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Push forward LC-MS-based therapeutic drug monitoring and pharmacometabolomics for anti-tuberculosis precision dosing and comprehensive clinical management

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Journal of Pharmaceutical Analysis 2024年第1期14卷 16-38页

作者： Nguyen Quang Thu Nguyen Tran Nam Tien Nguyen Thi Hai Yen Thuc-Huy Duong Nguyen Phuoc Long Huy Truong Nguyen Department of Pharmacology and pharmacogenomics Research Center Inje University College of MedicineBusan47392Republic of Korea Department of Chemistry University of EducationHo Chi Minh City700000Viet Nam Faculty of Pharmacy Ton Duc Thang UniversityHo Chi Minh City700000Viet Nam

The spread of tuberculosis(TB),especially multidrug-resistant TB and extensively drug-resistant TB,has strongly motivated the research and development of new anti-TB drugs.New strategies to facilitate drug combinations,including pharmacokinetics-guided dose optimization and toxicology studies of first-and second-line anti-TB drugs have also been introduced and recommended.Liquid chromatography-mass spectrometry(LC-MS)has arguably become the gold standard in the analysis of both endo-and exo-genous compounds.This technique has been applied successfully not only for therapeutic drug monitoring(TDM)but also for pharmacometabolomics analysis.TDM improves the effectiveness of treatment,reduces adverse drug reactions,and the likelihood of drug resistance development in TB patients by determining dosage regimens that produce concentrations within the therapeutic target window.Based on TDM,the dose would be optimized individually to achieve favorable outcomes.Pharmacometabolomics is essential in generating and validating hypotheses regarding the metabolism of anti-TB drugs,aiding in the discovery of potential biomarkers for TB diagnostics,treatment monitoring,and outcome evaluation.This article highlighted the current progresses in TDM of anti-TB drugs based on LC-MS bioassay in the last two decades.Besides,we discussed the advantages and disadvantages of this technique in practical use.The pressing need for non-invasive sampling approaches and stability studies of anti-TB drugs was highlighted.Lastly,we provided perspectives on the prospects of combining LC-MS-based TDM and pharmacometabolomics with other advanced strategies(pharmacometrics,drug and vaccine developments,machine learning/artificial intelligence,among others)to encapsulate in an all-inclusive approach to improve treatment outcomes of TB patients.

关键词： Tuberculosis Therapeutic drug monitoring LC-MS MIPD Pharmacometabolomics Precision medicine

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Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus

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World Journal of Hepatology 2024年第3期16卷 366-378页

作者： Kanuengnit Choochuay Punna Kunhapan Apichaya Puangpetch Sissades Tongsima Pornpen Srisawasdi Abhasnee Sobhonslidsuk Somnuek Sungkanuparph Mohitosh Biswas Chonlaphat Sukasem Program in Translational Medicine Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand School of Pharmacy Walailak UniversityNakhon Si Thammarat 80161Thailand laboratory for pharmacogenomics Division of Pharmacogenomics and Personalized MedicineSomdech Phra Debaratana Medical CenterDepartment of PathologyFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand Department of Medical Sciences Ministry of Public HealthNonthaburi 11000Thailand National Biobank of Thailand National Center for Genetic Engineering and BiotechnologyPathum Thani 12120Thailand Division of Clinical Chemistry Department of PathologyFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand Division of Gastroenterology and Hepatology Department of MedicineFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand Chakri Naruebodindra Medical Institute Faculty of Medicine Ramathibodi HospitalMahidol UniversitySamut Prakan 10540Thailand Department of Pharmacy University of RajshahiRajshahi 6205Bangladesh pharmacogenomics Clinic Bumrungrad Genomic Medicine InstituteBumrungrad International HospitalBangkok 10110Thailand Research and Development laboratory Bumrungrad International HospitalBangkok 10110Thailand MRC Centre for Drug Safety Science Department of Pharmacology and TherapeuticsInstitute of SystemsMolecular and Integrative BiologyUniversity of Liverpool Liverpool L693GLUnited Kingdom Faculty of Pharmaceutical Sciences Burapha UniversityChonburi 20131Thailand

BACKGROUND The prevalence of metabolic-associated fatty liver disease(MAFLD)is a growing public health issue in people living with human immunodeficiency virus(PLWH).However,the pathophysiology of MAFLD is still unknown,and the role of genetic variables is only now becoming evident.AIM To evaluate the associations of gene-polymorphism-related MAFLD in PLWH.METHODS The study employed transient elastography with a controlled attenuation parameter≥248 dB/m to identify MAFLD in patients from a Super Tertiary Hospital in central Thailand.Candidate single-nucleotide polymorphisms(SNPs)were genotyped using TaqMan®MGB probe 5'nuclease assays for seven MAFLD-related genes.Statistical analyses included SNP frequency analysis,Fisher's Exact and Chi-square tests,odds ratio calculations,and multivariable logistic regression.RESULTS The G-allele carriers of PNPLA3(rs738409)exhibited a two-fold rise in MAFLD,increasing by 2.5 times in MAFLD with human immunodeficiency virus infection.The clinical features and genetic patterns imply that LEP rs7799039 A-allele carriers had a nine times(P=0.001)more significant chance of developing aberrant triglyceride among PLWH.CONCLUSION The current study shows an association between PNPLA3 rs738409 and LEP rs7799039 with MAFLD in PLWH.

关键词： PNPLA3 LEP Metabolic-associated fatty liver disease People living with HIV Thai

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Cancers of the lung, head and neck on the rise: perspectives on the genotoxicity of air pollution

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Chinese Journal of Cancer 2014年第10期33卷 476-480页

作者： Ian Chi Kei Wong Yuen-Keng Ng Vivian Wai Yan Lui pharmacogenomics and Precision Therapeutics laboratory Department of Pharmacology and PharmacyLi Ka Shing Faculty of MedicineThe University of Hong Kong

Outdoor air pollution has been recently classified as a class I human carcinogen by the World Health Organization(WHO). Cumulative evidence from across the globe shows that polluted air is associated with increased risk of lung, head and neck, and nasopharyngeal cancers—all of which affect the upper aerodigestive tract. Importantly, these cancers have been previously linked to smoking. In this article, we review epidemiologic and experimental evidence of the genotoxic and mutagenic effects of air pollution on DNA, purportedly a key mechanism for cancer development. The alarming increase in cancers of the upper aerodigestive tract in Asia suggests a need to focus government efforts and research on reducing air pollution, promoting clean energy, and investigating the carcinogenic effects of air pollution on humans.

关键词：空气污染头颈部癌症遗传毒性肺癌世界卫生组织上升实验证据

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mRNA enrichment protocols determine the quantification characteristics of external RNA spike-in controls in RNA-Seq studies

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Science China(Life Sciences) 2013年第2期56卷 134-142页

作者： QING Tao YU Ying DU TingTing SHI LeMing Center for pharmacogenomics School of PharmacyFudan University

RNA-Seq promises to be used in clinical settings as a gene-expression profiling tool;however,questions about its variability and biases remain and need to be addressed.Thus,RNA controls with known concentrations and sequence identities originally developed by the External RNA Control Consortium(ERCC) for microarray and qPCR platforms have recently been proposed for RNA-Seq platforms,but only with a limited number of samples.In this study,we report our analysis of RNA-Seq data from 92 ERCC controls spiked in a diverse collection of 447 RNA samples from eight ongoing studies involving five species(human,rat,mouse,chicken,and Schistosoma japonicum) and two mRNA enrichment protocols,i.e.,poly(A) and RiboZero.The entire collection of datasets consisted of 15650143175 short sequence reads,131603796(i.e.,0.84%) of which were mapped to the 92 ERCC references.The overall ERCC mapping ratio of 0.84% is close to the expected value of 1.0% when assuming a 2.0% mRNA fraction in total RNA,but showed a difference of 2.8-fold across studies and 4.3-fold among samples from the same study with one tissue type.This level of fluctuation may prevent the ERCC controls from being used for cross-sample normalization in RNA-Seq.Furthermore,we observed striking biases of quantification between poly(A) and RiboZero which are transcript-specific.For example,ERCC-00116 showed a 7.3-fold under-enrichment in poly(A) compared to RiboZero.Extra care is needed in integrative analysis of multiple datasets and technical artifacts of protocol differences should not be taken as true biological findings.

关键词： mRNA 量化特征控制协议富集分析工具基因表达数据分析

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Evolution of breast cancer therapeutics: Breast tumour kinase's role in breast cancer and hope for breast tumour kinase targeted therapy

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World Journal of Clinical Oncology 2014年第3期5卷 299-310页

作者： Haroon A Hussain Amanda J Harvey Brunel Institute for Cancer Genetics and pharmacogenomics Biosciences Brunel University (London)

There have been significant improvements in the detection and treatment of breast cancer in recent decades. However, there is still a need to develop more effective therapeutic techniques that are patient specific with reduced toxicity leading to further increases in patients' overall survival; the ongoing progress in understanding recurrence, resistant and spread also needs to be maintained. Better understanding of breast cancer pathology, molecular biology and progression as well as identification of some of the underlying factors involved in breast cancer tumourgenesis and metastasis has led to the identification of novel therapeutic targets. Over a number of years interest has risen in breast tumour kinase(Brk) also known as protein tyrosine kinase 6; the research field has grown and Brk has been described as a desirable therapeutic target in relation to tyrosine kinase inhibition as well as disruption of its kinase independent activity. This review will outline the current "state of play" with respect to targeted therapy for breast cancer, as well as discussing Brk's role in the processes underlying tumour development and metas-tasis and its potential as a therapeutic target in breast cancer.

关键词： Breast tumour kinase Protein tyrosine kinase 6 Breast neoplasms Targeted molecular therapy Intracellular signaling peptides and proteins Protein kinase inhibitors

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Mechanistic insight into lysyl oxidase in vascular remodeling and angiogenesis

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Genes & Diseases 2023年第3期10卷 771-785页

作者： Zhao-Jun Wang Qi-Wen Guan Hong-Hao Zhou Xiao-Yuan Mao Fang-Hui Chen Department of Clinical Pharmacology Xiangya HospitalCentral South UniversityChangshaHunan 410008China Institute of Clinical Pharmacology Central South UniversityHunan Key Laboratory of PharmacogeneticsChangshaHunan 410078China Engineering Research Center of Applied Technology of pharmacogenomics Ministry of EducationChangshaHunan 410078China National Clinical Research Center for Geriatric Disorders ChangshaHunan 410008China Department of Pharmacy The First Affliated Hospital of Gannan Medical UniversityGanzhouJiangxi 341000China

Vascular remodeling and angiogenesis are two key processes in the maintenance of vascular homeostasis and involved in a wide array of vascular pathologies. Following these processes, extracellular matrix (ECM) provides the mechanical foundation for vascular walls. Lysyl oxidase (LOX), the key matrix-modifying enzyme, has been demonstrated to significantly affect structural abnormality and dysfunction in the blood vessels. The role of LOX in vascular remodeling and angiogenesis has always been the subject in the current medical research. Therefore, we presently make a summarization of the biosynthesis of LOX and the mechanisms involved in vascular remodeling and angiogenesis, as well as the role of LOX in diseases associated with vascular abnormalities and the therapeutic potential via targeting LOX. In particular, we give a proposal that LOX likely reshapes matrisome-associated genes expressions in the regulation of vascular remodeling and angiogenesis, which serves as a mechanistic insight into the critical role of LOX in these two aspects. Additionally, LOX has also dual effects on the vascular dysfunction, namely, inhibition of LOX for improving hypertension, restenosis and malignant tumor while activation of LOX for curing arterial aneurysm and dissection. LOX-targeted therapy may provide a promising therapeutic strategy for the treatment of various vascular pathologies associated with vascular remodeling and angiogenesis.

关键词： Angiogenesis Disease pathology Lysyl oxidase Therapeutic target Vascular homeostasis Vascular remodeling

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Identification of colorectal cancer metastasis markers by an angiogenesis-related cytokine-antibody array

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世界胃肠病学杂志：英文版 2012年第7期18卷 637-645页

作者： Ana Abajo Nerea Bitarte Ruth Zarate Valentina Boni Ines Lopez Marisol Gonzalez-Huarriz Javier Rodriguez Eva Bandres Jesus Garcia-Foncillas laboratory of pharmacogenomics Division of OncologyCenter for Applied Medical ResearchUniversity of NavarraAvda Pio XII 5531008 PamplonaSpain Department of Oncology University Clinic of NavarraUniversity of NavarraAvda Pio XII 5531008 PamplonaSpain

AIM:To investigate the angiogenesis-related protein expression profile characterizing metastatic colorectal cancer (mCRC) with the aim of identifying prognostic markers.METHODS:The expression of 44 angiogenesissecreted factors was measured by a novel cytokine antibody array methodology.The study evaluated vascular endothelial growth factor (VEGF) and its soluble vascular endothelial growth factor receptor (sVEGFR)-1 protein levels by enzyme immunoassay (EIA) in a panel of 16 CRC cell lines.mRNA VEGF and VEGF-A isoforms were quantified by quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR) and vascular endothelial growth factor receptor (VEGFR)-2 expression was analyzed by flow cytometry.RESULTS:Metastasis-derived CRC cell lines expressed a distinctive molecular profile as compared with those isolated from a primary tumor site.Metastatic CRC cell lines were characterized by higher expression of angiogenin-2 (Ang-2),macrophage chemoattractant proteins-3/4 (MCP-3/4),matrix metalloproteinase-1 (MMP-1),and the chemokines interferon γ inducible T cell α chemoattractant protein (I-TAC),monocyte chemoattractant protein I-309,and interleukins interleukin (IL)-2 and IL-1α,as compared to primary tumor cell lines.In contrast,primary CRC cell lines expressed higher levels of interferon γ (IFN-γ),insulin-like growth factor-1 (IGF-1),IL-6,leptin,epidermal growth factor (EGF),placental growth factor (PlGF),thrombopoietin,transforming growth factor β1 (TGF-β1) and VEGF-D,as compared with the metastatic cell lines.VEGF expression does not significantly differ according to the CRC cellular origin in normoxia.Severe hypoxia induced VEGF expression up-regulation but contrary to expectations,metastatic CRC cell lines did not respond as much as primary cell lines to the hypoxic stimulus.In CRC primary-derived cell lines,we observed a twofold increase in VEGF expression between normoxia and hypoxia as compared to metastatic cell lines.CRC cell lines express a similar pattern of VEGF isoforms (VEGF 121,VEGF 165 and VE

关键词：血管生成细胞因子血管内皮生长因子受体识别标记阵列抗体大肠癌逆转录聚合酶链反应

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Exo+ proofreading polymerases mediate genetic analysis and its application in biomedical studies

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Acta Pharmacologica Sinica 2005年第3期26卷 302-306页

作者： Duan-fang LIAO~2 Lin-ling CHEN~2 Cui-ying PENG~2 Jia ZHANG~2 Kai LI~(2,3,4)2 Division of Pharmacogenomies,SNP Institute,School of Life Science,Nanhua University,Hengyang 421001,China 3 Department of Human Genetics,City of Hope National Medical Center,Duarte,CA,USA Division of pharmacogenomics SNP Institute School of Life Science Nanhua University Hengyang China Department of Human Genetics City of Hope National Medical Center Duarte USA

Polymerases with a proofreading function in their internal 3′ to 5′ exonucleasepossess high fidelity for DNA replication both in vivo and in vitro.The obstaclefacing Exo+ polymerases for single nucleotide polymorphism （SNP） detection couldbe bypassed by using primer-3′-termini modification.This hypothesis has beenwell tested using three types of modified allele specific primers with:3′ labeling,3′to 5′exonuclease resistance,and 3′dehydroxylation.Accordingly,three new SNPassaying methods have been developed to carry out genome-wide genotyping,taking advantage of the enzymatic properties of Exo+polymerases.These newmutation detection assays are widely adaptable to a variety of platforms,includ-ing multi-well plate and microarray technologies.Application ofExo+polymerasesto genetic analysis,including genotyping that is mostly relevant to pharma-cogenetics,high-fidelity gene expression profiling,rare mutation detection andmutation load assay,will help to accelerate the pace of personalized medicine.Inthis review paper,we will first introduce three new assays that we have recentlydeveloped,and then describe a number of their applications in pharmacogeneticsand in other biomedical studies.

关键词： single nucleotide polymorphism DNA primers DNA-directed DNA polymerase

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Effect of ABCB1 3435C>T transporter gene polymorphism on plasma efavirenz concentration in HIV-1 infected Thai adults

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Asian Pacific Journal of Tropical Medicine 2020年第6期13卷 266-271页

作者： Sahapat Barusrux Napatrupron Koomdee Rattanaporn Sukprasong Weerawat Manosuthi Monpat Chamnanphon Apichaya Puangpetch Chonlaphat Sukasem Veeranoot Nissapatorn Maria de Lourdes Pereira School of Allied Health Sciences and Research Excellence Center for Innovation and Health Products Walailak UniversityNakhon Si ThammaratThailand Division of pharmacogenomics and Personalized Medicine Department of PathologyFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand laboratory for pharmacogenomics Somdech Phra Debaratana Medical CenterRamathibodi HospitalThailand Bamrasnaradura Infectious Diseases Institute Ministry of Public HealthThailand Clinical Pharmacokinetics and pharmacogenomics Research Unit Department of PharmacologyFaculty of MedicineChulalongkorn UniversityBangkokThailand CICECO-Aveiro Institute of Materials and Department of Medical Sciences University of Aveiro3810-193 AveiroPortugal

Objective:To investigate the influence of ABCB1 polymorphisms on the plasma level of efavirenz in Thai adult cases infected with HIV-1.Methods:A single nucleotide polymorphism of ABCB13435 C>T(rs1045642)in the gene encoding ABCB1 was genotyped using real-time PCR-based alleles in 149 HIV-infected Thai adults receiving efavirenz treatment.Plasma concentrations of efavirenz were measured by high-performance liquid chromatography 12 hr after administration.The relationship between plasma efavirenz concentrations and ABCB13435 C>T polymorphisms was analyzed.Results:Logistic regression analysis showed no significant predictors of high plasma efavirenz concentration in relation to age,gender,body weight,CD4 count and plasma HIV-1 RNA,blood biochemical parameters,antiretroviral duration or ABCB13435 C>T polymorphisms,except for height(OR=0.902,95%CI:0.835-0.973)(PT was0.446.The frequency of the heterozygous mutant ABCB13435 C/T was 53.02%(n=79),ABCB13435 T/T homozygous mutant was 18.12%(n=21)and the wild type ABCB13435 C/C genotype was 28.86%(n=43).The overall median plasma concentration of efavirenz in 149 HIV-infected Thai cases was 2.41 mg/L[IQR:(1.46-4.12)mg/L].The plasma concentration of efavirenz was higher in cases with ABCB13435 T/T homozygous mutant[2.73 mg/L,IQR:(2.02-4.19)mg/L]and ABCB13435 C/T heterozygous mutant[2.29 mg/L,IQR:(1.41-4.28)mg/L]genotypes compared to the wild type ABCB13435 C/C homozygous[2.1 mg/L,IQR:(1.37-3.53)mg/L].However,there was no statistically significant difference in the efavirenz concentration between the different genotypes(P>0.05).Objective:To investigate the influence of ABCB1 polymorphisms on the plasma level of efavirenz in Thai adult cases infected with HIV-1.Methods:A single nucleotide polymorphism of ABCB13435 C>T(rs1045642)in the gene encoding ABCB1 was genotyped using real-time PCR-based alleles in 149 HIV-infected Thai adults receiving efavirenz treatment.Plasma concentrations of efavirenz were measured by high-performance

关键词： Transporter gene ABCB13435C>T Efavirenz HIV-1 Thai

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The genetics and biology of KRAS in lung cancer

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Chinese Journal of Cancer 2013年第2期32卷 63-70页

作者： Peter M.K.Westcott Minh D.To Pharmaceutical Sciences and pharmacogenomics Program University of California SanFrancisco Helen Diller Comprehensive Cancer Center University of California SanFrancisco Thoracic Oncology Program Department of SurgeryUniversity of California SanFrancisco

Mutational activation of KRAS is a common oncogenic event in lung cancer and other epithelial cancer types.Efforts to develop therapies that counteract the oncogenic effects of mutant KRAS have been largely unsuccessful,and cancers driven by mutant KRAS remain among the most refractory to available treatments.Studies undertaken over the past decades have produced a wealth of information regarding the clinical relevance of KRAS mutations in lung cancer.Mutant Kras-driven mouse models of cancer,together with cellular and molecular studies,have provided a deeper appreciation for the complex functions of KRAS in tumorigenesis.However,a much more thorough understanding of these complexities is needed before clinically effective therapies targeting mutant KRAS-driven cancers can be achieved.

关键词： RAS基因肺癌生物学遗传学基因突变致癌作用临床意义小鼠模型

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