepaw grasping ability was observed by hanging experiment, and the mouse forepaw was hung on the grasping force detector at the same time. 1 point: both paws can be caught; 2 points: only one paw can be caught; 3 points: both paws cannot be caught. The results are shown in Figure 1B.
  • levofloxacin 60mg/kg can significantly reduce the neurobehavioral score of mice and improve the forelimb grasping ability of mice; levofloxacin 20mg/kg can significantly improve the forelimb grasping ability of mice.
  • mice were anesthetized and sacrificed by decapitation, and whole brains were quickly frozen at -40°C and sliced.
  • the first knife is at the midpoint of the line connecting the anterior pole of the brain and the optic chiasm; the second knife is at the optic chiasm; the third knife is at the funnel handle; the fourth knife is between the funnel handle and the caudal pole of the posterior lobe, and the thickness of each slice is 2 mm.
  • Brain tissue sections were incubated with 0.5% (mass volume percent) 2,3,5-triphenyltetrazolium chloride (TTC) solution at 37°C for 15 min, and then replaced with 4% (mass volume percent) paraformaldehyde for 20 min .
  • TTC 2,3,5-triphenyltetrazolium chloride
  • TTC reacts with succinate dehydrogenase in the mitochondria of living cells to generate red formazan, which is used to represent living cells (ie, the dark color in the black-and-white image), while the white area is not
  • red formazan which is used to represent living cells (ie, the dark color in the black-and-white image)
  • the stained area is the infarcted area.
  • levofloxacin 20mg/kg and 60mg/kg can significantly reduce the volume of cerebral infarction in mice.
  • Example 3 The effect of levofloxacin on the integrity of blood-brain barrier in mice with cerebral ischemia-reperfusion injury
  • Brain slices were cut along the midline of the brain, and the wet weight of the right hemisphere was weighed, homogenized in 1 ml of 50% (mass volume percent) trichloroacetic acid and centrifuged (10,000 rpm, 20 minutes). The concentration of Evans blue was measured with a fluorescence reader (excitation at 620 nm, emission at 680 nm) and expressed in ng/mg brain tissue as shown in Figure 3B.
  • Evans blue is a commonly used azo dye preparation, because its molecular weight is similar to that of plasma albumin, and it has a high affinity with plasma albumin in blood, so it is often used for tracer observation in neuroscience research. Integrity of the blood-brain barrier (BBB). Determination of blood-brain barrier integrity Since plasma albumin cannot penetrate the blood-brain barrier under normal conditions, when staining, if the nervous system is intact, Evans blue bound to plasma albumin cannot make it stained. When the brain barrier is disrupted, Evans blue can enter the nervous system and color it.
  • BBB blood-brain barrier
  • levofloxacin or its pharmaceutically acceptable salt for anti-cerebral ischemia-reperfusion injury can reduce the volume of cerebral infarction, improve neurological dysfunction, and protect the blood-brain barrier function. It is a drug suitable for stroke prognosis and recovery period.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Heart & Thoracic Surgery (AREA)

Abstract

Application de lévofloxacine ou de sels pharmaceutiquement acceptables de cette dernière dans la préparation de médicaments contre les lésions cérébrales d'ischémie-reperfusion ou de produits de soins de santé. La lévofloxacine ou des sels pharmaceutiquement acceptables de cette dernière sont utilisés pour traiter des lésions cérébrales d'ischémie-reperfusion, sont aptes à réduire le volume d'infarcissement cérébral, à atténuer un dysfonctionnement neurologique et à protéger la fonction de barrière hémato-encéphalique, et sont applicables à la période de pronostic et de récupération d'une apoplexie.
PCT/CN2020/115620 2020-09-16 2020-09-16 Application de lévofloxacine ou de sels pharmaceutiquement acceptables de cette dernière dans la préparation de médicaments contre les lésions cérébrales d'ischémie-reperfusion ou de produits de soins de santé WO2022056736A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/115620 WO2022056736A1 (fr) 2020-09-16 2020-09-16 Application de lévofloxacine ou de sels pharmaceutiquement acceptables de cette dernière dans la préparation de médicaments contre les lésions cérébrales d'ischémie-reperfusion ou de produits de soins de santé

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/115620 WO2022056736A1 (fr) 2020-09-16 2020-09-16 Application de lévofloxacine ou de sels pharmaceutiquement acceptables de cette dernière dans la préparation de médicaments contre les lésions cérébrales d'ischémie-reperfusion ou de produits de soins de santé

Publications (1)

Publication Number Publication Date
WO2022056736A1 true WO2022056736A1 (fr) 2022-03-24

Family

ID=80775781

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/115620 WO2022056736A1 (fr) 2020-09-16 2020-09-16 Application de lévofloxacine ou de sels pharmaceutiquement acceptables de cette dernière dans la préparation de médicaments contre les lésions cérébrales d'ischémie-reperfusion ou de produits de soins de santé

Country Status (1)

Country Link
WO (1) WO2022056736A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101679397A (zh) * 2007-03-23 2010-03-24 纽尔亚商股份有限公司 具有nos抑制活性的喹诺酮、四氢喹啉及其相关化合物
CN106573006A (zh) * 2014-08-21 2017-04-19 葛兰素史密斯克莱知识产权发展有限公司 作为药物的rip1激酶抑制剂杂环酰胺
US9968616B2 (en) * 2014-10-25 2018-05-15 The Chinese University Of Hong Kong Discovery of FDA-approved drugs as inhibitors of fatty acid binding protein 4 using molecular docking screening

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101679397A (zh) * 2007-03-23 2010-03-24 纽尔亚商股份有限公司 具有nos抑制活性的喹诺酮、四氢喹啉及其相关化合物
CN106573006A (zh) * 2014-08-21 2017-04-19 葛兰素史密斯克莱知识产权发展有限公司 作为药物的rip1激酶抑制剂杂环酰胺
US9968616B2 (en) * 2014-10-25 2018-05-15 The Chinese University Of Hong Kong Discovery of FDA-approved drugs as inhibitors of fatty acid binding protein 4 using molecular docking screening

Similar Documents

Publication Publication Date Title
JP7082115B2 (ja) 異常な新生血管形成を伴う眼疾患を処置するためにニンテダニブを使用する組成物および方法
KR102382077B1 (ko) 우르소데옥시콜산을 함유하는 시각장애 예방 또는 치료용 조성물
WO2012096411A1 (fr) Méthode de prévention ou traitement de maladie intestinale inflammatoire réfractaire
WO2020068986A1 (fr) Formulations pour le traitement de la maladie de l'œil sec
KR102578102B1 (ko) 엔도텔린 수용체 길항제의 국소 안용 제형
JP5934229B2 (ja) 眼血管疾患の処置のための投与計画
TWI740051B (zh) 用於治療中風及減少神經損傷的化合物及其用途
WO2017053923A1 (fr) Traitement de la conjonctivite virale à l'aide de la ranpirnase et/ou de l'amphinase
WO2022056736A1 (fr) Application de lévofloxacine ou de sels pharmaceutiquement acceptables de cette dernière dans la préparation de médicaments contre les lésions cérébrales d'ischémie-reperfusion ou de produits de soins de santé
US20210046025A1 (en) Injection for Protecting Ischemic Myocardium and Preparation Method thereof
CN112057454B (zh) 左氧氟沙星或其药物可接受盐在制备抗脑缺血再灌注损伤的药物或保健品中的应用
JPH08507774A (ja) 手術後の悪心および嘔吐の治療のためのグラニセトロンの使用
JP5791064B2 (ja) 医薬用組成物
ES2324200T3 (es) Medicamentos oftalmologicos retino-protectores, que comprenden ramipril o ramiprilato.
CN108186639A (zh) 一种盐酸奈康唑的药物组合物
US6441009B1 (en) Agent and method of preventing and treating heavy metal exposure and toxicity
CN103845330A (zh) 一类降低眼压的化合物及其用途
WO2009097138A1 (fr) Compositions antivirales et procédés de traitement
WO2024109724A1 (fr) Complexe d'inclusion de butadiène-cyclodextrine, composition pharmaceutique, leur procédé de préparation et utilisation associée
EP3833378A1 (fr) Traitement des verrues
CN103848837A (zh) 一类降低眼压的化合物及其用途
CN103845321A (zh) 一类降低眼压的化合物及其用途
CN103845334A (zh) 一类降低眼压的化合物及其用途
WO2016047662A1 (fr) Agent thérapeutique contre les accidents vasculaires cérébraux
WO2017117774A1 (fr) Utilisation de butylidènephtalide

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20953594

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20953594

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 11.08.2023)