| PurposeOxycodone is commonly used in postoperative intravenous analgesia in clinic.However,the dosage of Oxycodone and the occurrence of adverse reactions in different patients after conventional surgery are significantly different.Studies have shown that oxycodone is mainly metabolized by cytochrome P450(cytochrome P450)enzyme in the liver.CYP3A4 enzyme is the main metabolic enzyme,and the activity of CYP3A4 enzyme is significantly different between individuals,and the gene encoded by oxycodone is also polymorphic.Studies have shown that the metabolic differences among individuals may depend on the genetic polymorphism of CYP3A4.CYP3A4 * 18 B is the most frequently detected single nucleotide polymorphism in China.However,it is not clear whether the CYP3A4 * 18 B polymorphism affects the activity of CYP3A4 enzymes,leading to differences in intravenous dosage of oxycodone in different patients after gastrointestinal surgery.In this paper,CYP3A4 * 18 B polymorphism and CYP3A4 enzyme activity were studied to analyze the genetic factors of individual differences in postoperative analgesic efficacy of Oxycodone in patients with gastrointestinal diseases,and to provide theoretical support for clinical formulation of Oxycodone postoperative analgesic regimen.Method1.Research objects380 patients underwent gastrointestinal surgery under general anesthesia,aged 35-65 years,BMI within the normal range,and postoperative analgesia was required.Except for patients with severe cardiovascular and cerebrovascular diseases,diabetes mellitus,liver disease,kidney disease,history of smoking,alcoholism,pain,and longterm dependence on analgesic drugs,no drugs or foods that enhance or attenuate the enzymatic response of liver CYP3A4 enzyme were taken 4 weeks before surgery.CYP3A4*18B gene test results were divided into three groups: wild type homozygote(CYP3A4*18/*18),mutant heterozygote(CYP3A4*18/*18B)and mutant heterozygote(CYP3A4*18B/*18B).2.Analgesia and anesthesia The study was conducted with the consent of the hospital ethics committee and the patient,and informed consent was signed.The anesthesia was induced by intravenous administration of midazolam(MDZ),propofol,remifentanil and cis-atracurium benzenesulfonate,and sustained intravenous infusion of propofol and remifentanil,as appropriate.Cis-atracurium was injected intermittently,general anesthesia drugs were suspended at the end of operation,tracheal catheter was removed when the patient's mind and breathing were satisfactory.Visual analog scale(VAS)was used to record the degree of pain after operation,and patient-controlled intravenous analgesia was performed with electronic analgesia pump.Analgesia,PCIA).The drugs in the intravenous pump were oxycodone 100 mg and 10 mg,and 100 ml was added to normal saline.The intravenous injection pump was set as follows: the background dose of oxycodone was 0.5 mg/h,the additional dose was 2 mg/h,the maximum dose was 14.5 mg/h,and the locking time was 5 minutes.Effective analgesia is defined as active VAS score < 3 points,when reached the maximum hourly,if the VAS score is still > 3 points,it can assist other analgesics.The consumption of oxycodone,the average VAS score and the incidence of adverse reactions in each 24 h were recorded.3.Polymorphism detectionPolymorphisms were detected by phenol-chloroform method to extract DNA from peripheral venous blood of patients.Polymerase chain reaction-restriction fragment length polymorphism(PCR-RELP)was performed to detect CYP3A4*18B gene.The reliability of genotyping was verified by PCR amplifier gene detection.4.The Activity detection of CYP3A4 enzymeThe activity of CYP3A4 was detected by using midazolam(MDZ)as probe drug.After anesthesia induction,5 ml of peripheral venous blood was extracted at 1 hour.The concentration of midazolam(MDZ)and its metabolite 1'-OHMDZ were measured by liquid chromatography-mass spectrometry(LC-MS),and the ratio of 1'-OHMDZ to MDZ was used as enzyme activity.Measurement index.5.Statistical classificationStatistical analysis used SPSS 17.0 software for statistical analysis,measurement data used as statistical description,counting data used for testing,testing as a test to measure the distribution of alleles and genotypes,to determine whether it conformed to the Hardy-Weinberg equilibrium;through Fisher's test precision probability to measure alleles between different races.The probability of occurrence,the data of multiple groups were analyzed by one-way difference and LSD,and the consumption of oxycodone between groups was analyzed by covariance to eliminate the influence of confounding factors on the experimental results.Fisher's exact probability method was used to test the incidence of adverse reactions,and the linear relationship between the number of mutated alleles and oxycodone consumption was analyzed by rank correlation analysis,and the linear correlation analysis was used to measure the relationship between variables.The level of inspection is standard =0.05.Result1.General informationAmong 380 patients,210 were female and 170 were male.The visual analogue score was(5.8± 1.3),(2.1±0.6)in the first 24 hours after operation and(1.2 ± 0.6)in the second 24 hours after operation.The dosage of xycodone was(39.0 ±20.2)mg in the first 24 hours and(19.1±4.2)mg in the second 24 hours.Postoperative vomiting rate was 27.6%,mild analgesia rate was 1.8%,pruritus rate was 0.9%,and no other adverse reactions were observed.2.The probability of CYP3A4*18B allele inpatientsThe mutation probability of CYP3A4*18B allele in Chinese Han patients undergoing gastrointestinal surgery was 29.6%.The distribution of alleles and genotypes accorded with Hardy-Weinberg equilibrium(p > 0.05).The probability of CYP3A4 * 18 B allele was similar to that of Asians(24.8%)and Chinese hyperlipidemia(26.9%)(p > 0.05).3.The effects CYP3A4*18B polymorphism on oxycodone gastrointestinal CYP3A4 activity and postoperative patientsThe influence of CYP3A4 * 18 B gene polymorphism on the activity of CYP3A4 and postoperative oxycodone analgesia in gastrointestinal tract patients There was no significant difference in the general condition among three groups: wild type homozygote(CYP3A4 * 18 /* 18),mutant heterozygote(CYP3A4 * 18 /* 18B)and mutant homozygote(CYP3A4 * 18 B /* 18B)(p > 0.05).There was no significant difference in the average VAS score between groups within the hour(p > 0.05);there was significant difference in the consumption of oxycodone among the three groups 24 hours after operation(p > 0.05);the consumption of oxycodone in CYP3A4 * 18 B /* 18 B group(26.0 + 10.1)mg was lower than that in CYP3A4 * 18 /* 18 group(40.7±18.7)mg and CYP3A4 * 18 / * 18 B group(39.7±22.3)mg;and the consumption of oxycodone in CYP3A4 * 18 /* 18 There was a negative correlation between the number of CYP3A4*18 alleles and the number of alleles(r=-0.14,p<0.05).CYP3A4 activity was significantly lower in CYP3A4 * 18 B /* 18 B group(0.32±0.12)than in CYP3A4 * 18 /* 18 B group(0.42±0.11)and CYP3A4 * 18 /* 18 group(0.42±0.12).There was no significant difference in the incidence of adverse reactions during postoperative analgesia among the three groups(p > 0.05).Conclusion1.The mutation frequency of CYP3A4*18B allele was 29.6% in Chinese Han patients undergoing gastrointestinal surgery.2.CYP3A4*18B was a functional mutation,which was associated with CYP3A4 activity and decreased intravenous oxycodone analgesia consumption within 24 hours after operation. |
PDF Full Text Request