CN118045071B - Combined medicine for treating ischemic cerebral apoplexy and application thereof - Google Patents
Combined medicine for treating ischemic cerebral apoplexy and application thereof Download PDFInfo
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- CN118045071B CN118045071B CN202410447206.2A CN202410447206A CN118045071B CN 118045071 B CN118045071 B CN 118045071B CN 202410447206 A CN202410447206 A CN 202410447206A CN 118045071 B CN118045071 B CN 118045071B
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- citicoline
- camphene
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- acceptable salt
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a combined medicine for treating ischemic cerebral apoplexy and application thereof, wherein the active ingredients comprise (+) -2-camphene and citicoline or pharmaceutically acceptable salts thereof, wherein the (+) -2-camphene and the citicoline or the pharmaceutically acceptable salts thereof respectively become independent administration units, or the (+) -2-camphene and the citicoline or the pharmaceutically acceptable salts thereof form a combined administration unit together. The combined medicine of the medicines exerts remarkable synergy, has the advantages of effectively reducing or avoiding serious adverse reactions generated in the process of preventing and/or treating ischemic cerebral apoplexy compared with single medicine, and improving the effect of preventing and/or treating ischemic cerebral apoplexy.
Description
Technical Field
The application relates to the technical field related to biological medicine. More particularly, relates to a combined drug of borneol for treating ischemic cerebral apoplexy and application thereof.
Background
The pathological changes after cerebral apoplexy are various and complicated, blood vessels and nerves are closely related, the aim of neuroprotection is gradually changed from single neuroprotection to the protection of nerves and blood vessel integrity, and the concept of 'neurovascular unit' is generated (Chen Ping, chen Liyun, wang Yongjun. The research on neurovascular unit protection of ischemic stroke is [ J ]. Chinese journal of apoplexy, 2007 (12): 1003-1008). Neurovascular units include neurons, glia, vascular cells (endothelial cells, pericytes and smooth muscle cells) and a whole body of basal matrix within the brain vasculature.
The blood brain barrier and cerebral blood flow are precisely controlled by neurovascular units, thereby maintaining a steady state brain microenvironment. Endothelial cells form a highly specialized membrane around blood vessels; pericytes in the central nervous system contribute to neurogenesis and angiogenesis, and pericytes located within blood vessels can act as pluripotent vascular stem cells. Loss of pericytes results in reduced expression of specific Tight Junction (TJ) proteins and subsequent disruption of the blood brain barrier. Astrocytes extend the terminal foot to pericytes and smooth muscle cells to regulate their contraction and relaxation, thereby regulating cerebral blood flow. Astrocytes also regulate the balance of synaptic glutamate and changes in ion metabolism in neuronal cells in part by Ca 2+. All neurovascular unit components are closely related in structure, functionally indispensable, and can maintain brain homeostasis.
Inflammatory response, excitatory amino acid toxicity, oxidative stress, etc. after ischemia reperfusion injury severely affect neuronal cell function and death. The astrocytes are widely connected through gaps, nutrient substances can be transmitted through the gaps in a physiological state, the intracellular calcium pump and the intracellular sodium pump can be disordered in a cerebral ischemia state, meanwhile, the gaps are damaged, ca 2+ and toxic substances are rapidly transmitted, so that the astrocytes release a large amount of glutamic acid, and excitatory amino acid toxicity is aggravated. Microglia are immune cells inherent in the brain, and release a large amount of inflammatory factors after cerebral ischemia, and the accumulated inflammatory factors not only damage normal functions of neurons, but also damage vascular endothelial cells and damage blood brain barrier structures, thereby aggravating cerebral edema. Vascular endothelial cells are extremely vulnerable to damage by factors such as oxygen radicals, inflammatory factors and the like after cerebral ischemia occurs, so that the blood flow of cerebral vessels is changed, the integrity of blood brain barrier is destroyed, and the brain damage is aggravated. Neurovascular units play an important role in regulating blood brain barrier integrity, cell preservation, inflammatory immune response and repair during or after stroke .（Wang L, Xiong X, Zhang L, Shen J. Neurovascular Unit: A critical role in ischemic stroke. CNS Neurosci Ther. 2021 Jan;27(1):7-16.）
The complex changes after cerebral ischemia also reveal why most neuroprotective drugs have little effect in clinical practice, and the curative effect is not obvious because the most neuroprotective drugs only have neurons and cannot protect the whole neurovascular unit, the protective object is single, and the action mechanism is relatively single. Based on the above, it is necessary to further study drugs that can protect against multiple targets of the neurovascular unit as a whole, and achieve the effect of protecting brain cells by multi-effect synergy.
At present, common neuroprotectants in domestic clinic comprise butylphthalide, edaravone dextroamphetamine, citicoline, aceglutamide and the like.
Citicoline is a cell membrane stabilizer, studies have shown that citicoline acts at various times and biochemical stages of the ischemic cascade, has effects （Martynov MY, Gusev EI. Current knowledge on the neuroprotective and neuroregenerative properties of citicoline in acute ischemic stroke. J Exp Pharmacol. 2015 Oct 1;7:17-28;Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport.Neurobiology of Disease 18 (2005) 336-345.）. in alleviating glutamate toxicity, oxidative stress, apoptosis and Blood Brain Barrier (BBB) dysfunction, and some studies have shown that citicoline is not consistently effective in patients with cerebral stroke, a randomized, placebo-controlled trial evaluating citicoline for moderately severe ischemic stroke has not shown that the recent meta-analysis of the difference （Dávalos, Antoni et al. Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet (London, England) vol. 380,9839(2012): 349-57.）. between the two groups suggests that the clinical benefit of citicoline in treating ischemic stroke is limited （Secades, Julio J et al. Citicoline for Acute Ischemic Stroke: A Systematic Review and Formal Meta-analysis of Randomized, Double-Blind, and Placebo-Controlled Trials. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association vol. 25,8 (2016): 1984-96.）.
(+) -2-Borneol, also called dextro-borneol or (+) -borneol, is the main component of natural borneol (the 2015 edition of Chinese pharmacopoeia prescribes that the content of dextro-borneol in natural borneol is not less than 96%). The dextro borneol is a bicyclo-monoterpene compound which exists in the volatile oil of a plurality of Chinese herbal medicines, has various medicinal effects, such as easy penetration of blood brain barrier, promotion of medicine absorption, and bidirectional regulation and protection of central nervous system against ischemia and injury of circulatory system; and has anti-inflammatory, antioxidant and GABA receptor function enhancing effects (Euro J Pharma 2017, 811:1-11). The GABA can be regulated to negatively regulate glutamate excitotoxicity in neuron cells, and simultaneously has the advantages of improving survival rate of ischemia damaged neurons, reducing damage and apoptosis of the neuron cells, reducing the decline of neuron cell tight junction protein under inflammatory conditions and inhibiting the inflammatory level of microglial cells; reducing cerebral infarction area caused by ischemic cerebral apoplexy and improving the neurobehavioral characteristics of the ischemic cerebral apoplexy.
In the prior art, (+) -2-borneol is generally used as a drug adjuvant for treating cerebral apoplexy and other diseases, wherein (+) -2-borneol is the main component of natural borneol, and borneol is a clinically common traditional Chinese medicine, and the traditional Chinese medicine mainly takes the effects of restoring consciousness, inducing resuscitation, clearing heat, relieving pain, preventing corrosion and promoting granulation, is often used as a drug guiding agent to increase the treatment effect of other drugs, and the "materia medica derivative" indicates that borneol is weak in single action and active in adjuvant action ").
Citicoline is currently clinically often treated in combination with other drugs, such as edaravone right camphene combined citicoline to treat ischemic stroke (Li Shizun, hu Tao, hu Linzhuang the effect of edaravone right camphene combined citicoline to treat ischemic stroke [ J ]. Clinical medical engineering, 2023 (010): 030); butylphthalide injection and citicoline sodium are combined to treat ischemic cerebral apoplexy (Yang Liying, li Gongying. Butylphthalide injection and citicoline sodium are combined to treat curative effect of ischemic cerebral apoplexy and influence on cognitive function of patient [ J ]. Hainan medicine, 2021, 32 (7): 5.); cerebral infarction is treated by combining the injection for refreshment and the citicoline (Zhou Kui, tang Xiaobin, clinical research [ J ] of treating cerebral infarction by combining the injection for refreshment and the citicoline, modern medicine and clinic, 2019,34 (9): 2681-2685.). However, the treatment of cerebral apoplexy by combining (+) -2-camphene and citicoline has not been reported yet.
Disclosure of Invention
The invention aims to overcome the defects and the shortcomings of the existing citicoline or pharmaceutically acceptable salts thereof in the aspect of treating ischemic cerebral apoplexy, and provides a novel scheme for treating ischemic cerebral apoplexy.
A first object of the present invention is to provide the use of (+) -2-camphene for the preparation of a potentiator of citicoline or a pharmaceutically acceptable salt thereof for the prevention, amelioration or treatment of ischemic stroke disease, said use being devoid of edaravone.
A second object of the present invention is to provide the use of (+) -2-camphene and citicoline or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the prevention, amelioration or treatment of ischemic stroke diseases, said medicament being devoid of edaravone.
Still another object of the present invention is to provide a combination for treating ischemic stroke, which is characterized by comprising da (+) -2-camphol and citicoline or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable pharmaceutical excipients, wherein the combination does not contain edaravone.
The above object of the present invention is achieved by the following technical scheme:
The invention creatively combines (+) -2-camphol and the medicine citicoline or pharmaceutically acceptable salt thereof as the medicine for treating ischemic cerebral apoplexy, wherein the citicoline acts on neuron cells by improving the stability of cell membranes, but other mechanisms influence the exertion of the curative effect, so that the effect of treating ischemic cerebral apoplexy is limited.
The invention discovers that the (+) -2-camphene can effectively improve the treatment effect of the citicoline or the pharmaceutically acceptable salt thereof, reduce the effective concentration and the dosage, play the role of a synergistic agent, and the combined drug of the (+) -2-camphene and the citicoline has the effect of remarkably improving the survival of ischemia damaged neurons compared with the single (+) -2-camphene or the citicoline; has the functions of remarkably inhibiting the inflammatory level of microglial cells and reducing the decline and apoptosis of microglial cell tight junction proteins under inflammatory conditions compared with single (+) -2-camphol or citicoline; has the effect of remarkably reducing the damage level of the endothelial cells of the cerebral microvasculature compared with single (+) -2-camphol or citicoline; has the functions of remarkably reducing cerebral infarction area caused by ischemic cerebral apoplexy and improving the neurobehavioral characteristics of the ischemic cerebral apoplexy compared with single (+) -2-camphol or citicoline.
In certain embodiments, the effect of (+) -2-kaempferol in combination with citicoline or a pharmaceutically acceptable salt thereof is selected from the group consisting of: improving the survival rate of ischemia damaged neurons, reducing the decline and apoptosis of microglial tight junction protein under inflammatory conditions, and inhibiting the inflammatory level of microglial cells; reducing cerebral infarction area caused by ischemic cerebral apoplexy, and improving any one or combination of the neurobehavioral characteristics of the ischemic cerebral apoplexy.
In a first aspect, the invention provides the use of (+) -2-camphene for the preparation of a potentiator of citicoline or a pharmaceutically acceptable salt thereof for the prevention, amelioration or treatment of ischemic stroke.
In a second aspect, the invention provides the use of (+) -2-camphene and citicoline or pharmaceutically acceptable salts thereof in combination for the manufacture of a medicament for the prevention, amelioration or treatment of ischemic stroke disease.
In a third aspect, the use of (+) -2-camphene and citicoline or a pharmaceutically acceptable salt thereof in combination for the manufacture of a neuronal cytoprotective agent, anti-inflammatory agent, cerebrovascular barrier protective agent or anti-apoptotic agent for the prevention, amelioration or treatment of ischemic stroke disease.
Specifically, in the application of (+) -2-camphene and citicoline or pharmaceutically acceptable salts thereof, the mass ratio of (+) -2-camphene to citicoline is 1:1-1:10, preferably 1:5.
Specifically, in the above application of (+) -2-camphene and citicoline or pharmaceutically acceptable salts thereof, the pharmaceutically acceptable salts are metal salts of citicoline.
Preferably, the metal salt comprises any one of lithium, sodium, potassium, magnesium or calcium salt, preferably sodium or potassium salt.
Specifically, in the application of the (+) -2-camphene and citicoline or the pharmaceutically acceptable salts thereof, the combined medicament for preventing and/or treating ischemic cerebral apoplexy further comprises auxiliary materials;
Preferably, the auxiliary material is selected from any one or a combination of at least two of excipient, diluent, carrier, flavoring agent, adhesive or filler;
Preferably, the dosage form of the combined medicament for preventing and/or treating ischemic cerebral apoplexy is selected from any one of injection, oral preparation, external preparation or parenteral administration preparation.
Specifically, in the application of the (+) -2-camphene and citicoline or the pharmaceutically acceptable salt thereof, the active ingredients of the combined medicament for preventing and/or treating cerebral apoplexy comprise (+) -2-camphene and citicoline or the pharmaceutically acceptable salt, wherein the (+) -2-camphene and the citicoline or the pharmaceutically acceptable salt are respectively prepared into independent administration units, and then combined, or the (+) -2-camphene and the citicoline or the pharmaceutically acceptable salt are jointly prepared into combined administration units.
The invention has the following effects: the (+) -2-camphol combined citicoline has the efficacy obviously superior to that of single prescription in vitro and animal model test of ischemic cerebral apoplexy. The (+) -2-camphol can effectively improve the treatment effect of citicoline or pharmaceutically acceptable salt thereof, reduce the effective concentration and dosage and play the role of a synergistic agent.
Detailed Description
Further advantages and effects of the present application will become readily apparent to those skilled in the art from the present disclosure, by describing embodiments of the present application with specific examples.
Without intending to be limited by any theory, the following examples are meant to illustrate the medicaments, the methods of preparation, the uses, and the like of the present application and are not intended to limit the scope of the present application.
Examples
Example 1
In this example, the in vitro anti-inflammatory activity of each of the above groups on mouse brain microglial BV-2 was studied using different concentrations of (+) -2-kaempferol, citicoline, (+) -2-kaempferol+citicoline combination, and edaravone++ (+) -2-kaempferol+citicoline combination.
The test method comprises the following steps: taking a pre-prepared cell suspension, inoculating a 12-hole plate with 2.5X10 5 cells/hole and 1 mL/hole, placing the cell suspension in a 37 ℃ and 5% CO 2 incubator for culture overnight, collecting 80% of cells, discarding the original culture solution, adding different prepared test reagent solutions into each hole, adding the test reagent, and adding TNF-alpha+INF-gamma (the final concentration is 10 ng/mL). Meanwhile, a cell control group (without medicine and solvent) is arranged, and the culture is continued for 24 hours. The expression of IL-1 beta and IL-6 inflammatory factors in each group was detected by Q-PCR.
The results in tables 1 and 2 show that: the citicoline and the (+) -2-camphol with different concentrations can inhibit the expression of IL-1 beta and IL-6 mRNA secreted by mouse brain microglial cells BV-2 cells induced by TNF-alpha+INF-gamma; the combination of (+) -2-camphene and citicoline has the effect of remarkably inhibiting the inflammatory level of microglial cells more than single (+) -2-camphene or citicoline, and the halving treatment of the dosage of the citicoline and the (+) -2-camphene is carried out and then the combination is used, so that the inflammatory level of microglial cells can be remarkably inhibited, and the two medicines are suggested to have synergistic or synergistic effects. However, the introduction of edaravone reduces the inhibition effect of the combined drug. In the combined administration group of (+) -2-camphene and citicoline, different ratio combinations of (+) -2-camphene and citicoline (1:10, 1:5, 1:1) significantly inhibit microglial inflammation levels compared to the model group, 1 in these three ratios: 5 has the best effect of inhibiting inflammation. ( And (3) injection: TI:10ng/mL TNF- α+INF- γ, A: citicoline 10 μ M, B: (+) -2-camphol 1 μ M, C: (+) -2-camphol 2 μ M, D: (+) -2-camphol 10 μ M, E: edaravone 8 μm )
Example 2
In this example, the effect of each treatment group on the expression of mouse brain microglial cell BV-2 tight junction protein ZO-1 was tested using a combination of citicoline, (+) -2-camphol + citicoline.
The test method comprises the following steps: taking a pre-prepared mouse brain microglial cell suspension (BV-2), inoculating a 6-hole plate with 2.5X10 5 cells/hole and 2 mL/hole, culturing overnight in a 5% CO 2 incubator at 37 ℃, collecting 80% of cells, discarding the original culture solution, adding different prepared test reagent solutions into each hole, and then adding TNF-alpha+INF-gamma (final concentration 10 ng/mL). Meanwhile, a cell control group (without medicine and solvent) is arranged, and the culture is continued for 24 hours. Western Blot (Biyun) was used to examine the expression of zonulin ZO-1 from each group.
The results from table 3 show that: the citicoline, (+) -2-camphol and citicoline all have the effect of remarkably increasing the expression level of mouse brain microglial tight junction protein ZO-1 after induction of TNF-alpha+INF-gamma and protecting the barrier of mouse brain microglial cells. The combination of (+) -2-camphene and citicoline has more remarkable protection effect than single (+) -2-camphene or citicoline, and the dosage of citicoline and (+) -2-camphene is halved, and the combination administration can still show remarkable increase of the expression level of mouse brain microglial tight junction protein ZO-1 after TNF-alpha+INF-gamma induction, which suggests that the two medicines have synergistic or synergistic effect. And the introduction of edaravone can reduce the protection effect of the combined drug. ( And (3) injection: TI 10ng/mL TNF- α+INF- γ, A: citicoline 10 μ M, B: (+) -2-camphol 2 μ M, C: edaravone 8 μm )
EXAMPLE 3 anti-apoptosis study
In this example, the effect of each drug treatment group on expression of the mouse brain microglial BV-2 apoptosis protein C-Cas 3 in vitro was tested using citicoline, (+) -2-camphol, (+) -2-camphol+citicoline in combination, edaravone++ (+) -2-camphol+citicoline in combination.
The test method comprises the following steps: taking a pre-prepared mouse brain microglial cell suspension (BV-2), inoculating a 6-hole plate with 2.5X10 5 cells/hole and 2 mL/hole, culturing overnight in a 5% CO 2 incubator at 37 ℃, collecting 80% of cells, discarding the original culture solution, adding different prepared test reagent solutions into each hole, and then adding TNF-alpha+INF-gamma (final concentration 10 ng/mL). Meanwhile, a cell control group (without medicine and solvent) is arranged, and the culture is continued for 24 hours. Expression of apoptotic proteins (C-Cas 3) was detected in each group using Western Blot (Biyun sky).
The results from table 4 show that: the combination groups of citicoline, (+) -2-camphol and citicoline all have the effects of obviously reducing the protein level of mouse brain microglial apoptosis protein C-Cas 3 after induction of TNF-alpha+INF-gamma and inhibiting apoptosis. And the combination of (+) -2-camphol and citicoline has more remarkable inhibition effect than single (+) -2-camphol or citicoline, the dosage of citicoline and (+) -2-camphol is halved, and the combined administration can still obviously inhibit the apoptosis level of microglial cells, so that the two medicines have synergistic or synergistic effect. And the introduction of edaravone can reduce the protection effect of the combined drug. (note: TI:10ng/mL TNF-. Alpha. + INF-. Gamma., A: citicoline 5. Mu. M, B: (+) -2-camphol 2. Mu. M, C: edaravone 8. Mu.M).
Example 4
In this example, the study of the effects of each drug on glutamate-induced neuronal cytotoxicity was tested using citicoline, different concentrations of (+) -2-kaempferol, (+) -2-kaempferol + citicoline, edaravone + (+) -2-kaempferol + citicoline combinations.
The test method comprises the following steps: taking a pre-prepared neuron cell suspension (HT 22), inoculating 8000 cells/hole and 100 mu L/hole into a 96-well plate, placing the plate in a 37 ℃ and 5% CO 2 incubator for culture overnight, collecting 80% of cells, discarding the original culture solution, adding different prepared test reagent solutions into each hole, and then adding glutamic acid (L-Glu, the final concentration is 10 mM). Meanwhile, a cell control group (without medicine and solvent) is arranged, and the culture is continued for 24 hours. Cell viability was measured for each group using the CCK8 method (DOJINDO).
The results from table 5 show that: the combination of citicoline, (+) -2-camphene with different concentrations and (+) -2-camphene and citicoline can obviously increase the activity of HT22 cells of mouse brain neuron cells after glutamate induction. And the combination of (+) -2-camphene and citicoline can protect the activity of HT22 cells of mouse brain neuron better than single (+) -2-camphene or citicoline; the dose of citicoline and (+) -2-camphol is halved, and the combined administration can still obviously protect the activity of HT22 cells of brain neurons of mice, so that the two medicines have synergistic or synergistic effects. However, the introduction of edaravone reduces the effect of the combination. In the combined administration group of (+) -2-camphene and citicoline, the combined group (1:10, 1:5, 1:1) of different proportions of (+) -2-camphene and citicoline can obviously protect the activity of HT22 cells of brain neurons of mice compared with a model group, and 1 in the three proportions: 5, the protection effect is optimal. (note: A: citicoline 5 μ M, B: (+) -2-camphene 1 μ M, C: (+) -2-camphene 2 μ M, D: (+) -2-camphene 10 μ M, E: edaravone 8 μM).
Example 5
In this example, the effect of each drug on human brain microvascular endothelial cell permeability was tested using citicoline, different concentrations of (+) -2-kaempferol in combination with citicoline, edaravone++ (+) -2-kaempferol+citicoline in combination.
The test method comprises the following steps: a single-layer cell model is constructed by plating a Trans-well cell with a cell density of 1.0X 4 cells per well, after the cell is subjected to wall-attached culture for 5 days, the transmembrane resistance value of each group of cells is detected, no statistical difference exists among the cells, 25ng/mL TNF-alpha, and citicoline, different concentrations of (+) -2-camphol, (+) -2-camphol and citicoline are added for combined treatment, edaravone++ (+) -2-camphol and citicoline are combined for treatment, and after the cell is subjected to total culture for 24 hours, the transmembrane resistance value of the cells of each treatment group is detected.
Teer= [ cell-containing well resistance value-cell-free well (blank well) resistance value ] ×membrane area, trans-well cell membrane area is 0.3 cm 2.
The results from table 6 show that: the combined treatment of citicoline, different concentrations of (+) -2-camphol and citicoline obviously increases the transmembrane resistance of human brain microvascular endothelial cells HCMEC/D3 cells after TNF-alpha induction. The protection of (+) -2-camphol at different concentrations showed dose dependency. And the combination of (+) -2-camphene and citicoline has the effect of remarkably increasing the transmembrane resistance of human brain microvascular endothelial cells HCMEC/D3 cells after TNF-alpha induction compared with single (+) -2-camphene or citicoline, and halving the dose of citicoline and (+) -2-camphene, and the combined administration can remarkably increase the transmembrane resistance of human brain microvascular endothelial cells HCMEC/D3 cells after TNF-alpha induction, thereby prompting that the two drugs have synergistic or synergistic effects. And the introduction of edaravone can be known to reduce the effect of the combined drug. In the combined administration group of (+) -2-camphene and citicoline, the combination of different proportions of (+) -2-camphene and citicoline (1:10, 1:5 and 1:1) can obviously increase the transmembrane resistance of human brain microvascular endothelial cells HCMEC/D3 cells after TNF-alpha induction compared with a model group, and the effect is the best in the three proportions of 1:5. ( And (3) injection: a: citicoline 10 μ M, B: (+) -2-camphol 1 μ M, C: (+) -2-camphol 2 μ M, D: (+) -2-camphol 10 μ M, E: edaravone 8 μm )
EXAMPLE 6 study of drug efficacy in rat models of ischemic cerebral apoplexy
In this example, drug efficacy comparison studies of (+) -2-camphene+citicoline ((+) -2-camphene: citicoline=1:5) in rat models of ischemic stroke.
The test method comprises the following steps: the MCAO model was prepared by a wire-plug method, cerebral blood flow reperfusion was performed after 1.5 h ischemia in rats, and the samples of citicoline, (+) -2-camphol, etc. were administered by tail vein injection after 2.2 h, 24, h reperfusion, and the therapeutic effect of each administration group on MCAO rats was evaluated. Sham rats were treated the same as model rats except that they were not embolized. The experimental rats were divided into 7 groups (N.gtoreq.10): sham, model, (+) -2-kaempferol (0.5 mg/kg), (+) -2-kaempferol (1 mg/kg) and citicoline (5 mg/kg), combination 1 (citicoline 2.5 mg/kg+ (+) -2-kaempferol 0.25 mg/kg), combination 2 (citicoline 2.5 mg/kg+ (+) -2-kaempferol 0.5 mg/kg). After 24h, the neuro-functional behavioural score and the percentage of cerebral infarction area were observed.
The results show (see Table 7) that the cerebral infarction area of the solvent control group is 57.71%; compared with the solvent control group, the citicoline group infarct area is reduced by 2.33%, the (+) -2-camphene 0.5 mg/kg group infarct area is reduced by 11.1%, the (+) -2-camphene 1 mg/kg administration group infarct area is reduced by 14.78%, the combination 1 infarct area is reduced by 18.66%, and the combination 2 infarct area is reduced by 20.87%. The results show that after the reduction of the administration doses of citicoline and (+) -2-camphene, the reduction of cerebral infarction area of rats by the combined administration group is still significantly larger than that of the independent (+) -2-camphene administration group or citicoline administration group, which indicates that the two medicines have synergism or synergy. Wherein the infarct size of (+) -2-camphene 0.5 mg/kg+citicoline 2.5mg/kg group (1:5 group) is minimal, suggesting that: the combined administration of (+) -2-camphene 0.5 mg/kg + citicoline 2.5mg/kg (1:5 group) is superior to the combined administration of (+) -2-camphene 0.25 mg/kg + citicoline 2.5mg/kg (1:10 group).
Meanwhile, the neurobehavioral scores of stroke rats are obviously reduced by the (+) -2-camphene and citicoline administration groups, and as can be seen from table 7, the neurobehavioral score of the combined drug group 1 is 1.80+/-0.79, the neurobehavioral score of the combined drug group 2 is 1.40+/-0.52, which are smaller than that of the single drug group (2-camphene and citicoline), and the drug effect of the (+) -2-camphene 0.5 mg/kg+citicoline 2.5mg/kg combination (1:5 group) is optimal. (note: A: citicoline, B: (+) -2-camphol).
Claims (13)
1. Application of (+) -2-camphene in preparing synergist for preventing, improving or treating ischemic cerebral apoplexy diseases by citicoline or pharmaceutically acceptable salt thereof, wherein the application does not contain edaravone.
2. The use according to claim 1, wherein the mass ratio of (+) -2-camphene and citicoline is 1:1-1:10.
3. The use according to claim 1, wherein the pharmaceutically acceptable salt is a metal salt of citicoline.
4. The application of the combination of the (+) -2-camphene and citicoline or the pharmaceutically acceptable salt thereof in preparing medicines for preventing, improving or treating ischemic cerebral apoplexy or medicines for improving the preventing, improving or treating ischemic cerebral apoplexy is provided, wherein the combined medicines do not contain edaravone, and the mass ratio of the (+) -2-camphene to the citicoline is 1:1-1:10.
5. The use of claim 4, wherein the medicament is a neuronal cell protectant, microglial anti-inflammatory agent, anti-apoptotic agent or cerebrovascular barrier protectant.
6. The use according to claim 4, wherein the pharmaceutically acceptable salt is a metal salt of citicoline.
7. The use according to any one of claims 4 to 6, wherein the medicament for the combination of (+) -2-camphol and citicoline or a pharmaceutically acceptable salt thereof further comprises an adjuvant.
8. The use according to claim 7, wherein the adjuvant is selected from any one or a combination of at least two of a carrier, a flavouring agent, a binder or a filler.
9. The use according to claim 8, wherein the filler is a diluent.
10. The use as claimed in claim 7 wherein the dosage form of the medicament for the combination of (+) -2-camphene and citicoline or pharmaceutically acceptable salt thereof is selected from the group consisting of oral or parenteral dosage formulations.
11. The use as claimed in claim 7 wherein the dosage form of the medicament for the combination of (+) -2-camphene and citicoline or pharmaceutically acceptable salts thereof is selected from injectable or topical formulations.
12. The combined medicine for preventing and/or treating ischemic cerebral apoplexy is characterized in that the active ingredients of the medicine comprise (+) -2-camphene and citicoline or pharmaceutically acceptable salt, the combined medicine does not contain edaravone, and the mass ratio of the (+) -2-camphene to the citicoline is 1:1-1:10.
13. The combination of claim 12, wherein the (+) -2-kaempferol and the citicoline or pharmaceutically acceptable salt are separately formulated into separate dosage units for reconstitution; or the (+) -2-camphol and the citicoline or pharmaceutically acceptable salt are made into a combined administration unit.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102475769A (en) * | 2010-11-25 | 2012-05-30 | 陈冠卿 | Synergistic agent for treating hemiplegia |
| CN110248649A (en) * | 2017-07-07 | 2019-09-17 | 苏州沪云新药研发股份有限公司 | (+) -2- baras camphor promotees the application in sphingosine kinase-1 and/or the drug of BDNF expression up-regulation in preparation |
| CN115518057A (en) * | 2021-10-18 | 2022-12-27 | 苏州沪云新药研发股份有限公司 | Application of camphanol in preparation of medicine for treating ischemic stroke |
| WO2024051848A1 (en) * | 2022-09-09 | 2024-03-14 | 北京达尔文细胞生物科技有限公司 | Pharmaceutical composition for preventing and treating nervous system lesions and application thereof |
-
2024
- 2024-04-15 CN CN202410447206.2A patent/CN118045071B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102475769A (en) * | 2010-11-25 | 2012-05-30 | 陈冠卿 | Synergistic agent for treating hemiplegia |
| CN110248649A (en) * | 2017-07-07 | 2019-09-17 | 苏州沪云新药研发股份有限公司 | (+) -2- baras camphor promotees the application in sphingosine kinase-1 and/or the drug of BDNF expression up-regulation in preparation |
| CN115518057A (en) * | 2021-10-18 | 2022-12-27 | 苏州沪云新药研发股份有限公司 | Application of camphanol in preparation of medicine for treating ischemic stroke |
| WO2024051848A1 (en) * | 2022-09-09 | 2024-03-14 | 北京达尔文细胞生物科技有限公司 | Pharmaceutical composition for preventing and treating nervous system lesions and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| 胞磷胆碱治疗缺血性脑卒中及相关疾病的研究进展;张惠婷等;交通医学;20131231;第27卷(第1期);第34-36、39页，尤其是第34页左栏第1-2段 * |
| 胞磷胆碱钠联合依达拉奉右莰醇治疗急性缺血性脑卒的临床疗效观察;赖智宗等;现代诊断与治疗;20231031;第34卷(第20期);第3052-3054页 * |
| 醒脑静注射液联合胞磷胆碱钠注射液治疗急性脑梗死的临床效果;王亚娟等;临床医学研究与实践;20200831;第5卷(第23期);第133-135页，尤其是讨论 * |
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