Pharmacogenomics and migraine: possible implications

Pharmacogenomics is the science about how inherited factors influence the effects of drugs. Drug response is always a result of mutually interacting genes with important modifications from environmental and constitutional factors. Based on the genetic variability of pharmacokinetic and in some cases pharmacodynamic variability we mention possible implications for the acute and preventive treatment of migraine. Pharmacogenomics will most likely in the future be one part of our therapeutic armamentarium and will provide a stronger scientific basis for optimizing drug therapy on the basis of each patient’s genetic constitution.     

抗哮喘药物β2肾上腺素受体激动剂的药物基因组学研究进展

尽管目前临床上用于治疗哮喘的药物有许多种,但这些药物对部分患者的疗效却很差。有证据表明这种个体差异与个人的基因差异密切相关。本文主要针对临床上常用的治疗哮喘的药物β2-肾上腺素受体激动剂的药物基因组学进行综述,并提出了今后有关这一领域的研究方向,用以提高药物治疗效果,减少副作用,并降低患者的治疗费用。     

State of Play of Pharmacogenetics and Personalized Medicine in Heart Failure

Heart failure is a common disease with high levels of morbidity and mortality. A large body of evidence guiding treatment shows prognostic benefit with beta‐blockers and angiotensin‐converting enzyme inhibitors, while diuretics are commonly prescribed for symptomatic benefit. Wide variation in drug response between clinically similar patients is a significant problem. Evidence suggests this may have a genetic component. Variation in candidate genes including the beta‐1, beta‐2, and alpha‐2 adrenergic receptors, the renin–angiotensin–aldosterone pathway and genes involved in renal electrolyte handling with diuretics may be important. Single‐nucleotide polymorphisms (SNPs) potentially influencing drug response include the Arg 389 Gly variant and the Ser 49 Gly variant in the beta‐1 adrenergic receptor, the Arg 16 Gly, Gln 27 Glu, and Thr 164 Ile polymorphisms within the beta‐2 adrenergic receptor, an insertion at the 287th base pair in the angiotensin‐converting enzyme and the Gly 264 Ala mutation in the sodium chloride co‐transporter. However, research addressing the clinical significance of these polymorphisms has yielded conflicting results that have had no influence on clinical practice. Genome‐wide association studies may provide an alternative approach to discovering genetic variations influencing drug response, a relatively unchartered area in heart failure management. If future work in this area produces a strong case that variation in drug response has a specific and clinically meaningful genetic component, this could be used to guide drug dosing based on genotype; a step forward in the journey toward personally tailored medicine.     

Critical comments for roles of biomarkers in the diagnosis and treatment of cancer

A biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic/pharmacodynamic responses to a therapeutic intervention”. Various assays, including immunohistochemistry, gene constitution such as amplification, mutation, and rearrangement, gene and protein expression analysis such as single gene or protein expression, exhaustive analysis and gene or protein signature and single nucleotide polymorphism have been used to identify biomarkers in recent years. No therapeutic effects have yet been predicted based on the results of such exhaustive gene analysis because of low reproducibility although some correlate with the prognosis of patients. Biomarkers such as HER2 for breast cancer or EGFR mutation for lung cancer and KRAS mutation in colon cancer have contributed to identify a patient population that might show a good and bad treatment response, respectively. On the other hand, other biomarkers such as bcr-abl, c-kit gene mutation and CD20 expression, which are positive for CML, GIST and B cell lymphoma, respectively, have crucial biological significance but have not necessarily been used for practical clinical screening since pathological diagnosis coincide with finding of biomarkers. Hence, much work remains to be done in many areas of biomarker research.     

遗传药理学与高血压药物治疗进展

遗传药理学对于解释药物反应的个体差异并进行个体化用药具有重要意义。近年来其新技术在高血压治疗等方面的临床应用引起了广泛关注。本文结合本临床评价中心实践经验,从药代动力学和药效动力学方面对与高血压治疗相关的基因多态性研究进展,及其对高血压个体化治疗的影响进行综述。可以认为基因芯片技术等药物基因组学的新发展,必将对高血压等疾病的个体化治疗发挥更显著的促进作用。     

Watson and Crick 50 years on. From double helix to pharmacogenomics

The second half of the 20th century has seen quantum leaps in our understanding of molecular biology. The technological advances, which facilitated the recent successful completion of the Human Genome Project, have provided the tools for deciphering the complexity of the human condition. At present, the function of only 50% of genes is known. However, as understanding of the human genome improves, a plethora of gene targets for treating disease will be uncovered - leading to therapies which will be considered revolutionary. Genome related science has begun to impact almost every facet of medicine including anaesthesia and intensive care. Better understanding of interindividual differences will enable better prediction of illness susceptibility as well as response to treatment. These insights will permit therapies to be tailored to individuals or racial groups. At present, there is only rudimentary knowledge of factors controlling gene regulation, but in the future, better understanding of gene-environment interactions and gene expression will enable pharmaceutical companies to develop new therapies and permit clinicians to optimise their effects, without recourse to current laborious testing regimens. As genomic science progresses, new ethical, legal, social and philosophical dilemmas will also continue to emerge.     

Pharmacogenomics and addiction to opiates

The risk of initiating and maintaining the use of opiates up to the point of abuse and dependence is to a large degree genetically transmitted and is separate from genetic risk factors for addiction to other drugs of abuse. Pharmacogenetic studies have so far focused on obvious candidate genes that are expected to be involved either in the pharmacokinetics or in the pharmacodynamics of opioids in the mesolimbic reward system of the brain. The few findings of a positive allelic association rarely withstand replication in independent case-control or less stratification-prone family-based association samples. A pharmacogenomic approach in the best sense of the word, however, involves an unbiased, genome-wide, parallel search for risk genes and gene expression patterns. So far, only quantitative trait loci mapping studies of inbred rodent strains and differential expression studies using high-density DNA microarrays fulfill these requirements. The present state of pharmacogenomic and pharmacogenetic studies in animals and humans with respect to opiate addiction is reviewed in this paper.     

Role of platelet glycoprotein polymorphisms in cardiovascular diseases

Atherothrombosis is the leading cause of death in western countries. Major complications of atherothrombotic disease, which are responsible for a large burden of morbidity and mortality, are acute coronary syndromes, ischemic stroke, and peripheral occlusive disease. Plaque rupture, platelet adhesion, aggregation, and thrombosis may lead to unstable angina and may progress to myocardial infarction as well as to ischemic stroke. Platelet membrane glycoprotein receptors mediate crucial reactions in acute thrombosis and chronic processes of atherogenesis. The platelet glycoprotein GP IIb/IIIa, which is the most abundant platelet receptor, also represents the drug target of a novel class of anti-platelet drugs, which includes abciximab, tirofiban, and eptifibatide. The genes encoding the three major platelet glycoprotein receptors (GP Ib/IX/V, GP Ia/IIa, and GP IIb/IIIa) are subject to considerable genetic variability. This paper reviews how polymorphisms in the platelet glycoprotein receptors affect platelet function, susceptibility to atherothrombosis and its major complications including myocardial infarction, stroke, and complications following percutaneous coronary interventions, and individual variability of drug response. Recent data on platelet glycoprotein receptor polymorphisms as modifiers of drug action and as predictors of drug response offer the perspective of individualized drug treatment. Prospective studies will show whether this approach is useful or not. As the data reviewed here show clearly, future clinical trials should routinely take into account genetic susceptibility factors and modifiers, both for study design and for predefined patient stratification.Abbreviations ACS Acute coronary syndrome - CI Confidence interval - DCA Directional coronary atherectomy - GP Glycoprotein - MACE Major adverse cardiac event - MI Myocardial infarction - PCI Percutaneous coronary intervention - PTCA Percutaneous transluminal coronary angioplasty - RR Relative risk - SCD Sudden cardiac death - VWF Von Willebrand factor