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WO2020138556A1 - Composition pharmaceutique pour inhiber la vasoconstriction - Google Patents

Composition pharmaceutique pour inhiber la vasoconstriction Download PDF

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Publication number
WO2020138556A1
WO2020138556A1 PCT/KR2018/016821 KR2018016821W WO2020138556A1 WO 2020138556 A1 WO2020138556 A1 WO 2020138556A1 KR 2018016821 W KR2018016821 W KR 2018016821W WO 2020138556 A1 WO2020138556 A1 WO 2020138556A1
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Prior art keywords
bupivacaine
vasodilation
induced
levchromacarim
phenylephrine
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Korean (ko)
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손주태
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Gyeongsang National University Hospital
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Gyeongsang National University Hospital
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • 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
    • A61P9/08—Vasodilators for multiple indications

Definitions

  • the present invention relates to a pharmaceutical composition for inhibiting vasodilation.
  • Lipid emulsions effectively treat cardiovascular suppression caused by the administration of toxic doses of local anesthetics.
  • the proposed basic mechanisms include lipid absorption and shuttle, fatty acid supply, enhanced myocardial contractility, reduction of mitochondrial disorders, inhibition of cardiac sodium channel blockade, reduction of phosphorylation of glycogen synthase kinase-3 and reduction of nitric oxide production.
  • Lipid emulsions are widely used in the treatment of local anesthetic poisoning.
  • the administration of toxic doses of bupivacaine causes severe myocardial suppression and electrophysiological changes in the heart, leading to hemodynamic suppression.
  • administration of toxic doses of local anesthetics including bupivacaine, ropivacaine, and mepivacaine causes vasoconstriction.
  • Toxic dose bupivacaine decreases blood flow to the organs due to increased posterior load associated with vasoconstriction and myocardial suppression.
  • a decrease in blood flow caused by systemic toxicity of a local anesthetic causes a conditional physiological condition such as ischemia, hypoxia, and acidosis, causing a protective response of vasodilation of ATP -sensitive potassium (K ATP ) channel-induced vascular smooth muscle.
  • local anesthetics such as lidocaine, R-(+)-bubivacaine, mepivacaine reduce vasodilation caused by the K ATP channel agonist levchromacarim in isolated blood vessels.
  • Intralipid® composed of 100% long-chain fatty acids in various types of lipid emulsions, is widely used as a therapeutic agent for local anesthetic systemic toxicity.
  • the long-chain fatty acids contained in Intralipid® are composed of linoleic acid (53%), oleic acid (24%), palmitic acid (11%), alpha linoleic acid (8%) and stearic acid (4%).
  • linoleic acid which constitutes the largest group of long-chain fatty acids (53%) in Intralipid®, activates the K ATP channel and causes membrane hyperpolarization in the pancreas.
  • K ATP channels are expressed in various vascular smooth muscle cells.
  • the K ATP channel plays an important role in regulating vascular responses to various endogenous substances and pharmacological vasodilators by regulating smooth muscle membrane and polarization.
  • Control of the K ATP channel contributes to the regulation of blood vessel tension and blood flow.
  • the effect of lipid emulsion and linoleic acid on inhibition by local anesthetics on vasodilation caused by K ATP channels in isolated blood vessels is unknown.
  • An object of the present invention is to provide a composition capable of inhibiting the inhibition of vasodilation.
  • a pharmaceutical composition for inhibiting vasodilation reduction comprising linoleic acid.
  • composition of 1 above, wherein the vasodilation is by levchromacarim treatment.
  • composition of 1 above wherein the reduction in vasodilation is due to local anesthetic treatment.
  • composition of 4 above wherein the local anesthetic is at least one selected from the group consisting of bupivacaine, ropivacaine, and mepivacaine.
  • composition of 4 above, wherein the local anesthetic is bupivacaine.
  • composition of 1 above wherein the inhibition of vasodilation is performed on vascular smooth muscle.
  • composition of the present invention is excellent in inhibiting the effect of vasodilation.
  • ANOVA ANOVA
  • n represents the number of isolated aorta of rats.
  • DF Effect of lipid emulsion (LE) on local anesthetic mediated reduction of toxic doses on levchromacarim-induced vasodilation in isolated rat mesenteric arteries without endothelium.
  • n represents the number of mesenteric arteries of the isolated rat.
  • Data are presented as mean ⁇ standard deviation and as a percentage of phenylephrine induced maximum contraction. Data were analyzed by one-way ANOVA (ANOVA) followed by Bonferroni's multiple comparison test, or Mann-Whitney test.
  • n represents the number of isolated aorta of rats.
  • Rev chroma Karim (10 -5 M) to the maximum chroma or rev Karim vasodilation induced by (10 -5 M) the number of the maximum chroma Rev Karim concentration needed to cause half the vasodilation (log ED 50) induced by: * p ⁇ 0.001 versus GF109023X or genistein alone, ⁇ p ⁇ 0.001 versus bupivacaine alone.
  • the effect of bupivacaine ((D), n 10) on vasodilation.
  • Data are presented as mean ⁇ standard deviation and as a percentage of phenylephrine induced maximum contraction. Data were analyzed by one-way ANOVA (ANOVA) followed by Bonferroni's multiple comparison test, unpaired Student's t-test.
  • n represents the number of isolated aorta of rats.
  • n denotes the number of isolated aorta of rats Levromacarim (10 -5 M) induced maximal vasodilation or log ED 50 : * p ⁇ 0.01, ⁇ p ⁇ 0.001 versus GF109203X plus LE, # p ⁇ 0.001 versus GF109203X plus Bupivacaine.
  • Figure 4 Effect of bupivacaine and lipid emulsion on membrane potential and total cell current of lev chromacarim treated vascular smooth muscle cells.
  • the bar graph summarizes the effect of levchromacarim, bupivacaine and lipid emulsions on whole cell current. The current level was determined at +60 mV. Data were analyzed by one-way ANOVA and post hoc comparisons using Tukey's test. * p ⁇ 0.05 versus control. ⁇ p ⁇ 0.05 versus Rev chromacarim alone. # p ⁇ 0.05 versus bupivacaine + lev chromacarim.
  • SPSS 17.0 SPSS Inc., Chicago, IL, USA
  • FIG. 7 Bupivacaine (10 -5 M), GF109203X (3 x 10 -6 M) and lipid emulsion (LE, 1) for phenylephrine-induced protein kinase C (PKC) phosphorylation in rat aortic smooth muscle cells (RAVSMCs). %), alone or in combination.
  • PKC protein kinase C
  • RAVSMCs were treated with phenylephrine alone (10 -6 M) for 10 minutes, pretreated with phenylephrine (10 -6 M) for 1 minute, treated with bupivacaine (10 -5 M) for 9 minutes, and GF109203X (3 x 10 -6 M) for 70 minutes, phenylephrine (10 -6 M) for 1 minute, bupivacaine (10 -5 M) for 9 minutes, LE (1%) for 40 minutes Treated with phenylephrine (10 -6 M) for 1 minute, treated with bupivacaine (10 -5 M) for 9 minutes, or pretreated with GF109203X for 30 minutes, treated with LE (1%) for 40 minutes, and phenylephrine (10 -6 M) for 1 minute and bupivacaine (10 -5 M) for 9 minutes.
  • p-PKC phosphorylated PKC.
  • t-PKC total PKC. * p ⁇ 0.001 versus control. ⁇ p ⁇ 0.001 versus phenylephrine alone. # p ⁇ 0.001 versus phenylephrine + bupivacaine. ⁇ p ⁇ 0.001 versus GF109203X + Phenylephrine + Bupivacaine
  • the present invention provides a pharmaceutical composition for inhibiting vasodilation reduction comprising linoleic acid.
  • the present inventor devised the present invention in view of finding that linoleic acid can inhibit a decrease in vasodilation. This is thought to be due to the activation of the linoleic acid K ATP channel (potassium channel). It is known that when potassium channels are opened, muscle relaxation causes vasodilation.
  • Reduction of vasodilation in the present specification may be, for example, by local anesthetic treatment, but is not limited thereto.
  • the local anesthetic may be, for example, one or more selected from the group consisting of bupivacaine, ropivacaine, and mepivacaine, and specifically, bupivacaine.
  • Reduction of vasodilation herein may be, for example, by treatment with a toxic dose of a local anesthetic.
  • the toxic dose may vary depending on various factors such as the species, weight, and local anesthetic of the target individual. For example, in adult cases, 10 -5 M or more for bupivacaine and 5 ⁇ 10 -5 for ropivacaine M or more, in the case of mepivacaine, may be 3 x 10 -4 M or more, but is not limited thereto.
  • inhibition of vasodilation may be performed on vascular smooth muscle, but is not limited thereto.
  • the vasodilation may be, for example, by treatment with a vasodilator, and may be, for example, by treatment with levcromakalim.
  • Lipid emulsions are fatty acid emulsions and include linoleic acid.
  • Other known short chain, heavy chain or short chain fatty acids may be further included.
  • long chain fatty acids have chains of C14 or more
  • medium chain fatty acids have chains of C6 to C12
  • short chain fatty acids have chains of C5 or less.
  • Specific examples include linoleic acid, oleic acid, palmitic acid, alpha linoleic acid, and stearic acid, but are not limited thereto.
  • Intralipid® having only 100% long-chain fatty acids, but any of those containing linoleic acid may be used without limitation.
  • composition of the present invention may further include a pharmaceutically acceptable carrier, and may be formulated together with the carrier.
  • pharmaceutically acceptable carrier refers to a carrier or diluent that does not stimulate the organism and does not inhibit the biological activity and properties of the administered compound.
  • a pharmaceutical carrier that is acceptable in a composition formulated as a liquid solution, as a sterile and biocompatible material, saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary.
  • diluents such as aqueous solutions, suspensions, emulsions, pills, capsules, granules or tablets.
  • composition of the present invention is applicable to any formulation containing linoleic acid as an active ingredient, and can be prepared in oral or parenteral formulations.
  • the pharmaceutical formulation of the present invention is oral, rectal, nasal, topical (including cheek and sublingual), subcutaneous, vaginal or parenteral; intramuscular and subcutaneous. And intravenous) or forms suitable for administration by inhalation or insufflation.
  • the composition of the present invention is administered in a pharmaceutically effective amount.
  • the effective dose level depends on the type of patient's disease, severity, drug activity, sensitivity to the drug, time of administration, rate of administration and release, duration of treatment, factors including concurrently used drugs, and other factors well known in the medical field. Can be determined.
  • the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art.
  • the dosage of the composition of the present invention can vary greatly depending on the patient's weight, age, sex, health, diet, administration time, administration method, excretion rate, and disease severity. For example, it may be 0.01 ⁇ g to 1 g per 1 kg of body weight, and may be administered in units of daily, weekly, monthly, or yearly, divided into once to several times per unit period, or continuously administered for a long time using an infusion pump. Can be. The number of repeated doses is determined taking into account the time the drug stays in the body and the concentration of the drug in the body. The composition may be administered to prevent recurrence even after being treated according to the course of disease treatment.
  • compositions of the present invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a subject.
  • Formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.
  • the present invention provides a pharmaceutical composition for vasodilation comprising linoleic acid.
  • linoleic acid can activate the K ATP channel (potassium channel) to cause vasodilation, and the pharmaceutical composition of the present invention can be utilized for vasodilation purposes.
  • Linoleic acid and pharmaceutical compositions are as described above.
  • vasodilation may be performed on, for example, vascular smooth muscle, but is not limited thereto.
  • the components of the Krebs solution are: 118 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO 4 , 2.4 mM CaCl 2 , 25 mM NaHCO 3 and 11 mM glucose.
  • the isolated aorta was cut into 2.5 mm long rings.
  • the endothelium was removed from the isolated descending thoracic aorta by inserting a 25 gauge needle into the lumen of the separated aorta and rolling the separated aorta for several seconds.
  • the isolated rat aorta was suspended in a Grass isometric transducer (FT-03; Grass Instrument, Quincy, MA, USA) connected to a 10 mL organ bath maintained at 37°C.
  • FT-03 Grass Instrument, Quincy, MA, USA
  • a resting tension of 3.0 g was used for the isolated aorta of the rat and maintained for 120 minutes to reach equilibrium.
  • the Krebs solution in the engine tank was aerated with oxygen (95%) and carbon dioxide (5%) to maintain the pH from 7.35 to 7.45.
  • the Krebs solution in the trachea holding suspended isolated aorta was replaced with a fresh Krebs solution every 30 minutes.
  • acetylcholine (10 -5 M) was administered to the trachea to confirm endothelial removal.
  • Less than 15% relaxation induced by acetylcholine was considered to be the removal of the endothelium from the isolated rat aorta.
  • the isolated rat aorta was then washed several times with fresh Krebs solution to restore the reference resting tension (3.0 g).
  • Measurement of the isometric tension of the rat mesenteric artery was performed as follows.
  • the mesenteric artery was quickly excised and placed in a cold Krebs solution.
  • the blood vessel was cut into 1 mm wide loop pieces and placed in a 3 mL tissue bath holding two L-shaped rings, one of which was a force transducer (MLT050, ADInstruments, to measure isometric tension). Colorado Springs, CO, USA).
  • the blood vessel tension was recorded on a computer equipped with PowerLab/400 (ADInstruments). Data were analyzed by the Chart 5 program.
  • 0.5 g of resting tension was used for the isolated rat mesenteric artery, and the 0.5 g tension was maintained for 90 minutes to reach equilibrium before each experiment.
  • the endothelium was mechanically removed by gently rubbing with moistend cotton, and the endothelium removal was confirmed in the absence of the acetylcholine-induced relaxation reaction (10 -6 M) of contraction induced by 10 -5 M phenylephrine.
  • the isolated rat mesenteric artery was washed with fresh Krebs solution to restore the resting tissue tension (0.5 g) to the basal state.
  • nitric oxide which is basically produced from the endothelium, causes more vasodilation induced by levchromacarim through the cyclic guanosine monophosphate path than in the rat aorta where the endothelium is completely removed from the rat aorta with complete endothelium.
  • the direct effect of local anesthetics on isolated rat aorta weakens vasoconstriction with endothelial nitric oxide production stimulated by local anesthesia.
  • endothelial-free blood vessels were used to avoid factors that interfered with the interpretation of experimental results, such as increased vasodilation by levchromacarim due to increased endothelial nitric oxide release mediated by the local anesthetic.
  • the vascular endothelium was removed and pre-treated with L-NAME because the residual endothelium remaining after removal could affect vasodilation.
  • lipid emulsion lipid emulsion, Intralipid® 20%
  • lipid emulsion Intralipid® 20%
  • lipid emulsions (0.1%, 0.25% and 1%) for 20 minutes before adding phenylephrine to the trachea.
  • aortic rings were post-treated with 10 -5 M bupivacaine with or without lipid emulsion alone or a mixture of GW1100 and lipid emulsion when contraction induced by phenylephrine (10 -6 M) progressed.
  • levchromacarim (10 -8 to 10 -5 M) was administered in an accumulating manner to obtain levchromacarim dose-response curve.
  • PKC protein kinase C
  • GF109203X 3 ⁇ 10 -6 M
  • tyrosine kinase inhibitor genistein 10 -5 M
  • K ATP channel antagonist glibenclamide 5 ⁇ 10 -6 M
  • a portion of the aortic ring was treated with 10 -5 M bupivacaine when contraction with phenylephrine (10 -6 M) in the GF109203X alone or in combination with GF109203X and lipid emulsions progressed.
  • phenylephrine (10 -6 M) was stable and produced continuous contraction
  • levchromacarim (10 -8 to 10 -5 M) was administered in a cumulative manner to obtain a levchromacarim dose-response curve.
  • CAE and bupivacaine (10 -5 M) corresponding to a mixture of 1% lipid emulsion and 10 -5 M bupivacaine were treated in the aortic ring.
  • Vascular smooth muscle cells isolated from rat thoracic aorta by enzymatic digestion, 10% heat-inactivated fetal bovine serum, Dulbecco's modified Eagle's medium supplemented with 100 U/mL penicillin and 100 mg/mL streptomycin (Carlsbad, CA, USA) ). Cells were grown at 5% CO 2 , 37° C., and medium was changed every 2 days until the cells were dense. Cells were proliferated through trypsin treatment. Cells of line 5-9 were inoculated at a density of 10 7 cells in a 100 mm dish and cultured until the cells reached 70% density. Dense cells were further cultured in serum-free medium for 15 hours prior to the experiment.
  • vascular smooth muscle cells and HEK-293 cells were plated on glass cover slips coated with poly-L-lysine in a culture dish and incubated at 37° C., 5% CO 2 .
  • Vascular smooth muscle cells and HEK-293 cells were used 1 day after plating, and 2-3 days after transfection.
  • Electrophysiological recordings were performed on rat aortic smooth muscle cells and transfected HEK-293 cells using a patch clamp amplifier (Axopatch 200, Axon Instruments, Union City, CA, USA). Briefly, single channel current was HEK-transfected with a DNA fragment encoding the green fluorescent protein of rat Kir6.2 (AB043638), ATP-binding cassette subfamily C member 9 (Abcc9 [SUR2], NM_013040) and pcDNA3.1. 293 cells.
  • the current was filtered at 2 kHz using an 8-pole Bessel filter (-3 dB; frequency device, Haverhill, MA, USA) and from a computer (Samsung) using a Digidata 1320 interface (Axon Instruments, Union City, CA, USA). Analysis was made at a sampling rate of 20 kHz. The threshold detection of the channel aperture was set to 50%. Single channel currents were analyzed with a pCLAMP program (version 10, Axon) with a dead time filter of 100 microseconds (0.3 / cutoff frequency). Channel activity (NPo, where N is the number of channels in the patch and Po is the probability that the channel is open) was determined at ⁇ 1-2 min of the current record. The single channel current trace shown in the figure was filtered to 2 kHz.
  • the pipette and bath solution contained (mM) 150 KCl, 1 MgCl 2 , 5 EGTA and 10 HEPES (pH 7.3).
  • the pH was adjusted to the desired value with HCl or KOH.
  • the crude solution contains 135 NaCl, 5 KCl, 1 CaCl 2 , 1 MgCl 2 , 5 glucose and 10 HEPES (mM), and the pipette solution is 150 KCl, 1 MgCl2, 5 EGTA and 10 HEPES ( pH 7.3). All solutions were prepared with Milli-Q water (18.2 M ⁇ -cm at 25°C).
  • Bupivacaine (10 -5 M) dissolved in Krebs solution was emulsified by mixing with Intralipid® at different concentrations (0%, 0.25%, 1%, 2%, 5% and 10%) for 30 minutes by a rotator. . After centrifugation at 75,000 g for 40 minutes, the non-emulsified bupivacaine of the aqueous layer was measured with an ultra high performance liquid chromatography-four pole flight time mass spectrometer (UPLC-Q-TOF MS; Waters, Milford, MA, USA). .
  • UPLC-Q-TOF MS Ultra high performance liquid chromatography-four pole flight time mass spectrometer
  • a non-emulsified bupivacaine sample was placed in an Acquity UPLC BEH C18 column (100 x 2.1 mm, 1.7 ⁇ m; Waters) equilibrated with water containing 0.1% formic acid, and linear aceto containing 0.1% formic acid gradient (5-100%) It was eluted with nitrile at a flow rate of 0.35 mL/min for 7 minutes.
  • the eluted bupivacaine was analyzed by Q-TOF MS (Waters) using multiple reaction monitoring and positive electron spray ionization mode.
  • the capillary and sampling cone voltages were set to 3 kV and 30 V, respectively.
  • the desolvent temperature and flow rate were 100°C and 800 L/h, respectively, and the source temperature was set to 400°C.
  • Lock spray with rosin-enkephalin (556.2771 Da) at a frequency of 10 seconds was used to ensure reproducibility and accuracy for all assays.
  • rosin-enkephalin 556.2771 Da
  • For quantitative analysis of bupivacaine multiple reaction monitoring modes were used, and the precursor and product ions of bupivacaine were 289.21 and 140.13, respectively. All mass data were collected and analyzed by UIFI version 1.8.2 (Waters).
  • the isolated protein was transferred to a polyvinylidene difluoride membrane using Trans-Blot® SD Semi-Dry Transfer Cells (Bio-Rad Laboratories, Hercules, CA, USA). After blocking the membrane with 5% bovine serum albumin (BioShop, Burlington, ON, Canada) in Tris buffered saline (pH 7.0), the primary antibody (anti-PKC and anti-phospho-PKC) was Tris-buffed with Tween-20. Diluted 1:1000 in 5% bovine serum albumin in saline and added. Immune complexes were detected with SuperSignal® West Pico chemiluminescent substrate (Thermo Scientific, Rockford, IL, USA). Band density was determined by density measurement software (Bio-Rad, Hercules, CA, USA).
  • Lev Chroma Karim was purchased from Tocris Bioscience (Bristol, United Kingdom).
  • GF109203X, glibenclamide, linoleic acid, diltiazem, L-NAME, phenylephrine and acetylcholine were purchased from Sigma-Aldrich (St. Louis, MO, USA).
  • GW1100 was purchased from Calbiochem (San Diego, CA, USA).
  • Intralipid® was donated by Fresenius Kabi Korea (Seoul, Korea).
  • Bupivacaine and mepivacaine were purchased from Leeyeon Pharmaceutical (Seoul, Korea) and Hana Pharmaceutical (Gyeonggi-do), respectively.
  • Lopivacaine was donated by Korea's AstraZeneca (North Ryde, NSW, Australia).
  • Anti-phospho-PKC antibodies and anti-PKC antibodies were purchased from Cell Signaling Technology (Beverly, Massachusetts, USA) and Santa Cruz Biotechnology (Santa Cruz, California, USA), respectively.
  • GF109203X, GW1100 and glibenclamide were dissolved in dimethyl sulfoxide (final dimethyl sulfoxide concentration: less than 0.1%).
  • Rev chromacarim was dissolved in ethanol (final ethanol concentration: 0.19%). Molar concentrations and percentages were used to indicate the final organ concentrations of the drug and lipid emulsion, respectively. Unless otherwise specified, the drug was dissolved in distilled water and then diluted with distilled water.
  • the logarithm of the drug concentration that produces 50% of the maximum vasodilation induced by levchromacarim (10 -5 M) or diltiazem (log ED 50 ) is the dose-response induced by levchromacarim or diltiazem Curves were calculated using a nonlinear regression analysis fitted to a Sigmoidal curve of Prism 5.0 (GraphPad Software, San Diego, CA, USA).
  • Lipid emulsions (0.1%, 1%) significantly reduced bupivacaine-mediated inhibition of maximal vasodilation induced by levchromacarim (10 -5 M) in the mesenteric arteries of isolated mice ( Figure 1D; p ⁇ 0.05), lipid emulsion (1%) significantly decreased the increase in bupivacaine mediated log ED 50 induced by levchromacarim (FIG. 1D; log ED 50 : p ⁇ 0.001). Only the highest concentration of lipid emulsion (1%) used in this experiment significantly reduced ropivacaine-mediated inhibition of maximal vasodilation induced by levchromacarim (10 -5 M) in the mesenteric artery with isolated endothelial removal. (Fig.
  • bupivacaine had no effect on vasodilation induced by levchromacarim in the rat aorta, where endothelial pretreatment with glibenclamide (5 x 10 -6 M) was removed (Figure 3C). Bupivacaine did not significantly alter diltiazem-induced vasodilation ( Figure 3D).

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Abstract

La présente invention concerne une composition pharmaceutique capable d'inhiber significativement la vasoconstriction comprenant de l'acide linoléique.
PCT/KR2018/016821 2018-12-28 2018-12-28 Composition pharmaceutique pour inhiber la vasoconstriction Ceased WO2020138556A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008525441A (ja) * 2004-12-22 2008-07-17 ドラッグテック コーポレイション 心血管用組成物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008525441A (ja) * 2004-12-22 2008-07-17 ドラッグテック コーポレイション 心血管用組成物

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
KARCIOGLU: "Use of lipid emulsion therapy in local anesthetic overdose", SAUDI MEDICAL JOURNAL, 2017, pages 985 - 993 *
LEE, S. H.: "Linoleic acid attenuates the toxic dose of bupivacaine-mediated reduction of vasodilation evoked by the activation of adenosine triphosphate-sensitive potassium channels", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 19, 26 June 2018 (2018-06-26), pages 1 - 21, XP055721791 *
OK, S.-H.: "Lipid emulsion for treating local anesthetic systemic toxicity", INTERNATIONAL JOURNAL OF MEDICAL SCIENCES, 14 May 2018 (2018-05-14) *
SHIN IIWOO ET AL.: "Lipid emulsion treatment of systemic toxicity induced by local anesthetics or other drugs", JOURNAL OF THE KOREAN MEDICAL ASSOCIATION, vol. 57, no. 6, June 2014 (2014-06-01), pages 537 - 544 *

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