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pharmacogenomics can improve antipsychotic treatment in schizophrenia

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Frontiers of Medicine 2013年第2期7卷 180-190页

作者： ingqing Xu Xi Wu Yuyu Xiong Qinghe Xing Lin He Shengying Qin Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders(Ministry of Education)Shanghai Jiao Tong UniversityShanghai 200030China Shanghai Genome Pilot Institutes for Genomics and Human Health Shanghai 200030China Institutes of Biomedical Sciences Fudan UniversityShanghai 200032China

Schizophrenia is a widespread mental disease with a prevalence of about 1%in the world population,and heritability of up to 80%.Drug therapy is an important approach to treating the disease.However,the curative effect of antipsychotic is far from satisfactory in terms of tolerability and side effects.Many studies have indicated that about 30%of the patients exhibit little or no improvements associated with antipsychotics.The response of individual patients who are given the same dose of the same drug varies considerably.In addition,antipsychotic drugs are often accompanied by adverse drug reactions(ADRs),which can cause considerable financial loss in addition to the obvious societal harm.So,it is strongly recommended that personalized medicine should be implemented both to improve drug efficacy and to minimize adverse events and toxicity.There is therefore a need for pharmacogenomic studies into the factors affecting response of schizophrenia patients to antipsychotic drugs to provide informed guidance for clinicians.Individual differences in drug response is due to a combination of many complex factors including ADEM(absorption,distribution,metabolism,excretion)process,transporting,binding with receptor and intracellular signal transduction.Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this interindividual variability in antipsychotics response.In addition,epigenetic factors such as methylation of DNA and regulation by miRNA have also been reported to play an important role in the complex interactions between the multiple genes and environmental factors which influence individual drug response phenotypes in patients.In this review,we will focus on the latest research on polymorphisms of candidate genes that code for drug metabolic enzymes(CYP2D6,CYP1A2,CYP3A4,etc.),drug transporters(mainly ABCB1)and neurotransmitter receptors(dopamine receptors and serotonin receptors,etc.).We also discuss the genome-wide pharmacogenomic study of schizophrenia and re

关键词： pharmacogenomics epigenetics schizophrenia antipsychotics

pharmacogenomics-based individualized treatment of hypertension in preterm infants: A case report and review of the literature

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World Journal of Clinical Cases 2023年第30期11卷 7440-7449页

作者： Lian-Fang Tang Ao Xu Kai Liu Department of Pediatrics The First People’s Hospital of Yunnan ProvinceKunming 650000Yunnan ProvinceChina Pulmonary and Critical Care Medicine Kunming Children’s HospitalKunming 650000Yunnan ProvinceChina

BACKGROUND Neonatal hypertension is a rare but potentially serious condition that requires careful monitoring and treatment.pharmacogenomics can help guide individualized drug therapy and improve outcomes.CASE SUMMARY We report a case of a preterm infant with multiple complications,including bronchopulmonary dysplasia(BPD),sepsis,intracranial hemorrhage,and hypertension.The infant was treated with various drugs,including dexamethasone and amlodipine.The infant was diagnosed with neonatal hypertension based on blood pressure measurements exceeding the 95th percentile for his age and sex.The possible causes of hypertension included dexamethasone,hydrochlorothiazide,spironolactone,and BPD.The infant was treated with oral amlodipine to lower his blood pressure.A pharmacogenomic test was performed to evaluate the genetic polymorphisms of ABCB1 and CYP3A5,which are involved in the metabolism and transport of dexamethasone and amlodipine.The infant’s blood pressure was well controlled after the dose of amlodipine was reduced according to the pharmacogenomic results.The infant had a stable general condition and was discharged on the 100th d after birth.CONCLUSION This case illustrates the importance of regular blood pressure monitoring and etiological investigation in preterm infants with hypertension.pharmacogenomics can provide useful information for individualized drug therapy and safety in this population.

关键词： pharmacogenomics Hypertension Preterm Infants Case report

Personalized medicine in non-small cell lung cancer: a review from a pharmacogenomics perspective

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Acta Pharmaceutica Sinica B 2018年第4期8卷 530-538页

作者： Wenxiao Jiang Guiqing Cai Peter C.Hu Yue Wang Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai The University of Texas MD Anderson Cancer Center Department of Molecular and Human Genetics Baylor College of Medicine

Non-small cell lung cancer is a prevalent and rapidly-expanding challenge to modern medicine. While generalized medicine with traditional chemotherapy yielded comparatively poor response rates and treatment results, the cornerstone of personalized medicine using genetic profiling to direct treatment has exalted the successes seen in the field and raised the standard for patient treatment in lung and other cancers. Here, we discuss the current state and advances in the field of personalized medicine for lung cancer, reviewing several of the mutation-targeting strategies that are approved for clinical use and how they are guided by patient genetic information. These classes include inhibitors of tyrosine kinase(TKI), anaplastic lymphoma kinase(ALK), and monoclonal antibodies. Selecting from these treatment plans and determining the optimal dosage requires in-depth genetic guidance with consideration towards not only the underlying target genes but also other factors such as individual metabolic capability and presence of resistance-conferring mutations both directly on the target gene and along its cascade(s).Finally, we provide our viewpoints on the future of personalized medicine in lung cancer, including target-based drug combination, mutation-guided drug design and the necessity for data of population genetics, to provide rough guidance on treating patients who are unable to get genetic testing.

关键词： Personalized medicine Non-small cell lung cancer pharmacogenomics Tyrosine kinase Anaplastic lymphoma kinase Inhibitor Monoclonal antibody

The Promise of pharmacogenomics in ReducingToxicity During Acute Lymphoblastic LeukemiaMaintenance Treatment

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Genomics, Proteomics & Bioinformatics 2017年第2期15卷 82-93页

作者： Shoshana Rudin Marcus Marable R. Stephanie Huang Biological Sciences Division University of Chicago Chicago IL 60637 USA Department of Medicine University of Chicago Chicago IL 60637 USA

Pediatric acute lymphoblastic leukemia(ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2–3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine(6-MP) and methotrexate(MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment.6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase(TPMT), nudix hydrolase 15(NUDT15), and potentially inosine triphosphatase(ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1(SLCO1B1) and dihydrofolate reductase(DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1(SLC19A1)and thymidylate synthetase(TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.

关键词： Acute lymphoblastic leukemia 6-Mercaptopurine Methotrexate pharmacogenomics Maintenance therapy

Vitamin pharmacogenomics： New Insight intoIndividual Differences in Diseases and DrugResponses

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Genomics, Proteomics & Bioinformatics 2017年第2期15卷 94-100页

作者： Hai-Yan He Mou-Ze Liu Yue-Li Zhang Wei Zhang Department of Clinical Pharmacology Xiangya Hospital Central South University Changsha 410008 China Institute of Clinical Pharmacology Central South University Hunan Key Laboratory of Pharmacogenetics Changsha 410078China International Medical Department Xiangya Hospital Central South University Changsha 410008 China National Clinical Research Center for Geriatrics Xiangya Hospital Central South University Changsha 410008 China

Vitamins are vital to sustain normal physiological function, metabolism, and growth for all living organisms. Being an integral component of coenzyme, vitamins can affect the catalytic activities of many enzymes and the expression of drug transporters. Genetic variations in metabolism and/or transporter genes of drugs can influence the exposure of the human body to drugs and/or their active metabolites, thus contributing to the variations in drug responses and toxicities.Nonetheless, pharmacogenomics studies on nutrients have been rarely summarized. In this article,we reviewed recent progress on vitamin pharmacogenomics, for a better understanding on the influence of vitamin-related gene polymorphisms on inter-individual differences in diseases and drug efficacy and safety.

关键词： Vitamin pharmacogenomics Single nucleotide polymorphism Genetic variation Individual difference

Monoclonal antibody pharmacogenomics in cancer treatment

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Journal of Cancer Metastasis and Treatment 2019年第11期4卷 23-35页

作者： Shigehiro Yagishita Akinobu Hamada Division of Molecular Pharmacology National Cancer Center Research InstituteChuo-kuTokyo 104-0045Japan

Conventionally, in the pharmacokinetic/pharmacodynamic analysis of small molecule compounds such as cytotoxic anticancer drugs, polymorphism analysis of genes related to absorption, distribution, metabolism, and excretion has been performed in addition to the analyses of blood concentrations of drugs. Such pharmacogenetic factors play an important role in predicting therapeutic effects and adverse events and in the proper use of drugs. With the recent launch of immune checkpoint inhibitors (ICIs) and the rapid development of antibody-drug conjugates (ADCs) currently underway, there is no doubt that antibody drugs, which are large molecule compounds, will become key drugs in anticancer drug treatment. However, the pharmacokinetic and pharmacodynamic analysis of antibody drugs is still not sufficient, and further elucidation of factors and mechanisms affecting their dynamics in the human body is necessary. Moreover, the pharmacogenomic factors of antibody drugs have not yet been fully studied. There are many factors that should be clarified, such as factors that regulate the host immune response in ICI therapy and the effects of ATP-binding cassette transporter and cytochrome P450 on the payload of ADCs. This review provides an outline of antibody drugs in cancer treatment and summarizes the pharmacogenomic factors of antibody drugs known to date.

关键词： pharmacogenomics antibody drug antibody-dependent cellular cytotoxicity immune checkpoint inhibitor antibody-drug conjugate

Development of two different pharmacogenomics detection methods for second-generation antipsychotic drugs quetiapine and aripiprazole

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Journal of Bio-X Research 2020年第1期3卷 21-26页

作者： Zhang Lichen Zhang Xingyu Zhang Xiaoqing You Guoling Fu Qihua Department of Laboratory Medicine Shanghai Children’s Medical CenterShanghai Jiao Tong University School of MedicineShanghaiChina

Objective:Second-generation antipsychotics are widely used in mental illness,but the treatment effects and side effects are affected by single nucleotide polymorphisms(SNPs)of related genes.Quetiapine and aripiprazole are two frequently used secondgeneration antipsychotic drugs.The aim of this study was to develop two different SNP detection methods for four SNP alleles associated with the pharmacokinetics of quetiapine and aripiprazole,based on high-resolution melting(HRM)and multicolor melting curve assay(MMCA)respectively.Methods:Whole genome DNA samples were obtained from 240 healthy people(107 females and 133 males)without genetic diseases.HRM methods were established using four kinds of specific primers and a saturated fluorescent dye.Each SNP allele with their own primers was detected in a single reaction.In the MMCA method,a multiplex polymerase chain reaction with 4 different-colored fluorescent probes was established to detect four SNP alleles in a single reaction.All experimental protocols were approved by the Ethics Committee of the Shanghai Children’s Medical Center,China(SCMC-201015)on November 22,2010.Results:Two detection methods for the pharmacogenomics of quetiapine and aripiprazole,based on HRM and MMCA respectively,were established in this study.The single-target HRM method can be completed in 96 minutes,whereas the quadruplex MMCA method takes 133 minutes.It was found that the results of HRM and MMCA for the four SNP alleles had 100%coincidence with Sanger sequencing in the 240 samples.Conclusion:This study developed two methods for the detection of four pharmacogenomic SNP alleles that correlated with quetiapine and aripiprazole.Both methods are rapid,cost-saving,highly accurate and potentially facilitate rational use of second-generation antipsychotics for clinical medication.

关键词： high-resolution melting multicolor melting curve assay pharmacogenomics second-generation antipsychotics SNP

pharmacogenomics in oral diseases

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World Journal of Stomatology 2013年第4期2卷 67-70页

作者： Sridharan Gokul Gokul Sapna Oral Pathology and Microbiology YMT Dental College and HospitalKhargharNavi Mumbai-410210MaharashtraIndia Department of Periodontics Nair Hospital Dental CollegeMumbai-400008MaharashtraIndia

The availability of newer technologies for identification and characterization of the human genome has enabled our understanding of the genetic variations in a majority of human diseases.Human genomic sequence varies in less than 1%among the different population group and these differences known as gene polymorphisms are the primary reasons for differences in individuals’response to various drug therapy.Also understanding the genetic changes may enable implementation of targeted therapy,thus providing for effective treatment strategies and minimizing the adverse side effects.pharmacogenomics is a recent development in the field of personalized medicine which focuses on the genetic determinants of drug response at the levels of entire human genome.It primarily deals with tailoring of drug therapy for every individual based on their genetic make-up and identifying new target in various diseases for drug therapy.While the application of pharmacogenomics in systemic illness is well researched,its role in oral diseases needs documentation.Identifying specific targets in periodontitis,head and neck cancer,infections and genetic disorders can be beneficial in discovery of new drugs.This editorial provides an overview of basics of pharmacoge-nomics,its current role in disease management and its potential role in various head and neck diseases.

关键词： pharmacogenomics Oral Cancer Periodontal diseases Genomic variations Targeted drug therapy

pharmacogenomics in colorectal cancer:current role in clinical practice and future perspectives

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Journal of Cancer Metastasis and Treatment 2018年第1期4卷 146-170页

作者： Francesca Battaglin Alberto Puccini Madiha Naseem Marta Schirripa Martin DBerger Ryuma Tokunaga Michelle McSkane Taline Khoukaz Shivani Soni Wu Zhang Heinz-Josef Lenz Division of Medical Oncology Norris Comprehensive Cancer CenterKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA Medical Oncology Unit 1 Clinical and Experimental Oncology DepartmentVeneto Institute of Oncology IOV-IRCCSPadua 35128Italy Department of Medical Oncology University Hospital of BernBern 3010Switzerland

The treatment scenario of colorectal cancer(CRC)has been evolving in recent years with the introduction of novel targeted agents and new therapeutic strategies for the metastatic disease.An extensive effort has been directed to the identification of predictive biomarkers to aid patients selection and guide therapeutic choices.pharmacogenomics represents an irreplaceable tool to individualize patients treatment based on germline and tumor acquired somatic genetic variations able to predict drugs response and risk of toxicities.The growing knowledge of CRC molecular characteristics and complex genomic makeup has played a crucial role in identifying predictive pharmacogenomic biomarkers,while supporting the rationale for the development of new drugs and treatment combinations.Clinical validation of promising biomarkers,however,is often an issue.More recently,a deeper understanding of resistance mechanisms and tumor escape dynamics under treatment pressure and the availability of novel technologies are opening new perspectives in this field.This review aims to present an overview of current pharmacogenomic biomarkers and future perspectives of pharmacogenomics in CRC,in an evolving scenario moving from a single drug-gene interactions approach to a more comprehensive genome-wide approach,comprising genomics and epigenetics.

关键词： Colorectal cancer pharmacogenomics RAS BRAF microsatellite instability dihydropyrimidine dehydrogenase UDP-Glucuronosyltrasferase A1 epidermal growth factor receptor vascular endothelial growth factor DNA methylation