Distribution of CYP2C9∗3 and VKORC1-1639G>A gene polymorphism in Anhui Han population and their influence on the stable dose of warfarin / 中国临床药理学与治疗学

AIM: To study the distribution of CYP2C9∗3 and VKORC1-1639G>A gene polymorphism in Han population in Anhui province and their influence on the stable dose of warfarin. METHODS: The blood samples of 1 169 patients from 6 tertiary general hospitals in 5 areas of Anhui province from January 2020 to December 2021 were selected, the genotype of CYP2C9∗3 and VKORC1-1639G>A was detected by fluorescent staining in situ hybridization technique. RESULTS: The distribution of CYP2C9∗3 genotypes in 1 169 patients: the frequencies of AA, AC and CC genes were 90.16%, 9.24% and 0.60%, respectively; The distribution of VKORC1 genotype: the frequencies of AA, AG and GG genes were 84.26%, 14.71% and 1.03% respectively; There was no significant difference between the two genotypes in gender, age and regional distribution (P>0.05). The average daily warfarin dose of CYP2C9∗3 AA genotype in 755 patients with stable warfarin dose was (3.02±0.59) mg/d, which was significantly higher than patients with AC genotype and CC genotype; The average daily warfarin dose of patients with VKORC1-1639AA genotype was (2.72±0.40) mg/d, which was significantly lower than that of patients with AG genotype and GG genotype (P<0.05). And the difference was statistically significant (P<0.05); There are significant differences in gender, age and clinical diagnosis between patients with stable dose of warfarin and those without stable dose (P<0.05). CONCLUSION: CYP2C9 and VKORC1 genotypes are associated with the stable dose of warfarin. Clinical anticoagulation therapy guided by CYP2C9 and VKORC1 genotypes can provide guidance for individualized medication of warfarin.

Ajustes Curriculares de las Escuelas de Odontología Chilenas en Periodo de Pandemia COVID-19

RESUMEN: Dada la expansión de la pandemia por COVID-19, se han implementado diversas medidas restrictivas, las cuales han afectado todos los ámbitos, incluido el educacional. A nivel internacional, las universidades han realizado diversos ajustes a sus programas curriculares para adaptarse a esta situación, siendo la carrera de Odontología particularmente afectada a causa de los cierres de clínicas y retraso en la adquisición de competencias clínicas. El objetivo del estudio es describir los principales ajustes curriculares de las carreras de Odontología de universidades chilenas, realizadas en periodo de pandemia en el año 2020, recopiladas a través de una encuesta. Se realizó un estudio observacional descriptivo, a través de una encuesta enviada a todos los representantes de las escuelas de Odontología de universidades chilenas. Se recopiló información sobre el contexto sanitario local, accesibilidad a las clínicas odontológicas, disponibilidad de tratamientos, vía de enseñanza, apoyo al bienestar mental e implicaciones futuras en la educación dental. De las 27 escuelas de Odontología nacionales, se obtuvieron 23 respuestas. Un 57% de las escuelas tuvo limitaciones en el acceso y en el tipo de tratamientos odontológicos realizados en sus centros clínicos. Todas las escuelas implementaron una modalidad online para reemplazar las actividades lectivas presenciales y un 42 % realizó actividades clínicas presenciales durante el año 2020. Todas las evaluaciones teóricas fueron realizadas de forma online, y un 82 % de las evaluaciones de competencias clínicas se retrasaron para ser realizadas posteriormente. Debido a las medidas restrictivas de la pandemia, las clases presenciales, evaluaciones teóricas y algunas actividades prácticas se realizaron en modalidad online. Dependiendo del contexto comunal y políticas internas universitarias, algunas escuelas de odontología pudieron realizar actividades prácticas presenciales. El plan de estudios académico en las escuelas de odontología se ha visto afectado de diferentes maneras como resultado de la pandemia de COVID-19.

ABSTRACT: The COVID-19 pandemic has caused several disruptions in medical education worldwide. Universities made curricular adjustments in order to adapt to this situation. Dentistry has been particularly affected by the lockdown measures resulting in the closure of dental clinics and the disruption of face to face personal training of students. The objective of this study was to describe the main curriculum adjustments made by the dental schools in Chile during 2020. A cross-sectional online survey was carried out which included representatives from all Dental Schools in Chilean Universities. The survey requested information related to local sanitary situations, accessibility to dental clinics, availability of treatments, teaching modality, support for mental well-being and future implications of dental education. Of 27 dental schools a total of 23 responses were received. It was found that 57 % of schools had limited access to dental clinics. All schools had implemented online modality to replace face-to-face theoretical training, 42 % were able to conduct clinical activities during 2020 and 82 % of clinical competency assessments were postponed. Due to the restrictive measures of the pandemic, the face-to-face classes, theoretical evaluations and some practical activities were performed online. Depending on the communal context, dental schools were able to execute practical activities. The academic curriculum in dental schools has been severely affected in different ways as a result of the COVID-19 pandemic.

A clinical study of genetic testing to guide the dosing of warfarin after heart valve replacement / 中华胸心血管外科杂志

Objective:To explore the role of genetic testing of VKORC1 and CYP2C9 in determining the dosage of warfarin after aortic valve replacement.Methods:A total of 172 patients receiving warfarin after aortic valve replacement were divided into a control group(86 cases) and an experimental(86 cases) group based on acceptance of genetic testing. In the experimental group, three loci of VKORC1 and CYP2C9 were tested by polymerase chain reaction-restriction fragment length polymorphism technique, and the initial dose of warfarin was determined based on the genetic testing results and warfarin oral-dose table recommended by U. S. Food and Drug Administration(FDA). In the control group, warfarin(3 mg/d) was used as the initial dose. The international normalized ratio(INR) of each patient was continuously monitored after medication. The percentages of patients meeting the target INR in the two groups at specific time points and at 3-month follow-up after discharge from the hospital were monitored, and the incidence of various adverse events was compared between the groups.Results:Based on the results of genetic testing, 68 patients received 3 mg/d(79.1%), 10 patients received 1.5 mg/d(11.6%), and eight patients received 6 mg/d(9.3%) as the initial dosages of warfarin in the experimental group. The percentages of the patients meeting the target INR on the third and sixth day of postoperative medication were 45.3% and 73.3%, respectively, in the experimental group, and 29.8% and 58.3%, respectively, in the control group( P<0.05). The INR critical values during hospitalization occurred in 2.3% in the experimental group and in 7.1% in the control group, while the percentage of the patients meeting the target INR after 3 months was 86.1% in the experimental group and 83.1% in the control group. Conclusion:Genetic testing may guide the selection of the initial dose of warfarin after heart valve replacement to rapidly achieve a stable dose.

Effects of CYP2C9*3 Gene Polymorphism on Therapeutic Efficacy of Benzbromarone in Lowering Uric Acid and Its Hepatotoxicity / 中国药房

OBJECTIVE：To study the effects o f CYP2C9*3 gene polymorphism on therapeutic efficacy of benzbromarone in lowering uric acid and its hepatotoxicity. METHODS ：A retrospective study was conducted to analyze the relevant clinical indicators and genotypes of 196 gout patients who received benzbromarone and CYP2C9*3 gene polymorphism test in Wuhan third hospital from Jan. 2018 to Sept. 2019. RESULTS ：Among 196 patients，179，15 and 2 patients with CYP2C9*3 genotypes * 1/*1， *1/*3 and * 3/*3 genotypes were found ，respectively，and the distribution of each genotype was in line with Hardy-Weinberg balance（P＞0.05）. Before treatment ，there were no significant differences in the levels of UA ，Scr，ALT，AST and CRP between *1/*1 genotype and * 1/*3+*3/*3 genotype（P＞0.05）. After 4 weeks of treatment ，the UA ，Scr，CRP levels of patients with * 1/*1 genotype as well as the UA and CRP levels of patients with * 1/*3+*3/*3 genotype were significantly reduced ，the UA level of patients with * 1/*1 genotype was significantly lower than that of patients with * 1/*3+*3/*3 genotype（P＜0.05 or P＜0.01）. The ALT and AST levels had no obvious changes in patients with different genotype before and after treatment ，and they were in the normal range. No serious abnormal liver function was observed during the treatment. CONCLUSIONS ：Therapeutic efficacy of benzbromarone in lowering uric acid in gout patients with CYP2C9*3 genotypes * 1/*1 genotype is better than that of * 1/*3 and * 3/*3 genotypes. However ，the gene polymorphism may be not associated with its hepatotoxicity.

Role of the C9ORF72 Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia / 神经科学通报·英文版

Since the discovery of the C9ORF72 gene in 2011, great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms; it is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS patients with C9ORF72 expansion show heterogeneous symptoms. Those who are C9ORF72 expansion carriers have shorter survival after disease onset than non-C9ORF72 expansion patients. Pathological and clinical features of C9ORF72 patients have been well mimicked via several models, including induced pluripotent stem cell-derived neurons and transgenic mice that were embedded with bacterial artificial chromosome construct and that overexpressing dipeptide repeat proteins. The mechanisms implicated in C9ORF72 pathology include DNA damage, changes of RNA metabolism, alteration of phase separation, and impairment of nucleocytoplasmic transport, which may underlie C9ORF72 expansion-related ALS/FTD and provide insight into non-C9ORF72 expansion-related ALS, FTD, and other neurodegenerative diseases.

Nutritional and Metabolic Support and the Treatment Strategy of Severe Corona Virus Disease 2019 (COVID-19) / 中华急诊医学杂志

The digestive tract is a target organ attacked by COVID-19. It is also the earliest affected organ other than the lung and must bear side effects from the anti-virus chemotherapy such as LPV/r. In this article, we aim to provide practical recommendations for a nutritional and metabolic management strategy for severe corona virus disease-19 (COVID-19) patients. These recommendations are based on the newest pathophysiological findings on the risk factors of malnutrition for COVID-19. We also systematically retrieve literatures on nutritional therapy for acute lung injuries from international and Chinese databases according to evidence-based principles. Our suggestions are: 1) Physicians should be mindful of gut injury when they focus on respiratory support, by monitoring and managing the nutritional status; 2) Periodical and dynamic nutritional risk evaluation is needed; 3) For severe patients, the feeding target of calorie and protein should be down-regulated; 4)The using of ω-3 fatty acids products should be in accordance with pharmacological indications; the forms and dosage should be determined individually.

Role of the C9ORF72 Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia / 神经科学通报·英文版

Since the discovery of the C9ORF72 gene in 2011, great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms; it is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS patients with C9ORF72 expansion show heterogeneous symptoms. Those who are C9ORF72 expansion carriers have shorter survival after disease onset than non-C9ORF72 expansion patients. Pathological and clinical features of C9ORF72 patients have been well mimicked via several models, including induced pluripotent stem cell-derived neurons and transgenic mice that were embedded with bacterial artificial chromosome construct and that overexpressing dipeptide repeat proteins. The mechanisms implicated in C9ORF72 pathology include DNA damage, changes of RNA metabolism, alteration of phase separation, and impairment of nucleocytoplasmic transport, which may underlie C9ORF72 expansion-related ALS/FTD and provide insight into non-C9ORF72 expansion-related ALS, FTD, and other neurodegenerative diseases.

Effects of CYP2C9 and VKORC1 genetic polymorphisms in Chinese Han population on maintenance dosage of warfarin / 中华检验医学杂志

Objective@#To analyze CYP2C9 and VKORC1 gene polymorphisms in Chinese Han population and their correlation with the maintenance dosage of warfarin.@*Methods@#From October 2017 to April 2018, 458 Chinese Han patients (213 males and 245 females, aged from 26 to 94 years old) who underwent coagulation analysis in Peking University People′s Hospital were included in this retrospective study. PCR-Fluorescent probe method was applied to detect CYP2C9*3 and VKORC1-1639A>G gene polymorphisms in 458 patients, and among them, 130 patients who took warfarin for anticoagulant therapy and reached the international standard ratio of prothrombin time (INR) within the range of 2.0-3.0 were recorded. The basic information, dosage of warfarin and INR were also recorded. The statistical analysis data were compared with the reference table of recommended dosage of warfarin for different genotypes of patients recommended by FDA and the formula of predicted dosage of warfarin was simply verified by SPSS.@*Results@#Among the 458 patients who took anticoagulant therapy, the genotype frequencies of CYP2C9*1/*1(AA), CYP2C9*1/*3(AC) and CYP2C9*3/*3(CC) were 90.8%, 8.5%, and 0.7%; the genotype frequencies of VKORC1-1639GG and VKORC1-1639AG were 0.9% and 14.2%; the genotype frequencies of VKORC1-1639AA was 84.9%. After INR was reached, the results showed that the variant CYP2C9*1/*3 and CYP2C9*3/*3 required lower daily maintain dosage [(2.92±1.29) mg] than wild-type CYP2C9*1/*1 patients did [(3.91±1.63) mg], with statistically significant difference (P=0.018). And variant VKORC1-AA required lower daily maintain dosage [(3.68±1.64) mg] than variant VKORC1-AG patients did [(4.54±1.29) mg], with statistically significant difference (P=0.001). The application dosage of warfarin in patients with different VKORC1+CYP2C9 genotypes was consistent with the recommended dosage of the FDA reference table. The prediction accuracy of miao 2007 formula was lower than that of IWPC formula, and 94.1% of patients′ dosages of warfarin were underestimated.@*Conclusion@#Patients with CYP2C9*3 or VKORC1-AA genotype required lower warfarin dosage. The CYP2C9 and VKORC1 gene polymorphisms had a certain correlation with maintenance dosage of warfarin.

Nurse empowerment through Pharmacogenetics / Empoderamento do enfermeiro por meio da Farmacogenética / Empoderamiento del enfermero a través de la farmacogenética

Objective: to verify the existence of elements that justify the use of pharmacogenetics by the Brazilian nurse. Method: this is a quantitative, cross-sectional, observational, descriptive study, whose final sample was 67 individuals. The participants were healthy at the time of the study and reported a history of previous use and the occurrence of adverse effects by drugs commonly used and metabolized by CYP2C9. We collected 4 mL of venous blood for subsequent DNA extraction by salting out method and genotyping of the CYP2C9*2 and CYP2C9*3 polymorphisms, using Polymerase Chain Reaction in real time using Taqman assays. Results: the use of drugs metabolized by CYP2C9 was frequent (more than 75% of the individuals have already used between 2 or 4 of these drugs). Regarding adverse events, there were 19 perceived symptomatic occurrences associated with drugs metabolized by CYP2C9. The allele frequency of the polymorphism * 2 and * 3 in the population studied was 11.1% and 7.5%, respectively, and there was a coincidence between the presence of alleles of low enzyme activity and the occurrence of adverse effects. Conclusion: there are elements that justify the adoption of pharmacogenetics in the nursing care to reduce the occurrence of adverse reactions to drugs metabolized by CYP2C9.

Objetivo: verificar a existência de elementos que justifiquem o uso da farmacogenética pelo enfermeiro brasileiro. Método: trata-se de um estudo quantitativo, do tipo transversal, observacional descritivo, cuja amostra final foi de 67 indivíduos. Os participantes estavam saudáveis no momento do estudo e reportaram histórico de uso prévio e ocorrência de efeitos adversos por fármacos comumente utilizados e metabolizados pela CYP2C9. Coletamos 4 mL de sangue venoso para posterior extração de DNA por método salting out e genotipagem dos polimorfismos CYP2C9*2 e CYP2C9*3 através de Polymerase Chain Reaction em tempo real, utilizando ensaios Taqman. Resultados: o uso de fármacos metabolizados pela CYP2C9 foi frequente (mais de 75% dos sujeitos já utilizaram entre 2 ou 4 desses fármacos). A respeito dos eventos adversos, houve 19 ocorrências sintomáticas percebidas, associadas a fármacos metabolizados pela CYP2C9. A frequência alélica do polimorfismo *2 e *3 na população estudada foi de 11,1% e 7,5%, respectivamente, com coincidência entre a presença dos alelos de baixa atividade enzimática e ocorrência de efeitos adversos. Conclusão: existem elementos que justificam a adoção da farmacogenética no cuidado do enfermeiro com objetivo de redução da ocorrência de reações adversas a fármacos metabolizados pela CYP2C9.

Objetivo: verificar la existencia de elementos que justifiquen el uso de la farmacogenética por parte del enfermero brasileño. Método: se trata de un estudio cuantitativo, transversal, observacional, descriptivo, cuya muestra final fue de 67 individuos. Los participantes estaban sanos en el momento del estudio e informaron un historial de uso previo y la aparición de efectos adversos por fármacos comúnmente utilizados y metabolizados por el CYP2C9. Recolectamos 4 ml de sangre venosa para la posterior extracción de ADN mediante el método de salazón y genotipificación de los polimorfismos CYP2C9 * 2 y CYP2C9 * 3 a través de la reacción en cadena de la polimerasa en tiempo real utilizando ensayos Taqman. Resultados: el uso de drogas metabolizadas por el CYP2C9 fue frecuente (más del 75% de las personas ya han usado entre 2 o 4 de estas drogas). Con respecto a los eventos adversos, hubo 19 casos sintomáticos percibidos asociados con medicamentos metabolizados por el CYP2C9. La frecuencia alélica del polimorfismo * 2 y * 3 en la población estudiada fue de 11.1% y 7.5%, respectivamente, y hubo una coincidencia entre la presencia de alelos de baja actividad enzimática y la aparición de efectos adversos. Conclusión: existen elementos que justifican la adopción de la farmacogenética en el cuidado del enfermero para reducir la aparición de reacciones adversas a los medicamentos metabolizados por el CYP2C9.

Efecto de las variantes de CYP2C9 sobre la dosis de losartán en hipertensos chilenos / Association between cytochrome p4502c9 polymorphisms and losartan dosing in hypertensive patients

Background Losartan is widely used in many clinicals settings. Its dosage is related to the genetic characteristics of CYP2C9 enzymatic activity, which metabolizes losartan to its active form E-3174, responsible for the antihypertensive effect. Aims To identify the frequency of allelic variants CYP2C9*2 and CYP2C9*3 in hypertensive patients and to compare genotypes with a healthy Chilean population. To relate polymorphisms with the losartan dosing to obtain an optimal blood pressure. Material and Methods We studied 30 patients with controlled essential hypertension using losartan with normal liver function, and 202 healthy people. Peripheral blood DNA genotyping was performed by polymerase chain reaction to identify the polymorphisms. Allelic and genotypic frequencies were compared. Results In hypertensive patients, allelic frequencies were 0.85 (CYP2C9*1), 0.05 (CYP2C9*2) and 0.1 (CYP2C9*3). Genotypic frequencies were 73.3% (CYP2C9*1/*1), 6.7% (CYP2C9*1/*2), 16.7% (CYP2C9*1/*3) and 3.3% (CYP2C9*2/3); observing a significantly higher frequency of the allele CYP2C9*3 (p=0.041) and CYP2C9*1/*3 genotype (p=0.04). A non-significant tendency to need a larger dose of losartan was observed with the CYP2C9 * 3 allele, with an odds ratio (OR) of 1.46 (95% confidence intervals (CI) 0.01-18.64). The same tendency was observed with the need to use losartan twice a day, obtaining an OR of 5.88 (CI 0.54 -62.14). Conclusions There could be a relationship between the presence of CYP2C9 polymorphisms and the pathogenesis of hypertension. The presence of CYP2C9*3 is associated with the need for higher doses of losartan, possibly due to a decrease in the conversion of losartan to E-3174.

Estudio de las variantes alélicas CYP2C9*2 y CYP2C9*3 en muestras de población mestiza peruana / Study of the allelic variants CYP2C9*2 and CYP2C9*3 in samples of the Peruvian mestizo population

Resumen Introducción. El citocromo CYP2C9 metaboliza, aproximadamente, el 15 % de los fármacos prescritos. Su gen presenta alelos cuyas frecuencias difieren entre grupos étnicos y poblaciones. Los alelos CYP2C9*2 y CYP2C9*3 dan cuenta de una enzima con actividad disminuida cuya frecuencia no ha sido determinada en la población mestiza peruana. Objetivo. Caracterizar la frecuencia de las variantes *2 (rs1799853) y *3 (rs1057910) del gen CYP2C9 en muestras de población mestiza peruana provenientes de Lima, Tacna y Junín. Materiales y métodos. Se hizo un estudio descriptivo, observacional y prospectivo, con muestreo no probabilístico, por conveniencia e incidental. Se incluyeron 218 sujetos según los criterios de inclusión y exclusión; todos los participantes otorgaron su consentimiento informado. El ADN genómico se obtuvo mediante hisopado de mucosa oral, y la detección de los genotipos para los alelos CYP2C9*2 y CYP2C9*3 se hizo mediante reacción en cadena de la polimerasa (PCR) en tiempo real, utilizando sondas TaqMan™. Resultados. Las variantes de CYP2C9*2 y CYP2C9*3 están presentes en la población mestiza peruana con frecuencias de 0,046 y 0,062, respectivamente. El análisis de las frecuencias genotípicas observadas permitió predecir que la frecuencia de fenotipos metabolismo intermedio sería del 15,13 % (CYP2C9*1/*2: 5,96 %; CYP2C9*1/*3: 9,17 %), y la de fenotipos de metabolismo lento, del 3,22 % (CYP2C9*2/*2: 1,38 %; CYP2C9*3/*3: 1,38 %; CYP2C9*2/*3: 0,46 %). Conclusiones. Se lograron determinar las frecuencias genotípicas y alélicas para las variantes *2 y *3 del gen CYP2C9 en una muestra no probabilística de población mestiza peruana. Las frecuencias obtenidas (0,046 y 0,062, respectivamente) están entre las esperadas para una población mestiza sudamericana con ascendencia amerindia, europea, africana y asiática.

Abstract Introduction: CYP2C9 metabolizes approximately 15% of the prescribed drugs. Its gene has alleles whose frequencies differ between ethnic groups and populations. The alleles CYP2C9*2 and CYP2C9*3 account for an enzyme with decreased activity and their frequencies have not been determined in the Peruvian mestizo population. Objective: To characterize the frequencies of the allelic variants *2 (rs1799853) and *3 (rs1057910) of CYP2C9 gen in the Peruvian mestizo population from Lima, Tacna y Junín. Materials and methods: We conducted an observational, prospective cross-sectional study with non-probabilistic, by convenience, and incidental sampling. We included 218 subjects according to the inclusion and exclusion criteria, all of whom had signed the informed consent. We obtained the genomic DNA from oral mucosa swab. For the detection of the CYP2C9*2 and CYP2C9*3 genotypes, we used real-time-polymerase chain reaction with TaqMan® probes. Results: The genotyping revealed that CYP2C9*2 and CYP2C9*3 variants have low frequencies (0.046 and 0.062, respectively). The frequency of intermediate metabolizers was 15.13% (CYP2C9*1/*2: 5.96%; CYP2C9*1/*3: 9.17%) and that of slow metabolizers was 3.22% (CYP2C9*2/*2: 1.38%; CYP2C9*3/*3: 1.38%; CYP2C9*2/*3: 0.46%). Conclusions: It was possible to determine the genotypic and allelic frequencies for the variants *2 and *3 of the CYP2C9 gene in a non-probabilistic sample of the Peruvian mestizo population. The frequencies obtained (0.046 and 0.062, respectively) corresponded to those expected for a South American mestizo population with Amerindian, European, African and Asian ancestry.

Correlation between CYP2C9, APOE gene polymorphisms and stable warfarin and model prediction dose / 中国胸心血管外科临床杂志

@#Objective    To investigate the effect of CYP2C9 and APOE on the dose of stable warfarin and model prediction in Hainan population. Methods    From August 2016 to July 2018, 368 patients who required heart valve replacement and agreed to take warfarin anticoagulation at the second department of cardiothoracic surgery in our hospital were enrolled, including 152 males aged 48.5–70.5 (60.03±10.18) years and 216 females aged 43.5–65.6 (54.24±11.35) years. CYP2C9 and APOE were amplified by polymerase chain reaction. The gene fragment was sequenced by the Single Nucleotide Polymorphisms (SNP) site. The patients' age, sex, weight, history of smoking and drinking, and the dose of stable warfarin were recorded. Regression analysis of these clinical data was made to construct a dose prediction model. Results    Among 368 patients, CYP2C9 genotype test results showed 301 patients (81.8%) with *1*1 genotype, and 67 patients (18.2%) with *1*3 type. For different CYP2C9 genotype patients, the difference was statistically significant in the dose of stable warfarin (P<0.05). The results of APOE genotype showed 93 patients (25.3%) with E2 genotype, 221 patients (60.1%) with E3 genotype, and 54 patients (14.7%) with E4 genotype; the dose of stable   warfarin in patients with different APOE genotypes was statistically significant (P<0.05). Multiple regression analysis showed that patients' age, body weight, and CYP2C9 and APOE genotypes were correlated with the dose of stable warfarin. The correlation coefficient R2 was 0.572, and the prediction model was statistically significant (P<0.05). Conclusion    CYP2C9 and APOE gene polymorphisms exist in Hainan population. There is significant difference in the dose of stable warfarin among different genotypes of patients. The model to predict stable warfarin can partly explain the difference of warfarin among different patients.

Effects of ω-3 polyunsaturated fatty acids from different sources on glucolipid metabolism in type 2 diabetic patients with dyslipidemia / 中华预防医学杂志

Objective@#To determine the effects of ω-3 polyunsaturated fatty acids from different sources on glucolipid metabolism in type 2 diabetic patients with dyslipidemia.@*Methods@#We recruited participants from the diabetes specialist clinic at the Guanlin hospital in Yixing city, Jiangsu Province from February 2017 to March 2017. A total of 180 subjects were randomly assigned to 3 g/day fish oil (FO), perilla oil (PO), or fish oil mixed with linseed oil (FLO) for 6 months. The basic conditions and fasting venous blood sample were obtained from each study subject at baseline, after 6 months of intervention. Serum glucose and lipid metabolism were investigated.@*Results@#A total of 156 subjects aged (62.6±8.6) years completed the final follow-up after 6 months (FO,54 subjects; PO,52 subjects; FLO,50 subjects). Among them,59 patients (37.8%) were male. Serum glucose, glycated hemoglobin, C peptide, insulin and homeostasis model assessment-insulin resistance were not significantly different among the three groups after 6 months. Serum triglyceride decreased, whereas high-density lipoprotein cholesterol increased in FO [1.33 (1.05,1.93) mmol/L, (1.36±0.29) mmol/L, respectively] compared with PO [1.71 (1.23, 2.17) mmol/L, (1.23±0.22) mmol/L, respectively] and FLO [1.51 (1.12, 2.22) mmol/L, (1.29±0.30) mmol/L, respectively] (P<0.05). Serum low-density lipoprotein cholesterol and apolipoprotein B decreased in PO [(2.60±0.57) mmol/L,(0.96±0.23) g/L, respectively] compared with FO [(2.89±0.76) mmol/L, (1.07±0.30) g/L, respectively] (P<0.05). Serum lipoprotein(a) decreased in FLO [130.7 (63.3,270.6) mg/L] compared with FO [137.4 (58.7,333.2) mg/L] (P<0.05). Serum free fatty acid decreased in FLO [(0.43±0.15) mmol/L] compared with PO [(0.53±0.22) mmol/L] (P<0.05).@*Conclusion@#The effects of ω-3 PUFA from different sources on glucose metabolism in type 2 diabetic patients with dyslipidemia are similar. Each of them has a good application prospect in improving lipid metabolism.

Functional Characterization of Pharmcogenetic Variants of Human Cytochrome P450 2C9 in Korean Populations

Human cytochrome P450 2C9 is a highly polymorphic enzyme that is required for drug and xenobiotic metabolism. Here, we studied eleven P450 2C9 genetic variants—including three novel variants F69S, L310V, and Q324X—that were clinically identified in Korean patients. P450 2C9 variant enzymes were expressed in Escherichia coli and their bicistronic membrane fractions were prepared The CO-binding spectra were obtained for nine enzyme variants, indicating P450 holoenzymes, but not for the M02 (L90P) variant. The M11 (Q324X) variant could not be expressed due to an early nonsense mutation. LC-MS/MS analysis was performed to measure the catalytic activities of the P450 2C9 variants, using diclofenac as a substrate. Steady-state kinetic analysis revealed that the catalytic efficiency of all nine P450 2C9 variants was lower than that of the wild type P450 2C9 enzyme. The M05 (R150L) and M06 (P279T) variants showed high k(cat) values; however, their K(m) values were also high. As the M01 (F69S), M03 (R124Q), M04 (R125H), M08 (I359L), M09 (I359T), and M10 (A477T) variants exhibited higher K(m) and lower k(cat) values than that of the wild type enzyme, their catalytic efficiency decreased by approximately 50-fold compared to the wild type enzyme. Furthermore, the novel variant M07 (L310V) showed lower k(cat) and K(m) values than the wild type enzyme, which resulted in its decreased (80%) catalytic efficiency. The X-ray crystal structure of P450 2C9 revealed the presence of mutations in the residues surrounding the substrate-binding cavity. Functional characterization of these genetic variants can help understand the pharmacogenetic outcomes.

Poly-PR in C9ORF72-Related Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Causes Neurotoxicity by Clathrin-Dependent Endocytosis / 神经科学通报·英文版

GGGGCC repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). It has been reported that hexanucleotide repeat expansions in C9ORF72 produce five dipeptide repeat (DPR) proteins by an unconventional repeat-associated non-ATG (RAN) translation. Within the five DPR proteins, poly-PR and poly-GR that contain arginine are more toxic than the other DPRs (poly-GA, poly-GP, and poly-PA). Here, we demonstrated that poly-PR peptides transferred into cells by endocytosis in a clathrin-dependent manner, leading to endoplasmic reticulum stress and cell death. In SH-SY5Y cells and primary cortical neurons, poly-PR activated JUN amino-terminal kinase (JNK) and increased the levels of p53 and Bax. The uptake of poly-PR peptides by cells was significantly inhibited by knockdown of clathrin or by chlorpromazine, an inhibitor that blocks clathrin-mediated endocytosis. Inhibition of clathrin-dependent endocytosis by chlorpromazine significantly blocked the transfer of poly-PR peptides into cells, and attenuated poly-PR-induced JNK activation and cell death. Our data revealed that the uptake of poly-PR undergoes clathrin-dependent endocytosis and blockade of this process prevents the toxic effects of synthetic poly-PR peptides.

Application value of ω-3 fish oil fat emulsion in the parenteral nutritional support treatment following radical gastrectomy for gastric cancer / 中华消化外科杂志

Objective@#To investigate the application value of ω-3 fish oil fat emulsion in the parenteral nutritional support treatment following radical gastrectomy for gastric cancer.@*Methods@#The retrospective cohort study was conducted. The clinical data of 60 patients who underwent radical gastrectomy for gastric cancer in Nanjing Medical University Affiliated Wuxi Second Hospital between January 2018 and December 2018 were collected. There were 37 males and 23 females, aged from 28 to 78 years, with an average age of 64 years. Thirty patients who received parenteral nutrition containing 100 mL of ω-3 fish oil fat emulsion after radical gastrectomy and 30 patients who received parenteral nutrition containing routine fat emulsion after radical gastrectomy were allocated into experimental group and control group, respectively. Observation indicators: (1) nutritional indicators in the perioperative period; (2) inflammatory indicators in the perioperative period; (3) immune indicators in the perioperative period; (4) postoperative complications. Measurement data with normal distribution were represented as Mean±SD, and comparison between groups was evaluated using the independent-sample t test. Count data were described as absolute numbers and percentages, and comparison between groups was analyzed using the chi-square test. Repeated measurement data were analyzed by the repeated measures ANOVA.@*Results@#(1) Nutritional indicators in the perioperative period: the levels of total protein, albumin, prealbumin, and transferrin from preoperative day 1 to preoperative day 6 were respectively changed from (60.2±3.0)g/L to (57.2±3.1)g/L, from (35.3±3.1)g/L to (37.0±1.8)g/L, from (186±24)mg/L to (172±17)mg/L, from (3.0±0.7)g/L to (2.4±0.4)g/L in the experimental group and from (60.6±2.4)g/L to (55.7±4.2)g/L, from (35.0±3.8)g/L to (36.0±3.8)g/L, from (184±18)mg/L to (173±25)mg/L, from (3.1±0.6)g/L to (2.2±0.8)g/L in the control group, with no significant difference in the changing trends between the two groups (F=0.79, 2.14, 0.03, 0.36, P>0.05). (2) Inflammatory indicators in the perioperative period: the levels of white blood cells, C-reactive protein, interleukin 6, and tumor necrosis factor-α from preoperative day 1 to preoperative day 6 were respectively from (7.2±1.1)×109/L to (10.2±0.9)×109/L, from (7.2±2.3)mg/L to (25.5±6.3)mg/L, from (16±3)ng/L to (24±4)ng/L, from (17±4)ng/L to (22±5)ng/L in the experimental group and from (7.4±0.8)×109/L to (13.0±1.3)×109/L, from (6.9±2.4)mg/L to (41.6±18.9)mg/L, from (17±4)ng/L to (45±8)ng/L, from (16±4)ng/L to (43±7)ng/L in the control group, respectively, with significant differences in the changing trends between the two groups (F=63.05, 51.65, 127.82, 104.91, P<0.05). (3) Immune indicators in the perioperative period: the levels of immunoglobulin A, immunoglobulin G, immunoglobulin M, CD4+, CD8+, and ratio of CD4+ /CD8+ from preoperative day 1 to preoperative day 6 were respectively from (1.5±0.4)g/L to (2.8±0.5)g/L, from (11.1±1.7)g/L to (14.0±1.2)g/L, from (0.77±0.28)g/L to (1.61±0.31)g/L, from 42%±6% to 46%±5%, from 23%±4% to 24%±3%, from 1.82±0.42 to 2.11±0.24 in the experimental group and from (1.4±0.4)g/L to (2.3±0.6)g/L, from (10.7±1.8)g/L to (11.9±1.4)g/L, from (0.69±0.23)g/L to (1.19±0.33)g/L, from 40%±5% to 39%±4%, from 24%±3% to 23%±3%, from 1.75±0.34 to 1.81±0.35 in the control group, respectively, showing significant differences in the changing trends of the levels of immunoglobulin A, immunoglobulin G, immunoglobulin M, CD4+, and ratio of CD4+ /CD8+ between the two groups (F=18.39, 15.20, 38.42, 9.55, 5.50, P<0.05), showing no significant difference in the changing trend of the levels of CD8+ between the two groups (F=0.89, P>0.05). (4) Postoperative complications: 5 patients had postoperative complications, with a incidence rate of 16.7%(5/30), including 1 of abdominal infection, 1 of incisional infection, and 3 of pulmonary infection, and all the 5 patients were cured after symptomatic treatment. Nine patients had postoperative complications, with a incidence rate of 30.0%(9/30), including 2 of abdominal infection, 2 of incisional infection, and 5 of pulmonary infection, and all the 9 patients were cured after symptomatic treatment. There was no significant difference in the incidence of postoperative complications between the two groups (χ2=1.491, P>0.05).@*Conclusion@#For patients who receive gastric cancer surgery, ω-3 fish oil fat emulsion can reduce the inflammatory response, improve their immune function and not increase postoperative complications.

Effect of iguratimod on diclofenac metabolism by CYP2C9 in rats and human recombinant CYP2C9 yeast cells

Iguratimod (IGU, also known as T-614), a novel disease modifying antirheumatic drug intended to cure patients with rheumatoid arthritis (RA). The purpose of this study is to evaluate the effect of IGU on the pharmacokinetics of CYP2C9 probe drug diclofenac and its metabolite 4′-hydroxy diclofenac in vivo and in vitro. In in vivo experiments, 24 rats were randomly assigned to three groups consisting of the control group (Normal saline), low dose IGU group (10 mg/kg) and high dose IGU group (30 mg/kg). Blood samples were collected from orbital sinuses vein before 1 hour and serial times of giving diclofenac (15 mg/kg) to all the rats. Plasma concentration of diclofenac and its metabolite 4´-hydroxy diclofenac were assayed by high performance liquid chromatography. Pharmacokinetic parameters were assessed by Winnonlin 6.4 pharmacokinetic software. Moreover, in vitro studies were performed in recombinant human CYP2C9 yeast cell system. IGU at low dose showed no significant differences in the pharmacokinetic parameters of diclofenac and 4-hydroxy diclofenac in vivo when compared with control group (p>0.005). However, at the high dose of IGU, the pharmacokinetic parameters of 4´-hydroxy metabolite of diclofenac increase in half-life (T1/2) and mean area under the curve (AUC0→24), while a decrease in mean clearance (CL, mL/h/kg) and volume of distribution Vz (mL/kg). In addition, in in vitro study, high doses of IGU reduces the metabolism rate of diclofenac. IGU at high dose significantly increase the pharmacokinetics parameters of 4´-hydroxy diclofenac in rats. Additionally, it also showed the potent inhibitory effect on diclofenac metabolism in recombinant human CYP2C9 yeast cells.

Influência do genótipo do citocromo P450 (CYP2C9) na eficácia clínica do tenoxicam após cirurgias de terceiros molares inferiores / Influence of cytochrome P450 (CYP2C9) genotype on clinical efficacy of tenoxicam after lower third molars surgeries

Atualmente, com os avanços da Farmacogenética, estudos estão demonstrando que a resposta individual de medicamentos pode ser diretamente afetada pela alteração da farmacocinética induzida pela genética de cada paciente, e isto pode induzir à ausência, redução, alteração ou aumento da atividade enzimática associada. Esse fato pode modificar a eficácia clínica de determinados medicamentos e, nos casos de anti-inflamatórios não esteroidais (AINEs), alterar sua capacidade de lidar com a dor e até aumentar a frequência e a gravidade dos efeitos adversos. Este estudo teve como objetivo genotipar e fenotipar o gene CYP2C9 em 89 pacientes saudáveis submetidos à cirurgia de terceiro molar inferior, sob medicação de 20 mg de tenoxicam por dia durante 4 dias, comparando a influência do gene na dor pós-operatória, edema, trismo, quantidade de medicamentos de socorro consumidos pelos pacientes, avaliação global e satisfação do paciente em relação à ingestão do medicamento. Trata-se de um ensaio clínico randomizado, desenvolvido no Departamento de Cirurgia e Traumatologia Bucomaxilofacial da Faculdade de Odontologia de Araçatuba (FOA/UNESP) e na Disciplina de Farmacologia do Departamento Ciências Biológicas da Faculdade de Odontologia de Bauru (FOB/USP). Foi realizado o sequenciamento genético dos participantes do estudo, a fim de verificar polimorfismos do gene CYP2C9, e estes dados foram cruzados com as características pós-operatórias acima mencionadas. Oitenta e nove participantes foram selecionados: 64 (74%) foram incluídos no grupo "Metabolizadores Normais" (CYP2C9 * 1 / * 1) e 25 participantes no grupo "Metabolizadores Intermediários/Lentos" (CYP2C9 * 1 / * 2, * 1 / * 3 e CYP2C9 * 2 / * 3, * 3 / * 3). Não foram encontradas diferenças estatisticamente significantes em todos os parâmetros avaliados. Em relação à dor, apesar dos dois grupos referirem baixos níveis de dor durante o pós-operatório, o grupo "Metabolizadores Normais" apresentou mais dor (p<0,05) nos períodos de 4, 5, 6, 7, 8, 10, 48 e 72 horas de pós-operatório, quando comparado ao ponto de tempo "zero", diferente do grupo "Metabolizadores Intermediários/Lentos" que relatou dor significativa apenas em 6 horas de pós-operatório, quando comparados com o tempo "zero". Na prática clínica, isso significa que indivíduos com atividade anormal do CYP2C9 (metabolizadores intermediários e lentos) apresentam uma exposição aumentada ao tenoxicam e provavelmente mostram níveis mais baixos de dor, mas também mostram provavelmente um risco maior de efeitos colaterais, que incluem sangramento gastrointestinal, distúrbios hemorrágicos e cardiovasculares, sendo provavelmente necessário que a dose habitual do medicamento seja revisada(AU)

One of the most accepted pharmacological protocols on third molar extraction surgeries involves the use of the non-steroidal anti-inflammatory drugs, as tenoxicam. Many studies present that the individual drug response could be directly affected by genetics induced pharmacokinetics alteration. Our study aimed to genotype and phenotype CYP2C9 gene in 89 health patients that were submitted to wisdom teeth surgical removal under medication of tenoxicam, comparing the gene influence on postoperative pain, edema, trismus, amount of rescue medication consumed, global evaluation and patient satisfaction regarding the medication. CYP2C9 gene was screened to evaluate polymorphisms and the genetic characteristics were crossed to aforementioned postoperative findings on a randomized clinical trial. 89 volunteers were splitted in two groups: 64 (74%) Normal Metabolizers (NM) group and 25 (26%) Intermediate/Slow Metabolizers (ISM) group. There were not found statistically significant difference between groups. The NM group referred more pain (p<0,05) at 4, 5, 6, 7, 8, 10, 48 and 72 postoperative hours time points when compared to time zero. In clinical practice it means that individuals with CYP2C9 abnormal activity (ISM) presented an augmented exposition to tenoxicam and referred lower pain levels, but also, they were probably more susceptible to adverse effects(AU)

Current research on the influence of genetic factors on warfarin maintenance dose / 中国胸心血管外科临床杂志

@#Warfarin is one of the most frequently prescribed oral anticoagulant. Many researches have shown that the genotypes have been strongly associated with warfarin maintenance doses. Especially, it has been accepted in academia that cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 subunit (VKORC1) could affect the warfarin maintenance doses. There are also many other genotypes that were reported to be related to warfarin doses, but the results have been in controversial so far. The studies found that the dose formula which contained the genetic factors and clinical information could accurately predict the maintenance dose of warfarin, however, its usefulness is suspected due to the inconsistent results of clinical trials. Large-sample and multi-center studies are necessary to verify the specific effects of gene and non-gene factors to warfarin dose; at the same time, testing constructed models or building new models help to improve the explained percentages of individual differences.

Effects of Coix-seed Reactive Derivatives (CRD) on Cytochrome P450 Isoforms CYP3A4, CYP2D6, CYP2C9 In Vitro / 日本補完代替医療学会誌

CRD, a Coix-seed Reactive Derivatives, has a novel mechanism in the treatment of various diseases. In the present study, a fluorometric-based high throughput method using cytochrome P450 (CYP)screening kit was adopted to evaluate in vitro inhibition potential of CRD (CRD 1 and CRD 2) on CYP isoenzymes by calculating remaining enzyme activities and inhibitory potential (IC50 values) using the determined values of fluorescence intensity. IC50　of CRD 1 and CRD 2 were as follows: CYP3A4; >500 µg/ml, 490 µg/ml, CYP2D6; >500 µg/ml，>500 µg/ml，CYP2C9; >500 µg/ml，339 µg/ml, respectively. The result showed that CRD exhibited little activity in the inhibition of CYP3A4, CYP2D6 and CYP2C9.