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OBJECTIVE To investigate the effect of gene polymorphism on opioid-induced constipation. METHODS The target genes related to opioid-induced constipation were screened out through searching guidelines， databases and evidence-based medical data， and then 100 cancer pain patients who received opioid drugs for analgesia were included as the study subjects. According to whether there were adverse effects of constipation after medication or not， they were divided into test group and control group， with 50 cases in each group. The target gene was detected by PCR or fluorescence in situ hybridization. The SNPStats program was used to carry out Hardy-Weinberg balance test and correlation analysis between gene polymorphism and opioid-induced constipation. The multivariate Logistic regression analysis was used to explore the relevant predictive factors of opioid-induced constipation， and receiver operating characteristic （ROC） curve of subjects was drawn to analyze the effectiveness of each predictive factor in predicting opioid-induced constipation. RESULTS CYP2D6， CYP3A5*3， ABCB1 and OPRM1 were selected as target genes for detection. The results of genotype detection showed that the frequency distribution of CYP2D6 （rs1065852， rs1135822， rs16947， rs28371725， rs28371735）， CYP3A5*3 （058rs776746）， ABCB1 （062rs1045642）， OPRM1 （047rs1799971） alleles were consistent with Hardy-Weinbergbalance test. The correlation analysis results showed that the proportion of genotype GG and AG in CYP3A5*3 （058rs776746， 163.com A＞G） and genotype AA and AG in OPRM1 （047rs1799971， A＞G） of patients was significantly higher in test group than that in the control group （P＜0.05）. Multivariate Logistic regression analysis showed that medication duration， CYP3A5*3 and OPRM1 gene polymorphism could be used as predictors of opioid- induced constipation in patients （P＜0.05）. The ROC curve analysis results showed that the areas under the ROC curves for medication duration and CYP3A5*3， OPRM1 gene polymorphism were 0.648， 0.640 and 0.670， respectively， with the optimal cutoff values of 124.0， 0.5 and 0.5， respectively. CONCLUSIONS Genotype GG and AG in CYP3A5*3 （058rs776746，A＞G） and genotype AA and AG in OPRM1 （047rs1799971，A＞G） are associated with opioid-induced constipation， which are expected to become clinical predictors of opioid-induced constipation， and more attention should be paid to the occurrence of constipation in patients who have been taking opioids for a long time.
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Caspofungin is the firs t echinocandin antifungal drug approved for serious fungal infections caused by Candida or Aspergillus. Currently ，caspofungin has been recommended as the first-line treatment for invasive Candida and the second-line treatment for invasive Aspergillus，for its safety and tolerability. However ，there are still probability of pharmacokinetic variability and the risk of low exposure in different populations. Herein the population pharmacokinetics-pharmacodynamics studies of caspofungin in children and adults were reviewed. The results indicate that the body surface area was the main factor affecting the distribution and clearance of caspofungin in pediatric patients. In adults ，the two-compartment model fits the caspofungin behavior best in vivo with the primary covariates of body weight and albumin level. The efficacy of caspofungin might be related to pharmacokinetics-pharmacodynamics parameters ，such as the ratio of area under blood concentration time curve to minimum inhibitory concentration （AUC/MIC），the ratio of peak concentration to minimum effective concentration （cmax/MEC）.
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OBJECTIVE: To explore the distribution characteristics of chemotherapy drug-related single nucleotide polymorphisms(SNPs) in cancer patients in our hospital, and to provide the clinical reference for clinical pharmacists to guide the individualized therapy of cancer patients based on SNPs. METHODS: Fluorescence-labelled specific probes were used to detect drug-related genes by fluorescence in situ hybridization. The drug-related SNPs of cancer patients from Apr 2016 to Dec 2018 in Peking University Cancer Hospital were retrospectively analyzed. SPSS24.0 software was used to statistically analyze the difference in the frequency distribution of alleles and genotypes, and the Hardy-Weinberg equilibrium test. The distribution characteristics of related gene loci in cancer patients in our hospital regarding the genotype frequency of different populations were studied. RESULTS: A total of 17 chemotherapy drug-related gene loci were detected in 2 554 patients. CYP2D6(100C>T) and ABCB1(2677T>G) were not consistent with Hardy-Weinberg equilibrium, while the remaining 15 loci were in Hardy-Weinberg equilibrium. The allele frequencies of DPD, CYP2D6 and UGT1A1 of the Chinese population are significantly different from those of foreign population, which are consistent with internal reports. CONCLUSION: The distribution of chemotherapy drug-related SNPs in Chinese tumor patients performs its characteristics. Clinical pharmacists should provide individualized medication advisements according to chemotherapy drug-related SNPs. Based on the application of pharmacogenomics, while referring to international databases such as PharmGKB, the interpretation of SNPs of the Chinese population should be combined with the characteristics of the Chinese population, and the database of the different population cannot be fully referenced.
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Ribavirin is a widely used nucleoside antiviral drug. During the epidemic of coronavirus disease 2019 (COVID-19), ribavirin was recommended for empirical treatment in the Clinical Management of Human Infection with COVID-19 (trial guidance v6). However, due to the large inter-individual variations in dose-response relationship, and extremely long terminal half time, it is necessary to perform therapeutic drug monitoring and individualized dose adjustment for ribavirin in special populations. In this article, the pharmacokinetics and therapeutic drug monitoring of ribavirin in different populations are reviewed in order to provide reference for clinical rational use and individualized medication of ribavirin for treatment of COVID-19.
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The intestinal flora is a diverse microbial community living in the digestive tract of humans and animals. This microbial community can modify drugs in unpredictable ways, leading to changes in the pharmacokinetics of drugs in vivo and affecting their clinical efficacy. Here we review drug metabolism mediated by intestinal flora from three aspects: prodrug activation, drug inactivation, and toxicity. The effect of the stable hypoxic environment on the composition and quantity of intestinal flora and the effect on drug metabolism are discussed. Understanding the influence of intestinal flora on drug metabolism is not only conducive to individualized medication, but also conducive to rational drug design, allowing us to predict and understand individual drug response and regulate the intestinal microbiome to improve drug efficacy, thus promoting personalized medicine.
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Objective To investigate the clinical efficacy of cyclosporine injection in subclinical or critical treatment of renal transplant patients，and to establish an individualized dosage regimen of cyclosporine injection by studying the effects of nine single nucleotide polymorphisms related to the pharmacokinetics of cyclosporine on the dose-adjusted trough concentration (C0/D′) of cyclosporine injection. Methods Blood samples and clinical data of 144 adult renal transplant patients who used cyclosporine injection were collected and recorded, then, their genotypes of CYP3A4*18B, CYP3A5*3, ABCB1 (C1236T, G2677T/A, C3435T), POR*28, PXR (C5705T, C39823T) and NFKB1-94 ins/del ATTG were determined by Sequenom MassARRAY® SNP methods. Then, the discrepancies of cyclosporine injection’s C0/D′ among the patients with different genotypes was compared and an individualized dosage regimen based on gene polymorphism of cyclosporine injection was established by using multivariate regression analysis. Results Cyclosporine injection improved serum creatinine level by 68.8% in renal transplant patients with subclinical or critical rejection, and the steady-state plasma concentration was (189.50±38.56) ng/ml. The CYP3A4*18B gene polymorphism was significantly correlated to C0/D' of cyclosporine injection, and the C0/D' of patients with *1/*1 genotype was significantly higher than patients of *18B/*18B genotype; but CYP3A5*3, ABCB1(C1236T, G2677T/A, C3435T), PXR C5705T, PXR C39823T, NFKB1-94 ins/del ATTG and POR*28 gene polymorphisms were not significantly correlated to C0/D' of cyclosporine injection. In the final regression model, hemoglobin and CYP3A4*18B gene polymorphisms were significantly correlated to C0/D' of cyclosporine injection. Conclusion Cyclosporine injection can effectively improve the serum creatinine level in patients with subclinical or critical rejection; CYP3A4*18B gene polymorphism is significantly correlated to C0/D' of cyclosporine injection.
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Objective To evaluate the safety and efficacy based on cytochrome P450(CYP)3A5*1 gene polymorphisms in guiding the individualized medication of tacrolimus (FK506) after liver transplantation. Methods Clinical data of 100 consecutively enrolled recipients who underwent liver transplantation for the first time were analyzed and randomly divided into experimental group and control group, with 50 cases in each group. The donors and recipients in the experimental group received preoperative CYP3A5 gene detection, and determined the FK506 medication regimen according to the CYP3A5*1 genotype. The compliance rate of FK506 target blood concentration, the recovery rate of liver function in the two groups of recipients at 7, 14, 28 d and 3, 6, 9, 12 months postoperatively, as well as the number of FK506 dosage adjustment during the follow-up were observed. The 1-year graft survival rate and the incidence of complications were recorded in both groups of recipients, such as acute rejection, infection, acute kidney injury, gastrointestinal symptoms, de novo hypertension, de novo diabetes, colds and rash, etc. Results The differences of the compliance rate of FK506 target blood concentration between the two groups of recipients at 7, 14 d after operation were statistically significant (both P < 0.05). There was no statistically significant difference between the two groups in the compliance rate of FK506 target blood concentration at 28 d and 3, 6, 9, 12 months and the recovery rate of liver function at the 7 observation time points after operation (all P > 0.05). The difference between the two groups of recipients in number of FK506 dose adjustment during follow-up was statistically significant (P=0.021). There were no statistically significant differences in 1-year graft survival rate and incidence of complications between the two groups of recipients after operation and during follow-up (all P > 0.05). Conclusions It is safe to guide individualized medication of FK506 after liver transplantation according to CYP3A5*1 gene polymorphism. It can increase the compliance rate of FK506 target blood concentration of recipients in the early postoperative stage, and can effectively reduce the number of dose adjustment duringfollow-up.
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Three-dimensional(3D)printing,a type of rapid prototyping technology,is based on a digital model file and prints layer-by-layer using adhesive materials,such as powdered metal or plastic. 3D printing has attracted much attention in the pharmaceutical field because of the various advantages,such as simple operation,good flexibility,high repeatability,wide adaptability,and more importantly,customized service. Currently,it is used in formulations of imme- diate release,sustained release,implants,etc. Recently,the integration of medical devices and drugs with 3D printing has been gaining popularity. This review not only summarizes the latest progress in techniques,materials,and pharma- ceutical dosage forms used in drug delivery system with 3D printing,but also analyzes its advantages and limitations, with the hope of providing reference for the development and application of 3D printing technology in drug delivery. This novel drug delivery system will bring new vitality to individualized medication.
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Three-dimensional (3D) printing,a type of rapid prototyping technology,is based on a digital model file and prints layer-by-layer using adhesive materials,such as powdered metal or plastic.3D printing has attracted much attention in the pharmaceutical field because of the various advantages,such as simple operation,good flexibility,high repeatability,wide adaptability,and more importantly,customized service.Currently,it is used in formulations of immediate release,sustained release,implants,etc.Recently,the integration of medical devices and drugs with 3D printing has been gaining popularity.This review not only summarizes the latest progress in techniques,materials,and pharmaceutical dosage forms used in drug delivery system with 3D printing,but also analyzes its advantages and limitations,with the hope of providing reference for the development and application of 3D printing technology in drug delivery.This novel drug delivery system will bring new vitality to individualized medication.
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OBJECTIVE :To introduce two commonly used algorithms for warfarin individualized medication——multiple regression analysis(MRA)and maximum a posterior Bayesian (MAPB), and provide reference for individualized medication of warfarin in clinical practice. METHODS: The principles of MRA and MAPB for warfarin individualized medication, as well as the decision support tools to realize MRA and MAPB, were introduced. The function of MAPB tool, including formulating an initial dosage regimen, adjusting the regimen and its application in special clinical situations, was described by five typical cases.RESULTS AND CONCLUSION :MLR is simple to calculate, however, it can only be used to formulate the initial dosage regimen and dose adjustment cannot be carried out, which limits it clinical application in a certain extent. The application of MAPB can not only develop individualized medication of warfarin and adjust dose according to international normalized ratio(INR) with satisfactory prediction performance, but also be applied in special cases with better flexibility, such as judging medication adherence and instructing withdrawal. It could serve as an effective decision support tool to be promoted vigorously, which has a promising prospect.
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Objective To provide reference for clinical pharmacist participating in the therapy for acute coronary syndrome. Methods Clinical pharmacist participated in the therapy for a case of acute coronary syndrome,helped physicians analyzing the possible reasons of anti-platelet drugs resistance, chose proper anti-platelet drug based on genetic testing, and adjusted the administration of statins. Results The platelet aggregation rate was reduced from 70.5% to 20.0%,and the liver injury was controlled after individualized medication. Conclusion The safety and efficacy of patients were improved through clinical pharmacist's actively participating in clinical practice .
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Objective To provide reference for clinical pharmacist participating in the therapy for acute coronary syndrome. Methods Clinical pharmacist participated in the therapy for a case of acute coronary syndrome,helped physicians analyzing the possible reasons of anti-platelet drugs resistance, chose proper anti-platelet drug based on genetic testing, and adjusted the administration of statins. Results The platelet aggregation rate was reduced from 70.5% to 20.0%,and the liver injury was controlled after individualized medication. Conclusion The safety and efficacy of patients were improved through clinical pharmacist's actively participating in clinical practice .
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OBJECTIVE:To explore the role of clinical pharmacists participating in the individualized treatment for purulent meningitis. METHODS:Clinical pharmacists participated in the therapy for a patient with purulent meningitis complicated with Staphylococcus aureus infection. According to patient's condition,clinical pharmacists assisted physicians to formulate preliminary therapeutic plan. Reviewing relevant guidelines,domestic and foreign literatures,clinical pharmacists suggested to combine with dexamethasone so as to relieve inflammatory reaction. According to the results of drug sensitivity test,based on vancomycin plasma concentration monitoring and population pharmacokinetics model fitting,clinical pharmacists suggested to reduce the dose of vanco-mycin to 0.5 g,ivgtt,q12 h. The pharmaceutical care were conducted throughout the therapy,including efficacy evaluation of an-ti-infective therapy,ADR monitoring,renal function monitoring,etc. RESULTS:Physicians adopted some suggestions of clinical pharmacists. The disease condition of the patient was recovred,and no ADR related to vancomycin was found. On the 16th day, the patient was discharged from the hospital. CONCLUSIONS:Clinical pharmacists participate in treatment of purulent meningitis, assist physicians to optimize therapy plan based on relevant guideline,literature,etiological examination,blood concentration moni-toring and pharmacokinetics model fitting results. It not only guarantee therapeutic efficacy of anti-infective therapy,but also pre-vent and reduce the occurrence of ADR.
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Objective:To study how to guide the individual dose of clopidogrel in line with the genetic testing results. Methods:Clinical pharmacists decided how to optimize the prescription of clopidogrel according to the genotype combined with the drug metabolism and drug interactions for three patients respectively with slow clopidogrel metabolism,intermediary metabolism and super fast metabolism. Results:The slow clopidogrel metabolism patient with subacute stent thrombosis after half a month of coronary stenting was switched to orally administrate with ticagrelor. The super fast metabolism patient suffered from repeatedly subcutaneous hemorrhage with antiplatelet therapy was suggested to lower the dose of clopidogrel,temporarily withdraw Maixuekang capsules and conventionally administrate with vitamin C tablets orally. The intermediary metabolism patient with late stent thrombosis co-treated with lansoprazole was suggested to increase the dose of clopidogrel or use ticagrelor instead,and when it was necessary,panxitorazole,ray Bella or the other ranitidine acid suppression drugs such as ranitidine could be considered. Conclusion:Through genetic testing and drug interactions,clinical pharmacists guide the clinical use of clopidogrel and the optimization of antiplatelet therapy.
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Objective To investigate the efficacy,safety,economy evaluation of CYP3A5 * 3 gene polymorphism in providing individualized administration for the use of tacrolimus (Tac) in renal transplantation recipients.Method Pyrophosphate sequencing method was used to determine the CYP3A5 * 3 genotype of renal transplant patients in the first day after surgery.Computer-generated random numbers were used to assign 60 patients into experiment group or control group.Both groups of patients were routinely given the initial dose of Tac (4.0 mg/day) in the first day after surgery.The patients in the experiment group were given different doses of Tac based on the different CYP3A5 * 3 genotypes at the third day after surgery [for AA,AG:0.12 mg/(kg day),and for GG:0.06 mg/(kg day)].The patients in the control group were given different dosages of Tac according to drug concentration.The patients were followed up for 12 months,and different parameters were compared between two groups.A decision tree model was populated with data from the study and used to economics evaluation.Result At day 5 after the transplantation,significantly more patients in the experiment group were within the Tac target C0 range [90％ (27/30)] as compared to the control group [46.67％ (14/30) (P＜0.05).At this time point,the median Tac C0was 5.08 [(2.5-8.7) μg/ L] in the experiment group vs.5.29 [(1.3-13.6) μg/L] in the control group (P＜0.05).When C0/ D was analyzed according to CYP3A5 * 3 genotype,we found the mean C0/D in the both groups with CY3A5 * 3/* 3 ＞CYP3A5 * 3/* 1 ＞ CYP3A5 * 1/* 1.It was noted that the time to achieve target Tas was (4.40 ± 0.97) in the experiment group,vs.(7.57 ± 3.42) in the control group.In total,the number of daily dose modifications was 11 in the experiment group and 49 in the control group in two weeks after transplantation (P＜0.05).Renal function at day 14 after transplantation and adverse events during 12 months of follow-up were similar in both groups.In total,10 adverse events were reported in the experiment group and 11 in the control group (P＞0.05).The results of costeffectiveness analysis showed that the cumulative costs and effects in the experiment group were ￥ 38 067 and 0.90 quality-adjusted life years gained,and those in the control group were ￥38 681 and 0.87 quality-adjusted life years gained,respectively.In the base case analyses,experiment group was more cost-effective.Conclusion Individualized adjustment of Tac doses for patients according to recipients different CYP3A5 * 3 genotypes is beneficial for reaching target concentration as soon as possible and more cost-effective.But the demonstration of the clinical relevance of this approach was not achieved.Higher methodological quality,and larger sample size study are still needed.
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OBJECTIVE: To evaluate the role of clinical pharmacist in individualized antiplatelet therapy in patients with percutaneous coronary intervention (PCI). METHODS: To review clinical pharmacist participating antiplatelet therapy based on genotype detection for one patient with stent thrombosis after PCI. RESULTS: Clinical pharmacist analyzed the causes of stent thrombosis after PCI by genotype detection, participated the adjustment of antiplatelet therapy and implemented pharmaceutical care and pharmaceutical education for the patient in order to ensure the safety and effectiveness of drug use. CONCLUSION: Clinical pharmacist participates making and regulating the therapeutic regimen to provide some evidences for individualized medication, which could be the entry points to pharmaceutical care.
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AIDS has become a global disease,and a variety of drugs are used in the treatment of AIDS ,but the interindividual variabilities in efficacy and toxicity remain important limitations for the use of these drugs.Studies have shown genetic polymor-phism is the main reason for interindividual variabilities of drug reaction.In recent years,scholars focused on the pharmacog-enomics of anti-AIDS drugs and found that genetic polymor-phisms,in large part,determine the interindividual variabilities of the responese of these drugs.This paper reviews the research progress on pharmacogenomics of the four types of anti-AIDS drugs commonly used in China,including nucleoside reverse transcriptase inhibitors (NRTIs),non-nucleoside reverse tran-scriptase inhibitors (NNRTIs),protease inhibitors (PIs)and integrase inhibitors (raltegravir).
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Objective To investigate the value of Cytochrome P450 (CYP3A5) * 3 gene polymorphism in providing individualized administration for the use of tacrolimus (Tac) in renal transplantation recipients.Method Pyrophosphate sequencing method was used to determine the CYP3A5 * 3 genotype of renal transplant patients in the first day after surgery.Sixty recipients were divided into experiment group and control group.Both groups of patients were routinely given the initial dose of Tac-4.0 mg/day in the first day after surgery.The experiment group of patients were given different doses of Tac based on the different CYP3A5 * 3 genotypes at the third day after surgery [for AA:0.12 mg/(kg· day),and for GG:0.06 mg/(kg· day)],and the control group of patients were given different dosages of Tac according to drug concentration.Different parameters were compared between two groups of patients:percentage of patients reaching the target concentration (3-8 μg/L) at the fifth day after surgery,days required to reach the target concentration level,times needed to adjust the dosage of Tac within two weeks.Result The percentage of patients reaching the target concentration in experiment group and control group was 90％ and 46.67％,respectively (P＜ 0.05).Days required to reach the target concentration were (3.67 ± 1.32) and (7.57 ± 3.42) on average,respectively (P ＜ 0.05).Times of adjusting the Tac dose in experiment group was significantly less than those in the control group (P＜0.05).In the experiment group,the target concentration was obtained even without dosage adjustment (70％).Conclusion Individualized adjustment of Tac doses for patients according to recipients' different CYP3A5 * 3 genotypes is beneficial for reaching target concentration as soon as possible,which is superior to traditional dosage regimen.
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Objective:To develop a simple and rapid HPLC method to determine the concentration and pharmacokinetics of gliqui-done in human plasma. Methods: Acetonitrile was used to precipitate plasma proteins directly and gliquidone was detected by an HPLC-fluorescence assay. The mobile phase consisted of acetonitrile-20 mmol·L-1 biphosphate potassium (80∶20, v/v, pH 2. 5). The flow rate was 1. 0 ml·min-1 . The excitation wavelength was 315 nm and the emission wavelength was 410 nm. Results:The line-arity of gliquidone in plasma was good from 0. 034 to 2. 2 μg·ml-1 and the quantitative lower limit was 0. 034 μg·ml-1 . The range of method recovery was 99. 23%-108. 11%, and that of extraction recovery was 85. 78%-88. 77%. The intra-and inter-day precision was both less than 10%. Both specificity and stability met the requirements. Gliquidone in plasma was determined using the above method after a single oral dose of 60 mg gliquidone tablets in 20 healthy volunteers, and then the pharmacokinetic parameters were ana-lyzed. The variation coefficients were close to or more than 50%. Conclusion:The method is simple, rapid and sensitive, and suit-able for the detection of gliquidone in a large quantity. Individualized administration of gliquidone should be considered due to the obvi-ous individual difference in pharmacokinetics.
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Oesity is a major global health problem. However, current therapeutic strategies for obesity are limited. Obesity results from an imbalance between energy intake and energy expenditure, and the treatment of obesity is based on the correction of this metabolic imbalance. Anti-obesity drugs can shift this balance in a favorable way by reducing food intake, altering metabolism, and by increasing energy expenditure. There is a growing consensus that pharmacotherapy is appropriate for many individuals who are unable to lose weight through less intensive measures. However, side effects may ensue phamacotherapy for obesity. Only two drugs (sibutramine and orlistat) are currently approved for the long-term treatment of obesity. Sibutramine inhibits the reuptake of serotonin and norepinephrine. Orlistat works by blocking the pancreatic lipase. However, phamarcotherapy may not be the ultimate resolution for obesity management. Because the underlying pathophysiology in each individual varies in many aspects, it is recommended to provide individualized and tailored medication in addition to other antiobesity supportive treatments.