Analysis on risk factors of clopidogrel resistance in patients with ischemic stroke / 药学实践杂志

Objective To investigate the risk factors of drug resistance in patients with ischemic stroke by clopidogrel therapy and provide references for promoting clinical individualized drug therapy. Methods A total of 202 inpatients diagnosed with ischemic stroke were admitted and given dual anti-treatment (aspirin+clopidogrel). CYP2C19 genotype was detected by microarray hybridization during hospitalization, and CYP2C19 gene polymorphisms were classified into fast metabolism group, medium metabolism group and slow metabolism group according to the type of drug metabolism. Patients were tested for platelet inhibition induced by adenosine diphosphate (ADP) according to thromboelastographic (TEG) on 7~14 d of drug administration. ADP <30% was classified as clopidogrel drug resistance group and ADP ≥30% as non-resistance group. Logistic regression analysis was used to study the risk factors for the development of clopidogrel resistance. Results Among 202 patients with ischemic stroke, 87 were in the resistant group and 115 in the non-resistant group. The proportion of patients with clopidogrel resistance combined with diabetes and the level of white blood cell count were higher than that in the non-resistant group, and the differences were statistically significant (P<0.05).The proportion of patients with clopidogrel resistance in the CYP2C19 intermediate metabolism group was significantly higher than that in the fast metabolism group, and the rate of platelet inhibition was also significantly lower than that in the fast metabolism group, all with statistically significant differences (P<0.05). Conclusion Combined diabetes mellitus, high white blood cell count levels and CYP2C19 mid-metabolic phenotype are independent risk factors for the development of clopidogrel resistance in patients with ischemic stroke.

Efficacy analysis of anti-platelet in the treatment of high-risk non-disabling ischemic cerebrovascular events guided by point-of-care testing of CYP2C19 gene / 中华神经科杂志

Objective:To explore the efficacy and safety of different anti-platelet regimens in the treatment of high-risk non-disabling ischemic cerebrovascular events (HR-NICE) guided by point-of-care testing of CYP2C19 gene. Methods:A single-centre, prospective, randomised, open-label, and blinded endpoint design was uesd in the study. From July 2020 to January 2022, HR-NICE patients were enrolled in the Stroke Green Channel and Department of Neurology of Xuzhou Central Hospital, and all patients were scraped the buccal mucosa for screening for CYP2C19 loss-of-function allele carriers by point-of-care testing . Patients with intermediate metabolism were defined as those who carried 1 loss-of-function allele and patients with poor metabolism were those who carried 2 loss-of-function alleles. This study reduced the test turnaround time to 1 hour by using a fully automated medical polymerase chain reaction analyzer for a point-of-care test of CYP2C19 genotype. CYP2C19 loss-of-function allele carriers were divided according to the random number table method into the conventional treatment group (clopidogrel 75 mg, once a day), the ticagrelor group (ticagrelor 90 mg, twice a day) and the intensive dose group (clopidogrel 150 mg, once a day) separately combined with aspirin (100 mg, once a day) dual antiplatelet for 21 days. Baseline information, Acute Stroke Org 10172 Treatment Trial staging, 90-day modified Rankin Scale score, occurrence of adverse events and severe adverse events were collected for all the 3 groups. The primary efficacy outcome was new stroke within 90 days, and the primary safety outcome was severe or moderate bleeding within 90 days. Results:A total of 716 patients were included: 240 in the conventional treatment group, 240 in the ticagrelor group and 236 in the intensive dose group. There was no statistically significant difference between the 3 groups at baseline (all P>0.05). There were 26 cases (10.8%) with new stroke events in the conventional treatment group, 11 cases (4.6%) in the ticagrelor group and 4 cases (1.7%) in the intensive dose group, with statistically significant differences among the 3 groups (χ 2=19.28, P<0.05), and the differences between the conventional treatment group and the ticagrelor group (χ 2=6.59, P=0.010) and between the conventional treatment group and the intensive dose group (χ 2=16.83, P<0.001) were statistically significant, whereas the difference between the ticagrelor group and the intensive dose group was not statistically significant ( P>0.05). In the 3 groups, there was 1 case (0.4%) of severe bleeding in the conventional treatment group, 6 cases (2.5%) in the ticagrelor group and none in the intensive dose group, which showed statistically significant differences (χ 2=7.23, P<0.05), and there was statistically significant difference between the ticagrelor group and the intensive dose group ( P=0.030). Among the patients with intermediate CYP2C19 metabolism, there were 13 cases (13/158, 8.2%) with 90-day recurrent stroke in the conventional treatment group, 4 cases (4/153, 2.6%) in the ticagrelor group, and 0 case (0/159) in the intensive dose group, with statistically significant difference (χ 2=16.04, P<0.001), and the differences between the intensive dose group and the conventional treatment group were statistically significant (χ 2=13.64, P<0.001), whereas there was no statistically significant difference between the intensive dose group and the ticagrelor group ( P>0.05). In the patients with 90-day recurrent stroke in the intensive dose group, there was 0 case (0/159) with intermediate metabolism and 4 cases (4/77,5.2%) with poor metabolism, with statistically significant differences ( P=0.011), whereas there were no statistically significant differences in the conventional treatment group and the ticagrelor group ( P>0.05). Conclusions:Screening carriers of CYP2C19 loss-of-function alleles by point-of-care testing can quickly and precisely guide the treatment of patients with non-cardiogenic HR-NICE. An intensive clopidogrel dose of 150 mg, once a day combined with aspirin was effective in reducing stroke recurrence with less occurrence of any bleeding and adverse events, and patients with intermediate CYP2C19 metabolism may be the best population to benefit.

The evaluation value of cytochrome P450 2C19 *2 gene polymorphism, Helicobacter pylori infection for clopidogrel effect in patients with coronary heart disease / 中国医师进修杂志

Objective:To explore the evaluation of cytochrome P450 2C19 *2 (CYP2C19 *2) gene polymorphism and Helicobacter pylori (Hp) infection for clopidogrel efficacy in patients with coronary heart disease. Methods:The clinical data of 113 patients with coronary heart disease from February 2016 to March 2020 in Suzhou High-tech Zone People′s Hospital were retrospectively analyzed. The CYP2C19 *2 gene polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, the Hp infection was detected by 13C urea breath test. The patients were treated with clopidogrel, the effect after 4 weeks was evaluated. The receiver operating characteristic (ROC) curve was used to evaluate the CYP2C19 *2 gene polymorphism and Hp infection for evaluating clopidogrel effect in patients with coronary heart disease. Results:The CYP2C19 *2 genotype in patients with coronary heart disease conformed to Hardy-Weinberg balance ( χ2 = 0.33, P>0.05). Among 113 patients with coronary heart disease, Hp infection was in 27 cases, and Hp non-infection in 86 cases. Among Hp infection patients, CYP2C19 *2 gene GG was in 2 cases, GA in 6 cases, AA in 19 cases; among Hp non-infection patients, CYP2C19 *2 gene GG was in 23 cases, GA in 46 cases, AA in 17 cases, there was statistical difference in CYP2C19 *2 gene polymorphism between the two ( χ2 = 24.35, P<0.01). After clopidogrel treatment, effectiveness was in 79 cases, inefficiency in 34 cases. Among effectiveness patients, YP2C19 *2 gene GG was in 20 cases, GA in 43 cases, AA in 16 cases; among inefficiency patients, CYP2C19 *2 gene GG was in 5 cases, GA in 9 cases, AA in 20 cases, there was statistical difference in CYP2C19 *2 gene polymorphism between the two groups ( χ2 = 16.35, P<0.01). The rate of Hp infection in effectiveness patients was significantly lower than that in inefficiency patients: 12.66% (10/79) vs. 50.00% (17/34), and there was statistical difference ( χ2 = 18.23, P<0.05). ROC curve analysis result showed that the area under the curve of CYP2C19 *2 gene polymorphism combined with Hp infection for evaluating clopidogrel effect in patients with coronary heart disease was larger than CYP2C19 *2 gent GG, GA, AA and Hp infection alone evaluating (0.973 vs. 0.869, 0.679, 0.884 and 0.728) . Conclusions:The CYP2C19 *2 gene polymorphism is associated with Hp infection in patients with coronary heart disease, and the CYP2C19 *2 gene polymorphism combined with Hp infection has the evaluation value for the efficacy of clopidogrel.

Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.

A case of mitochondrial membrane protein-associated neurodegeneration caused by C19orf12 p.Gly58Ser mutation / 中华神经科杂志

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare genetic diseases of nervous system. NBIA is characterized by varying degrees of abnormal iron metabolism and excessive iron deposition in brain tissue. The most common symptoms of NBIA are extrapyramidal symptoms. NBIA can also be associated with varying degrees of dysfunction of the pyramidal tract, cerebellum, peripheral nervous system, autonomic nervous system, mental cognition and vision functions. A patient with NBIA admitted to the Department of Neurology of Xijing Hospital in December 2020 was collected and analyzed for clinical features. Whole exome sequencing (WES) was employed to gene mutation screening, and pathogenicity analysis was performed according to the American College of Medical Genetics and Genomics (ACMG) guideline. The patient was a 13-year-old male with a chronic course of disease that began at the age of 4. The first symptom was spastic gait. With the progress of the disease, the patient developed mental retardation, arrhythmia, coughing from drinking water and loss of vision. Magnetic resonance imaging of the head showed atrophy of the optic nerve and hypointensity signal in bilateral substantia nigra and globus pallidus on T 2WI, fluid attenuated inversion recovery sequency, diffusion weighted imaging and susceptibility weighted imaging without "tiger eye sign" which was commonly found in pantothenate kinase associated neurodegeneration. The homozygous mutation c.172G>A (p.Gly58Ser) was found through WES. The proband′s father and mother are cousins (inbreeding), carried heterozygous variation of this locus. This novel mutation was not reported in mutation database. According to ACMG guideline, C19orf12 gene c.172G>A (p.Gly58Ser) was identified for possible pathogenic mutations. The conservative prediction of this locus suggests high conservatism. The final diagnosis of the patient was mitochondrial membrane protein-associated neurodegeneration (MPAN,NBIA type 4). This finding enriched the known mutation database of MPAN and provided a basis for further study of the disease.

The analysis on the correlation between CYP2C19 gene polymorphism and clopidogrel resistance in patients with acute coronary syndrome / 中国医师进修杂志

Objective:To analyze the relationship between CYP2C19 polymorphism and clopidogrel resistance (CR) in patients with acute coronary syndrome (ACS).Methods:One hundred and twenty-seven ACS patients treated with percutaneous coronary intervention (PCI) from June 2019 to June 2020 were enrolled, including 29 patients with CR(CR group) and 98 patients with none clopidogrel resistance (NCR, NCR group). The clinical data, coronary angiography results were compared between the two groups, the relationship of CYP2C19*2 and CYP2C19*3 polymorphisms and CR were analyzed.Results:The general data and coronary angiography between two groups had no significant differences ( P>0.05). There were differences in the distribution of isogenic genes and genotypes of CYP2C19 (rs4244285) and CYP2C19 (rs4986893) between the two groups ( P<0.05). Polymorphism of CYP2C19*2 and CYP2C19*3 was an important risk factor for CR ( OR = 14.688, 95% CI 3.652-59.063, P<0.01; OR = 7.228, 95% CI 2.412-21.663, P<0.01). Conclusions:CR is closely associated with CYP2C19*2 and CYP2C19*3 in ACS patients.

Influence of CYP2C19 genetic polymorphism on the Helicobacter pylori eradication efficacy in children in Chongqing / 中华实用儿科临床杂志

Objective:To investigate the distribution of CYP2C19 genotypes in Helicobacter pylori (Hp) infected children in Chongqing and the correlation of genotypes with gender, age and efficacy, and to provide a reasonable plan for Hp eradication in children in Chongqing. Methods:A prospective clinical cohort study was carried out on 156 children who were suspected of Hp infection and underwent gastroscopy in Children′s Hospital of Chongqing Medical University from March to July 2020. 13C-urea breath test ( 13C-UBT), rapid urease test (RUT) and histological examination were made for all the children included.Meanwhile, for Hp-positive children, the CYP2C19 genotypes were detected by using the polymerase chain reaction(PCR)-sequence-specific primer method, and their sensitivity to Clarithromycin and Amoxicillin was assessed.According to the genetic testing results, the CYP2C19 genotypes were divided into homozygous extensive metabolizer (HomEM), heterozygous extensive metabolizer (HetEM) and poor metabolizer (PM). The eradication outcomes of proton pump inhibitor combined with Amoxicillin and Clarithromycin (PAC) in different genotypes were observed.The measurement data that did not conform to the normal distribution were expressed with the median ( M), and the enumeration data were represented by the rate or the constituent ratio.The Chi- square test was used for comparison between groups, and P<0.05 indicated statistically significant difference. Results:(1)A total of 102 children were Hp positive.Positive rates of 13C-UBT, RUT and histologic results were 97.1% (99/102), 99.0% (101/102), and 90.2% (92/102), respectively.(2)Among the 102 Hp-infected children HomEM accounted for 45.1% (46/102), HetEM for 41.2% (42/102), and PM for 13.7% (14/102). (3)There were 50 males and 52 females in 102 Hp-infected children.The age range was 3 years to 17 years and 9 months (median: 9 years and 7 months). There was no significant difference in the distribution of CYP2C19 genotypes between females and males and among children of different ages (all P>0.05). (4)In 87 cases treated with PAC regimen, 36 cases failed to eradicated Hp in the initial treatment, including 18 cases of HomEM, 15 cases of HetEM, and 3 cases of PM.Hp was eradicated successfully in 51 cases, including 21 cases of HomEM, 21 cases of HetEM and 9 cases of PM.There was no statistically significant difference in the Hp eradication efficacy among children with different CYP2C19 genotypes treated by the PAC regimen ( P>0.05). (5) Among the 87 children, 45 children were sensitive to Clarithromycin, and 37 of them achieved successful Hp eradication.About 42 children were resistant to Clarithromycin, and Hp eradication was fulfilled in 14 of them.There was a statistically significant difference in the Hp eradication efficacy among Clarithromycin-resistant children treated by PAC regimen ( P<0.05). Conclusions:The CYP2C19 genotypes have no correlation with gender, age and Hp eradication efficacy of PAC in children with Hp infection in Chongqing.

Effect of antiplatelet strategy on prognosis of in patients with diabetes mellitus and acute coronary syndrome with different CYP2C19 genotype / 国际生物医学工程杂志

Objective:To investigate the effect of different P2Y12 inhibitors on the long-term prognosis of patients with diabetes mellitus (DM) and acute coronary syndrome (ACS), with or without the CYP2C19 loss-of-function (LOF) gene. Method:266 consecutive ACS patients undergoing percutaneous coronary intervention (PCI) were enrolled. According to the CYP2C19 LOF genotype, the patients were divided into rapid metabolizing-type (without the CYP2C19 LOF gene) and moderate-slow metabolizing type (with the CYP2C19 LOF gene). Each type was divided into the A group (with diabetes) and the B group (without diabetes). Each group was divided into the ticagrelor subgroup and the clopidogrel subgroup according to the type of P2Y12 platelet inhibitor. The MACE events were recorded for each subgroup over 3 years, and the prognostic impact of the CYP2C19 LOF genotype and the type of P2Y12 used were analyzed. Results:There were no significant differences in MACE, revascularization, stroke, heart failure rehospitalization, major bleeding, or all-cause mortality among subgroups of patients with rapid metabolizing type at 3 years after PCI (all P>0.05). In patients with moderate-slow metabolizing-type, the use of tegretol significantly reduced the probability of MACE events and cardiac revascularization (all P<0.01) and significantly reduced the reoccurrence of heart attack in patients with DM. Conclusions:In DM combined with ACS patients with rapid metabolizing type, the choice of different P2Y12 inhibitors after PCI had no significant effect on their prognosis. In DM combined with ACS patients with moderate-slow metabolizing type, tegretol not only significantly reduced the incidence of MACE, revascularization, and reinfarction, but also did not increase the risk of major bleeding. In terms of reducing the reoccurrence of heart attack, the benefit of using tegretol in the DM patients was greater than in the non-DM patients.

The effect of CYP2C19 genetic polymorphism on proton pump inhibitors and the efficacy of Hp eradication in children / 国际儿科学杂志

The polymorphism of CYP2C19 gene constitutes the basis for the difference in enzyme activity and affects the metabolism of many drugs including proton pump inhibitors.The distribution of CYP2C19 gene varies by region and race.The study on the relationship between CYP2C19 genotype and proton pump inhibitors is of great significance for the individualized treatment of Helicobacter pylori (Hp) in children.This paper reviews the effects of CYP2C19 gene polymorphism on proton pump inhibitors and the efficacy of Hp eradication in children.

Validation of compound C19 as a glutaminase C inhibitor / 药学学报

The mitochondrial enzyme glutaminase C (GAC) is highly expressed in a variety of cancer cells, resulting in increased glutamine metabolism and cancer development. Therefore, GAC has become a potential target for anti-tumor drug development. However, current GAC inhibitors shared similar structural characteristics, few new scaffolds were reported. By conducting a prokaryotic Escherichia coli expression system, human GAC protein of high-purity was obtained through lysozyme digestion combined with ultrasound dissociation, and cobalt magnetic beads purification, Moreover, we performed studies to validate interaction between small molecules and GAC protein through thermal shift assay, drug affinity responsive target stability assay, protein crosslinking and GAC enzyme activity detection. Meanwhile, a comprehensive small molecule-protein interaction confirmation and systematic pharmacodynamic study in vitro were carried out on compound C19, which was a reported GAC inhibitor screened from the Enamine database. Results showed that C19 directly bind to GAC protein, disturbed GAC tetramers formation, and inhibited its enzyme catalytic activity. By interfering GAC function, C19 dose-dependently suppressed GAC-mediated glutamine metabolism, reduced glutamate in cancer cells, and thus alleviated A549 and NCI-H1299 non-small cell lung cancer cell growth. Together, C19 was identified as a lead compound, providing a new strategy for the structural design of drugs targeting GAC.

Antiplatelet and myocardial protective effect of Shexiang Tongxin Dropping Pill in patients undergoing percutaneous coronary intervention: A randomized controlled trial / 中西医结合学报

BACKGROUND@#High on-clopidogrel platelet reactivity could be partially explained by loss-of-function alleles of CYP2C19, the enzyme that converts clopidogrel into its active form. Shexiang Tongxin Dropping Pill (STDP) is a traditional Chinese medicine to treat angina pectoris. STDP has been shown to improve blood flow in patients with slow coronary flow and attenuate atherosclerosis in apolipoprotein E-deficient mice. However, whether STDP can affect platelet function remains unknown.@*OBJECTIVE@#The purpose of this study is to examine the potential effects of STDP on platelet function in patients undergoing percutaneous coronary intervention (PCI) for unstable angina. The interaction between the effects of STDP with polymorphisms of CYP2C19 was also investigated.@*DESIGN, PARTICIPANTS AND INTERVENTION@#This was a single-center, randomized controlled trial in patients undergoing elective PCI for unstable angina. Eligible subjects were randomized to receive STDP (210 mg per day) plus dual antiplatelet therapy (DAPT) with clopidogrel and aspirin or DAPT alone.@*MAIN OUTCOME MEASURES@#The primary outcome was platelet function, reflected by adenosine diphosphate (ADP)-induced platelet aggregation and platelet microparticles (PMPs). The secondary outcomes were major adverse cardiovascular events (MACEs) including recurrent ischemia or myocardial infarction, repeat PCI and cardiac death; blood biomarkers for myocardial injury including creatine kinase-MB isoenzyme (CK-MB) and high-sensitive troponin I (hsTnI); and biomarkers for inflammation including intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and galectin-3.@*RESULTS@#A total of 118 subjects (mean age: [66.8 ± 8.9] years; male: 59.8%) were included into analysis: 58 in the control group and 60 in the STDP group. CYP2C19 genotype distribution was comparable between the 2 groups. In comparison to the control group, the STDP group had significantly lower CK-MB (P < 0.05) but similar hsTnI (P > 0.05) at 24 h after PCI, lower ICAM-1, VCAM-1, MCP-1 and galectin-3 at 3 months (all P < 0.05) but not at 7 days after PCI (P > 0.05). At 3 months, the STDP group had lower PMP number ([42.9 ± 37.3] vs. [67.8 ± 53.1] counts/μL in the control group, P = 0.05). Subgroup analysis showed that STDP increased percentage inhibition of ADP-induced platelet aggregation only in slow metabolizers (66.0% ± 20.8% in STDP group vs. 36.0% ± 28.1% in the control group, P < 0.05), but not in intermediate or fast metabolizers. The rate of MACEs during the 3-month follow-up did not differ between the two groups.@*CONCLUSION@#STDP produced antiplatelet, anti-inflammatory and cardioprotective effects. Subgroup analysis indicated that STDP inhibited residual platelet reactivity in slow metabolizers only.@*TRIAL REGISTRATION@#This study was registered on www.chictr.org.cn: ChiCTR-IPR-16009785.

Relationship between clopidogrel responsiveness and CYP2C19 genotype by thromboelastography in patients with coronary heart disease after PCI / 中国输血杂志

【Objective】 To explore the relationship between clopidogrel responsiveness and CYP2C19 gene polymorphism by thromboelastography(TEG) after PCI in patients with coronary heart disease, and its guiding significance for the use of clopidogrel after PCI. 【Methods】 A total of 246 patients who underwent PCI surgery in our hospital from June 2018 to May 2021 and routinely took clopidogrel maintenance treatment after the operation were selected.The platelet inhibition rate of the patients was detected by TEG to obtain their response to clopidogrel.The CYP2C19 genotype was detected, and the relationship between the patient′s responsiveness to clopidogrel and the CYP2C19 genotype was analyzed. 【Results】 The CYP2C19 genotypes in 246 patients were fast metabolizer (n=95), intermediate metabolizer (n=104) and slow metabolizer (n=47), with the mean ADP inhibition rate(%) at 46.27±21.41, 40.99±25.53 and 24.77±21.68, respectively.They were divided into clopidogrel resistant group (n=98) and clopidogrel normal response group (n=148). The three groups of patients with different CYP2C19 genotypes had no statistically significant differences in gender composition, age and platelet count (P>0.05), while significant differences in hypertension, diabetes and hyperlipidemia(P0.05), but they were all lower than those with slow metabolism patients (both P0.5). Statistically significant difference was noticed in the low responsiveness to clopidogrel by different CYP2C19 genotypes (P<0.05). The drug responsiveness of clopidogrel measured by TEG had strong correlation with the patient′s CYP2C19 genotype.When the ADP inhibition rate was the best cut-off value (27.10%), the sensitivity and specificity of CYP2C19 genotype being diagnosed as the slow metabolite type, was 73.37% and 70.21%, respectively. 【Conclusion】 The response of clopidogrel after PCI in patients with coronary heart disease is associated with CYP2C19 genotype polymorphism.The use of TEG to detect the ADP inhibition rate of patients has strong predictive effect on CYP2C19 genotype and has guiding significance on antiplatelet therapy in patients with coronary heart disease after PCI.

Qualidade de vida, sintomas de depressão e adesão ao tratamento em pacientes com trantorno depressivo maior / Quality of life, depression symptoms and adherence to treatment in patients with major depressive disorder / Calidad de vida, síntomas depresión y adhesión al tratamiento en pacientes con trastorno depresivo mayor

Introdução:Pacientes com depressão maior geralmente respondem ao tratamento com medicamentos antidepressivos, no entanto em 10% a 30% dos casos há apenas uma resposta parcial ou nenhuma resposta, entre os fatores que podem influenciar encontra-se o perfil das enzimas hepáticas metabolizadoras dos antidepressivos, tal como a CYP2C19.Objetivo:Caracterizar os indivíduos quanto ao perfil genético dospolimorfismos CYP2C19*2 ou CYP2C19*17 em pacientes com transtorno depressivo maior (TDM) tratados com citalopram ou escitalopram e compará-los em relação a adesão ao tratamento, sintomas de depressão e qualidade de vida.Metodologia:Trata-se de um estudo transversal realizado com 29 pacientes com TDM. Amostras de sangue foram coletadas para genotipagem de CYP2C19 por discriminação alélica TaqMan®. Após caracterização do perfil genético, os indivíduos foram comparados quanto aos dados demográfico e socioeconômico, adesão ao tratamento (TestedeMorisky-Green),sintomas de depressão (escala de Hamilton) e qualidade de vida (WHOQoL-BREF).Resultados:Quatro pacientes (13.8%) apresentaram polimorfismo para CYP2C19*2 e 10 pacientes (34.4%) para CYP2C19*17, com maior prevalência de CYP2C19*17 (p>0.05). Nenhuma associação significativa de características socioeconômicas, demográficas e clínicas entre os genótipos do CYP2C19.No TestedeMorisky-Green, aadesão moderada ao tratamento foi predominante nos pacientes CYP2C19*2 e CYP2C19*17 (p>0.05). Não foi observada associação entre sintomas de depressão e polimorfismos genéticos (p>0.05). Uma associação significativa entre o genótipo polimórfico CC do CYP2C19*17 com a satisfação com a saúde, enquanto o genótipo CT foi associado ao estado "nem satisfeito/nem insatisfeito" (p<0.05). A maioria dos indivíduos CYP2C19*2 e CYP2C19*17 relatou "necessidade de melhorar" em relação aos domínios de qualidade de vida físico, psicológico, social e ambiental (p>0.05).Conclusões:Os pacientes apresentaram maior prevalência do polimorfismo CYP2C19*17, com moderada adesão ao tratamento. Alguns pacientes, mesmo sob efeito da medicação, apresentaram sintomas de depressão moderado a intenso e relataram uma indefinição na satisfação da sua qualidade de vida (AU).

Introduction:Patients with major depression usually respond to treatment with antidepressant drugs, however in 10% to 30% of cases there is only a partial response or no response, among the factors that can influence is the profile of liver enzymes metabolizing antidepressants, such as CYP2C19.Objective:To characterize the individuals regarding the genetic profile ofCYP2C19*2or CYP2C19*17 polymorphisms in patients with major depressive disorder (MDD) treated with citalopram or escitalopram, and to compare themaccording to treatment adherence, symptoms of depression and quality of life.Methodology:This is cross-sectionalstudy carried out with 29 patients with MDD. Blood samples were collected for CYP2C19 genotyping by TaqMan® allelic discrimination. After characterization of the genetic profile, the individuals were compared regarding the demographic and socioeconomic data, treatment adherence (Morisky-GreenTest), symptoms of depression (Hamilton scale) and quality of life (WHOQoL-BREF).Results:Four patients showed (13.8%) CYP219*2 and 10 patients (34.4%) CYP219*17 polymorphisms.,withhigher prevalence of CYP219*17 (p>0.05). No association between socioeconomic, demographic, and clinical features with CYP2C19 genotypes was observed. In Morisky-GreenTest, moderate adherence to treatment was predominant for CYP2C19*2 and CYP219*17 patients (p>0.05). No statistically significant association was observed between symptoms of depression and genetic polymorphisms (p>0.05). A significant association between polymorphic CC genotype of CYP219*17 with health satisfaction, while the CT genotype was associated with "neither satisfied/nor dissatisfied" status (p<0.05). Most of the CYP2C19*2 and CYP2C19*17 subjects reported "need to improve" or "regular" regarding physical, psychological, social, and environmental domainsof quality of life(p>0.05).Conclusions:The patients showed a higher prevalence of CYP219*17 polymorphism, with moderate treatment adherence. Some subjects, even under the effect of the medication, presented moderate to intense symptoms of depression, and reported a lack of definition in the satisfaction of their quality of life (AU).

Introducción:Los pacientes con depresión mayor responder al tratamiento con antidepresivos, en 10% al 30% de los casos existe una respuesta parcial o nula, entre los factores que pueden influir se encuentra el perfil de enzimas hepáticas metabolizadoras de antidepresivos, como CYP2C19.Objetivo: Caracterizar a los individuos en cuanto al perfil genético depolimorfismos CYP2C19 *2 o CYP2C19 * 17 en pacientes con trastorno depresivo mayor (TDM) tratados con citalopram o escitalopram y compararlos en relaciónpara la adherencia al tratamiento, síntomas de depresión y la calidad de vida.Metodología: Estudio transversalcon 29 pacientes con TDM. Se recogieron muestras de sangre para la determinación del genotipo CYP2C19 mediante discriminación alélica TaqMan®, los individuos fueron comparados en cuanto a los datosdemográficosy socioeconómicos, adherencia (Prueba de Morisky-Green), síntomas de depresión (escala de Hamilton) y calidad de vida (WHOQoL-BREF).Resultados: Cuatro pacientes (13,8%) con polimorfismo CYP2C19*2 y 10 (34,4%) con CYP2C19 * 17,(p> 0,05). No existe una asociación significativa de las características socioeconómicas, demográficas y clínicas con los genotipos CYP2C19. La adherencia moderada al tratamiento fue predominante en los pacientes con CYP2C19*2 y CYP2C19*17 (p> 0,05). No hubo asociación entre síntomas de depresión y polimorfismos genéticos (p> 0.05). Una asociación significativa entre el genotipo polimórfico CYP2C19 * 17 CC con la satisfacción con la salud, mientras que el genotipo CT se asoció con el estado "ni satisfecho / no insatisfecho" (p <0.05). La mayoría de CYP2C19 * 2 y CYP2C19 * 17 individuos informaron "necesidad de mejorar" en relación con los dominios físico, psicológico, social y ambientalde calidad de vida(p> 0,05).Conclusiones: Los pacients mostraron una mayor prevalencia del CYP2C19 * 17, con adherencia moderada al tratamiento, síntomas de depresión moderada a intensay informaron una falta de definición en la satisfacción de su calidad de vida (AU).

Effects of Rabeprazole on the Pharmacokinetics of Clopidogrel and Its Active Metabolite in Healthy Volunteers with Different CYP2C19 Genotypes / 中国药房

OBJECTIVE：To investigate the effects of rabepr azole on the pharmacokinetic characteristics of clopidogrel and its active metabolite in healthy volunteers with different CYP2C19 genotypes. METHODS ：Healthy volunteers were selected as subjects，and then randomly divided into extensive metabolizer （EM）group，intermediate metabolizer （IM）group，and poor metabolizer（PM）group with 8 subjects in each group ，according to their CYP2C19 genotypes by random number table. In single-dose，randomized，open，two-cycle-crossover design ，each group was given Clopidogrel bisulfate tablets 300 mg or Clopidogrel bisulfate tablets 300 mg+Rabeprazole sodium enteric-coated tablets 20 mg. UPLC-MS/MS method was adopted to detect the concentration of clopidogrel and its active metabolite derivative （MP-H4）. The pharmacokinetic parameters were calculated and compared by DAS 2.0 software. RESULTS ：There was no statistical significance in clinical data as age ，height， body weight ，liver enzymes and serum creatinine among 3 kinds of metabolism subjects （P＞0.05）. Compared with subjects receiving clopidogrel alone ，cmax and AUC 0－t of clopidogrel of subjects combined with rabeprazole in EM group were increased by 36％ and 27％，while those of MP-H 4 were decreased by 34％ and 28％（P＜0.01）；cmax and AUC 0－t of clopidogrel of subjects combined with rabeprazole in IM group were increased by 19％ and 18％，while those of MP-H 4 were decreased by 19％ and 16％ （P＜0.05 or P＜0.01）；there was no statistical significance in cmax and AUC 0－t of clopidogrel and MP-H 4 in PM group after receiving rabeprazole additionally as well as tmax of clopidogrel and MP-H 4 in all metablism subjects ，compared with clopidogrel alone（P＞0.05）. CONCLUSIONS ：Among CYP2C19 EM and IM subjects ，combined use of rabeprazole can significantly increase the exposure of clopidogrel and decrease the exposure of its active metabolite MP-H 4，but has no significant impact on clopidogrel and its active metabolite in CYP2C19 PM subjects.

Effect of CYP2C19 gene polymorphism on clopidogrel concentration, platelet inhibition rate and safety in patients after PCI / 药学实践杂志

Objective To explore the effect of CYP2C19 gene polymorphism on clopidogrel plasma concentration, rate of platelet inhibition and safety. Methods We screen the patients who took clopidogrel after PCI in our hospital, according to the inclusion and exclusion criteria. Blood samples were collected on the 6th day after clopidogrel administration. Clopidogrel blood concentration was determine by RP-HPLC. The CYP2C19 genotype was detected by non-amplified immune hybridization. The rate of platelet inhibition was evaluated by the thromboelastogram. The results were analyzed by SPSS 20.0 software. Results A total of 87 patients were recruited, including 46 males and 41 females. Among them, 34 cases were fast metabolism. 38 cases were medium metabolism. 15 cases were slow metabolism. The result showed that there was no significant difference in drug concentration between fast and intermediate metabolism(P=0.667). There was a significant difference in drug concentration between slow metabolism and fast metabolism or medium metabolism(P<0.05). Analysis of variance and chi-square test showed that CYP2C19 gene polymorphism has a significant effect on clopidogrel platelet inhibition rate and safety (P<0.05). Conclusion Guiding clopidogrel clinical medication based on CYP2C19 genotype alone does not necessarily achieve better therapeutic effects. CYP2C19 genotype detection and blood concentration monitoring can be combined to guide the clinical individualized administration of clopidogrel

Analysis of Drug Resistance and Treatment of Refractory Helicobacter pylori Infection in Patients With Nodular Gastritis / 胃肠病学

Nodular gastritis is directly related to Helicobacter pylori (Hp) infection. Refractory Hp infection has significant impact on the treatment efficacy and prognosis of nodular gastritis. Aims: To analyze the spheroidization and antibiotic resistance of refractory Hp and PPI drug metabolic enzyme CYP2C19 gene polymorphism in patients with nodular gastritis, so as to promote the eradication rate of refractory Hp infection in patients with nodular gastritis. Methods: Refractory Hp infection patients with nodular gastritis from Oct. 2019 to Nov. 2020 at the Second Affiliated Hospital of Baotou Medical College were enrolled. Hp strains were cultured in microaerophilic environment. Immunohistochemistry was used to detect Hp spheroidization. Mutation sites of antibiotic resistance genes and host CYP2C19 gene polymorphism were detected by PCR. According to the results of genetic testing, individualized therapy was given and follow up was performed, the eradication rate of intention-to-treat was calculated. Results: A total of 42 patients with refractory Hp nodular gastritis were enrolled. Among them, lymphocyte accumulation was found in 33.3% patients. Hp spheroidization was found in 2 patients, and the spheroidization rates were 20% and 10%, respectively. There were 25 intensive metabolizer, 15 intermediate metabolizer and 2 poor metabolizer of CYP2C19. Antibiotic resistance gene detection showed that the drug resistance rate of amoxicillin, clarithromycin, levofloxacin, furazolidone, tetracycline, metronidazole were 4.8%, 38.1%, 35.7%, 47.6%, 42.9% and 61.9%, respectively. Twenty-two (52.4%) of the patients developed resistance to 3 or more antibiotics. The total eradication rate of intention-to-treat was 83.3%, of which high-dose dual therapy was 88.9%. Conclusions: Multi-antibiotic resistance and CYP2C19 may be the main reason for the failure of eradication of refractory Hp in nodular gastritis. Hp spheroidization has little effect on the efficacy of eradication therapy. The amoxicillin resistance rate is still significantly lower than that of other antibiotics, and high-dose dual therapy is a better option.

Factors Affecting the Initial Eradication Rate of Helicobacter pylori Infection / 胃肠病学

Background: Helicobacter pylori (Hp) infection is related to the occurrence of many upper digestive tract diseases, and the eradication rate has been decreasing year by year. Aims: To investigate the risk factors affecting initial eradication rate of Hp infection. Methods: Clinical data of 428 patients with Hp infection were retrospectively analyzed. Four regimens (14-day esomeprazole 20 mg + amoxicillin 750 mg, qid; 10-day esomeprazole 20 mg + amoxicillin 750 mg, qid; 14-day esomeprazole 20 mg + amoxicillin 1 000 mg, tid; 14-day esomeprazole 20 mg + bismuth 220 mg + amoxicillin 1 000 mg + clarithromycin 500 mg, bid) were given, and effect of antibiotic resistance on Hp eradication was analyzed, the relevant risk factors affecting the eradication rate of Hp were investigated. Results: The eradication rate of ITT analysis was 86.4%, PP analysis was 87.6%. The eradication rates of 4 regimens for ITT analysis were 90.8%, 79.8%, 82.7%, 91.9%, respectively, and were 90.8%, 81.2%, 85.1%, 92.7% for PP analysis, respectively. The antibiotic resistance rate was 30.3%, 97.4% and 36.8% for clarithromycin, metronidazole and levofloxacin, respectively. The recurrence rate of 116 patients was 4.3% after one year of eradication. Smoking, poor compliance, CYP2C19 gene polymorphism were risk factors for eradication rate of Hp (P<0.05). Conclusions: Smoking, poor compliance and ultra-rapid metabolizers, extensive metabolizers of CYP2C19 gene polymorphism can reduce Hp eradication rate. In clinical practice, patient education should be strengthened to urge patients to quit smoking. The quality of follow-up should be improved and proton pump inhibitor that has less impact on CYP2C19 gene polymorphism should be used, thereby increase the Hp eradication rate.

Correlation between CYP2C19 gene polymorphism and individualized medication in patients with ischemic stroke / 中国临床药理学与治疗学

AIM: To investigate the guiding role of individualized medication adjustment based on CYP2C19 metabolic typing in the treatment of ischemic stroke with clopidogrel, and to provide reference for clinical individualized medication. METHODS: The total of 80 patients with ischemic stroke were divided into the individualized drug instruction group with gene detection (n=40) and the control group without gene detection (n=40) according to whether they received CYP2C19 gene detection. According to the metabolism of CYP2C19, the individualized medication instruction group was divided into slow metabolic type, intermediate metabolic type, fast metabolic type and ultra-fast metabolic type. Patients with fast and ultra-fast metabolites were given clopidogrel dose of 75 mg once a day. Patients with intermediate metabolic type were given double clopidogrel dose of 150 mg once a day. Patients with slow metabolism were given tigrillo dose of 90 mg twice a day or aspirin dose of 100 mg once a day. The control group received 75 mg clopidogrel once a day. All patients enrolled in the groups were followed up for 3 months by outpatients or telephone. The incidence of vascular events and mRS scale scores were compared between the two groups. RESULTS: The incidence of vascular events in the individualized drug instruction group was significantly lower than that in the control group, and the incidence of mRS score(0-1) was significantly higher than that in the control group, with statistically significant differences (P<0.05). CONCLUSION: The individualized medication for patients with ischemic stroke by CYP2C19 gene detection can significantly reduce the incidence of adverse vascular events and improve the prognosis and living ability of patients.

Analysis of CYP2C19 gene polymorphism in patients with upper digestive system diseases in Anhui Province / 预防医学

Objective@#To analyze the CYP2C19 gene polymorphism in patients with upper digestive system diseases in Anhui Province, so as to provide evidence for individual treatment.@*Methods@#The 307 patients with upper digestive system diseases in the Department of Gastroenterology, The 901st Hospital of Combined Service Force of People＇s Liberation Army were selected. The CYP2C19 genotypes were detected by DNA microarray microarray. The CYP2C19 genotypes and metabolic types in different genders, ages and diseases were analyzed.@*Results@# There were 197 males ( 64.17% ) and 110 females ( 35.83% ) , with the age of ( 58.00±16.13 ) years old. The gene frequency of CYP2C19*1, CYP2C19*2 and CYP2C19*3 was 62.70%, 32.25% and 5.05%, respectively. There were 119 cases (38.76%) of *1/*1 ( 636GG, 681GG ), 129 cases ( 42.02% ) of *1/*2 ( 636GG, 681GA ) , 18 cases (5.86%) of *1/*3 ( 636GA, 681GG ) , 29 cases ( 9.45% ) of *2/*2 ( 636GG, 681AA ) , 11 cases ( 3.58% ) of *2/*3 ( 636GA, 681GA ) , and 1 cases ( 0.33% ) of *3/*3 ( 636AA, 681GG ). In terms of metabolisms, there were 119 cases ( 38.76% ) of fast metabolism type, 147 cases (47.88%) of intermediate metabolism type and 41 cases (13.35%) of slow metabolism type. There were no significant differences in CYP2C19 genotypes and metabolic types among the patients with different gender, age and digestive system diseases ( P＞0.05 ).@*Conclusion@#The CYP2C19 genotypes of patients with upper digestive system diseases were polymorphic, mainly the fast metabolism type and the intermediate metabolism type, which could provide reference for the clinical medication of individualized treatment of proton pump inhibitors.

Effects of clopidogrel resistence and CYP2C19 genotype on the clinical prognosis of patients with acute coronary syndrome undergoing percutaneous coronary intervention / 中华心血管病杂志

Objective: To investigate the effects of clopidogrel resistence and CYP2C19 genotype on the clinical prognosis of acute coronary syndrome(ACS) patients undergoing percutaneous coronary intervention(PCI). Methods: This study was a retrospective cohort study. ACS patients who underwent PCI in Beijing Anzhen Hospital from October 2015 to January 2017 were recruited. The inhibition rate of adenosine diphosphate(ADP) was monitored by thromboelastography. All of these patients were divided into clopidogrel resistance and non-resistance group according to the monitoring results. CYP2C19 genotype was detected by TaqMan probe-based real-time quantitative PCR. Patients were divided into slow, medium and fast metabolic group, according to the CYP2C19 genotype. After 12 months of follow-up, the end points included all-cause death, cardiac death, angina, myocardial infarction, stent thrombosis, ischemic stroke and hemorrhage were collected. Combined thrombotic events were defined as a composite of angina, myocardial infarction, stent thrombosis and ischemic stroke. The differences of the incidence of clinical events between groups were compared. Cox regression was used to analyze the effects of clopidogrel resistance and CYP2C19 genotype on the combined thrombotic events, cardiac death and hemorrhage. Results: A total of 1 696 patients were included, and the age was (59.4±9.6) years, with 1 280(75.5%) males. There were 471 cases(27.8%) in clopidogrel resistance group, and 1 225 cases(72.2%) in clopidogrel non-resistance group. There were 218 patients(12.9%) were in slow metabolic group, 668(39.4%) in medium metabolic group, and 810 (47.8%) in fast metabolic group. The median follow-up time was 13.3 months, and 131 cases were lost to follow-up, with a loss follow-up rate of 7.7%. Compared with the clopidogrel non-resistance group, the clopidogrel resistance group had a higher incidence of myocardial infarction(7.6%(36/471) vs. 5.1%(62/1 225), P=0.041), a lower incidence of hemorrhage (13.2%(62/471) vs. 17.9%(219/1 225), P=0.020) and minor hemorrhage(11.5%(54/471) vs. 15.8% (194/1 225), P=0.022). There were no statistically significant difference in all-cause death, cardiac death, angina, stent thrombosis, ischemic stroke and severe bleeding between clopidogrel resistance and non-resistance group(all P>0.05). There was no statistically significant difference in the incidence of endpoint events among different CYP2C19 genotypes (all P>0.05). Cox regression analysis showed that clopidogrel resistance was an independent factor of combined thrombotic events (OR=2.334, 95%CI 1.215-4.443, P=0.016) and bleeding events (OR=0.481, 95%CI 0.174-0.901, P=0.023). While CYP2C19 genotype was not independent factor for combined thrombotic events, cardiac death and hemorrhage (all P>0.05). Conclusion: For ACS patients after PCI, clopidogrel resistance can increase the risk of combined thrombotic events, but also reduce the risk of bleeding; while CYP2C19 genotype is not an independent factor for clinical prognosis.