| Local anesthetic poisoning can cause severe circulatory failure,and recent studies have demonstrated that nano-liposome therapy can rapidly reverse this serious complication in in vivo and clinical case reports.Some scholars in vivo and isolated heart of the local anesthetic toxicity model of the study found that timely fat emulsion input can promote the recovery of cardiomyocyte function.There are cases reported by the use of fat emulsion rapid recovery of amide antihler toxicity caused by cardiac arrest,also reported in the literature fat emulsion can be quickly reversed due to anesthetic toxicity caused by the central nervous system symptoms.Nano-liposomes are a class of fatty acid emulsions,but the physical and chemical properties of nano-liposomes are more uniform than ordinary fatty acid emulsions.The function of nano-liposomes to relieve myocardial toxicity caused by local anesthetics is more rapid and reliable.Nano-liposomes have a lipid microcapsule structure,the main component is the phospholipid bilayer,the core of the water phase.Common liposomes are micron-class lipid-like bilayer structures with a thickness of about 1 to 100 μm.If a suitable liposomal structure of lipid-like bilayer structure to join the appropriate surface active substances,can constitute nano-liposomes.Nano-liposomes not only have a significantly smaller particle diameter than ordinary liposomes,but also have a high degree of deformability.The dispersibility,stability,deformability,permeability and adsorption capacity of nanometer liposome structure in human body fluid system are significantly better than ordinary fat emulsion.Nano-liposomes their own adsorption capacity is very strong,is the ordinary fat emulsion adsorption several times or even several times.Nano-liposomes degradation rate faster than ordinary fat emulsion,infusion of nano-liposomes treatment of local anesthetic drugs after myocardial toxicity, almost all of the nano-liposomes were quickly metabolized by the body,and not in the body of which retention and accumulation caused by high Hyperlipidemia or excessive energy intake.Part I: High-purity linoleic acid nano-liposomes adsorbed bupivacaine molecules,reversing bupivacaine myocardial toxicityObjective: To observe the ability of high purity linoleic acid nano liposomes nano liposomes to adsorb local anesthetic(bupivacaine)and to reverse the degree of myocardial toxicity of local anesthetic(bupivacaine).Methods: 24-30 weeks old SD rats(weight 250g-300 g,male and female).Using 3 × 5 orthogonal design: 3 different concentrations of high purity linoleic acid nano liposomes × 5 measurement time points(5 minutes after completion of bupivacaine iv,high purity linoleic acid nano liposomes iv After completion of 0 minutes(ie 8 minutes after completion of bupivacaine iv),20 minutes after completion of bupivacaine iv measurement,40 minutes after completion of bupivacaine iv,60 minutes after completion of bupivacaine iv).75 SD rats were divided into 15 groups,5 in each group.Before the experiment,the rats were fasted for 8 hours,and 4% sevoflurane + 96% oxygen was inhaled by mask method.The rat supine position was placed on the small animal test bed.The rat limbs and head were fixed,Fluoride + 98% oxygen was maintained in the face of the mask,and the maintenance of the rats was anesthetized with vecuronium 0.08 mg / kg / hr.Anesthesia cut the middle of the neck skin and separation of trachea,with 16 puncture needle puncture,the outer sheath into the trachea inside the ventilator,set the respiratory rate of 38 to 45 times / min,tidal volume l0 ~ 12m1 / kg,The breathing ratio is set to 1: 2,and the oxygen flow rate is maintained at 1 L / min.The rat neck hair cut off,iodophor disinfection,incision and blunt separation of skin and neck muscle tissue,free from the common carotid artery about 1 to 2 cm,the wire closed carotid artery distal end,the arterial clip clip Carotid artery near the heart,the ductus arteriosus(filled with heparin dilution solution)to the proximal end of the insertion of the common carotid artery,with a tight ligation of the wire fixed.And then the rats were treated with bilateral femoral vein catheterization.SD rats were sacrificed by limb and ventral side hairs.The skin of the limbs was disinfected with iodophor solution.The ECG was electroporated into the subcutaneous fixation and the electrocardiogram(ECG)was recorded.Rats with femoral vein injection 0.5% bupivacaine injection 2mg/kg.min,monitoring ECG,once the occurrence of arrhythmia in rats model is successful.(B8)after the completion of the bupivacaine iv(B0),0 minutes after completion of the high purity linoleic acid nano liposomes(ie 8 minutes after completion of bupivacaine iv),bupivacaine iv 20 minutes after completion of measurement(B20),20 minutes after completion of bupivacaine iv(B40),and 60 minutes after completion of bupivacaine iv(B60).Blood samples were drawn from the carotid arteries at the time points,and then the rats were sacrificed and the rats were sacrificed.The following indicators include physiological indicators: BP,MAP,HR,Pa O2,Pa CO2,Sa O2;key indicators: ECG,myocardium bupivacaine content.Results: The basal body weights of different concentrations of nano-liposomes were: A1 group(335.2 ± 11.7)g,A2 group(327.7 ± 12.4)g,A3 group(340.6 ± 13.2)g,the difference between the three groups was not statistically significant(P = 0.231);heart rate were: A1(289.5 ± 8.56)times / min,A2 group(292.1 ± 8.77)times / min,A3 group(290.6 ± 7.95)times / min,the difference between the three groups was not statistically significant(P = 0.844);MAP were(103.3 ± 7.1)mm Hg,A3 group(104.1 ± 6.8)mm Hg,the difference between the three groups was not statistically significant(P = 0.865);different concentrations of nano-liposomes were given in the A1 group(102.3 ± 6.5)mm Hg(45.5 ± 11.7)seconds,A2 group(37.7 ± 12.6)seconds,A3 group(30.5 ± 13.4)seconds,and the time of ventricular arrhythmia continued for the duration of arrhythmia The increase of nano-liposome concentration was shortened,and the difference between the three groups was statistically significant(P = 0.032).The dosage of nano-liposomes during the duration of electrocardiogram arrhythmia in SD rats after different concentrations of nano-liposomes was: A1 group(10.5 ± 2.56)mg / kg,A2 group(7.1 ± 2.16)mg / kg,A3 group(5.6 ± 1.65)mg / kg,the amount of nano-liposomes required for duration of arrhythmia(P = 0.024).The difference between the three groups was statistically significant(P = 0.024).(353.5 ± 23.7)mg / kg,(314.1 ± 25.6)mg / kg and(265.6 ± 23.5)mg / kg,respectively,in the A1 to A3 group,The difference between the two groups was statistically significant(P <0.05).(267.3 ± 28.5)mg / kg,(231.5 ± 23.7)mg / kg and(198.4 ± 24.1)mg / kg,respectively,and the difference between the two groups was statistically significant(P <0.05).Conclusion: 1.High-purity linoleic acid nano-liposomes can reverse the local anesthetic(bupivacaine)of myocardial toxicity.The reversal process was time dependent and correlated with the concentration of high purity linoleic acid nano liposomes.2.High-purity linoleic acid nano-liposome adsorption Local anesthetic(bupivacaine)molecules in the high-purity linoleic acid nano-liposome drug concentration is high when the reverse effect B8,B20 at the time point of the speed fast.However,there was no significant difference in the content of bupivacaine in the myocardium at B40 and B60,suggesting that the adsorption of high-purity linoleic acid nano liposomes was dose-dependent,suggesting that clinical Appropriate increase in drug concentration and administration time.Part II: Molecular mechanisms of degradation of bupivacaine cardiomyocytes with high purity linoleic acid nanoparticlesObjective: To investigate the molecular mechanism of high purity linoleic acid nano liposomes in the removal of bupivacaine.Methods: SD rats aged 24-30 weeks(weight 250g-300 g,male and female).Randomized block design(experimental group: measured after 0 minutes of completion of bupivacaine iv,after 30 minutes of completion of high purity linoleic acid nano liposomes iv(8 minutes after completion of bupivacaine iv),Bubica Measurements were made after 40 minutes of completion of iv,60 minutes after completion of bupivacaine iv,2 hours after completion of bupivacaine iv,6 hours after completion of bupivacaine iv,and 1 control group(injection only Bupivacaine was not treated),and one normal control group(without injection of bupivacaine + without treatment)was measured at the above-mentioned time points.66 SD rats were divided into experimental group 30,control group 18 rats and normal control group 18.The rats were fasted for 8 hours before the experiment,and 4% sevoflurane + 96% oxygen was inhaled by mask method.The rat supine was placed on the small animal test bed,Rodent limbs and head,2% sevoflurane + 98% oxygen to maintain mask inhalation,vecuronium chloride 0.08 mg / kg / hr to maintain rat anesthesia.Anesthesia cut the middle of the neck skin and separate the trachea,with 16 puncture Needle to puncture,the outer sheath to stay into the trachea inside the ventilator,set the respiratory rate of 38 to 45 times / min,tidal volume l0 ~ 12m1 / kg,breathing ratio set to 1: 2,oxygen flow to maintain 1L / min.The rat neck hair cut off,iodophor disinfection,incision and blunt separation of skin and neck muscle tissue,free from the common carotid artery about 1 to 2 cm,the wire closed carotid artery distal end,the arterial clip Carotid artery near the heart,the ductus arteriosus(filled with heparin dilution solution)to the proximal end of the insertion of the common carotid artery,tightly connected with the wire fixed.Rats with femoral vein injection 0.5% bupivacaine injection 2mg / kg.min,monitoring ECG,once the occurrence of arrhythmia in rats model is successful.Determination of:(1)myocardial radioactive labeled bupivacaine content;(2)automatic biochemical analyzer to detect serum myocardial CKMB;(3)myocardial NO concentration.Determination of nitric oxide in rat myocardium by nitric acid reductase assay.Results: The content of bupivacaine in myocardium was 0 in the normal control group.The concentration of bupivacaine in the brain of B8,B40,B60,B120 and B360 was significantly higher than that in the control group(357.4 ±(123.6 ± 13.5)mg / kg and(88.6 ± 10.8)mg / kg respectively.The control group: B8,B40,B60(mg,(393.8 ± 48.5)mg / kg,(364.3 ± 39.8)mg / kg,(325.8 ± 33.6)mg / kg,(264.4 ± 26.8)mg / kg,respectively,at the B120 and B360 time points and(193.8 ± 23.2)mg / kg respectively.There was significant difference between the two groups(P<0.05).The levels of CKMB in the serum of the SD rats were significantly higher than those in the control group(P<0.05).The levels of CKMB in the normal control group were significantly higher than those in the control group(P<0.05).(3663.5 ± 22.7.6)U / L,(2567.4 ± 217.3)U / L,(1993.2 ± 112.5)U / L and(1688.6 ± 84.8)U / L,respectively.Control group:(4663.8 ± 445.5)U / L,(4661.3 ± 432.8)U / L,(4315.7 ± 324.6)U / L,(4562.4 ± 326.4)U(P <0.05),and the serum CK1 of B8,B40,B60,B120 and B360 / L and(4191.5 ± 326.2)U / L;B40,B60,B120,B360 time points between the groups were statistically significant(P<0.05).The levels of NO in myocardium of SD rats were significantly higher than those in control group(P<0.05).The levels of NO in myocardium were significantly higher than those in control group(P<0.05).(4.34 ± 0.43)μmol / gprot,(3.65 ± 0.36)μmol / gprot,(2.94 ± 0.33)μmol / gprot,(2.32 ± 0.25)μmol / gprot and(1.96 ± 0.28)μmol / gprot,respectively.The levels of NO in myocardium were(5.18 ± 0.55)μmol / gprot,(4.93 ± 0.58)μmol / gprot,(4.75 ± 0.56)μmol / gprot,(4.34 ± 0.44)μmol / b,Gprot and(4.25 ± 0.42)μmol / gprot.There was significant difference between B40,B60,B120 and B360 at the time points(P<0.05).Conclusion: Cardiomyocyte injury caused by bupivacaine toxicity occurs at the early stage of the toxic reaction,accompanied by excessive expression of TNF-α,NO and serum CKMB in cardiomyocytes.2.High-purity linoleic acid nano-liposomes can rapidly reverse the cardiomyocyte injury caused by bupivacaine toxicity,reduce the excessive expression of TNF-α,NO and other inflammatory factors,reduce serum CKMB,delay or even prevent the toxicity caused by myocardial irreversible damage. |
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