Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 6, Issue 2, 2008

Does the inclusion of children in pharmacogenomic research raise new ethical issues? Through an exploration of the relevant laws, policies, guidelines and literature, we have identified five areas of concern and assessed their potential impact. These include (1) the difficulty of assessing risk and the ethics of invasive sampling, (2) the consent and assent process, (3) the circumstances under which and to whom the results of trials should be returned, (4) the effect of pharmacogenomics on identifying and treating orphan groups, and (5) the effect of pharmacogenomics on the pediatric drug approval process and patient recruitment. We conclude that while including pharmacogenomics in research projects involving children does indeed raise ethical concerns, none of these are insurmountable, and in fact, pharmacogenomics provides a promising outlook for the development of research that will benefit children.

Adenocarcinomas of the upper gastrointestinal tract are characterized by a high mortality rate. Various multimodal therapy regimens are used to improve the patient's prognosis, but the majority of patients does not respond to treatment. Thus, the identification of biomarkers that could predict response is highly demanding. The chemotherapeutic regimens most commonly used for the treatment of adenocarcinomas of the upper gastrointestinal tract are mainly based on 5-fluorouracil (5FU), cisplatin and taxan derivates. Molecular markers related to the efficiency of these components have been analyzed in various studies. One example is thymidylate synthase (TS) the major target of 5FU. Expression of TS in tumors of the upper gastrointestinal tract has been found to correlate with the outcome of the patient in some studies, but the results are inconsistent. Polymorphisms in the promotor region of the gene have been reported, which influence the expression of the protein and a correlation of the genoytpes with patient's survival has been demonstrated. Markers related to the efficiency of cisplatin, encompass the DNA-repair genes. One example is the nucleotide excisison repair gene ERCC1, for which gene expression in upper gastrointestinal tumors as well as polymorphisms in the gene have been analyzed in relation to the patient's outcome. Genome wide screening methods, as cDNA-microarrays or differential qualitative and quantitative protein expression analysis recently have been reported to give promising results for the pretherapeutic discrimination of therapy responders and nonresponders. In this review we will summarize the current state on genetic alterations in upper gastrointestinal malignancies and on the role of polymorphisms and their implications for response prediction, with a focus on parameters in therapy related genes in the group of patients treated in the neoadjuvant setting.

Endotoxemia caused by Gram-negative bacteria can result in sepsis and organ dysfunction, which includes kidney damage and renal failure. Genetic polymorphisms in cytokine-encoding genes contribute to individual variance in inflammatory responses and have been postulated as being associated with an increased risk for cytokine-mediated disorders, such as sepsis-induced acute renal failure. There is a growing body of evidence that the β2-adrenoceptor (β2-AR) system has an anti-inflammatory influence on the cytokine network during the course of immunological responses. Indeed, activation of β2-ARs can modulate the production of pro- and anti-inflammatory cytokines, such as TNF-β and interleukin( IL)-1, -6, -10, -12, in some tissues and organs. An altered expression or function of β2-ARs has been considered to be a pathogenetic factor in some inflammatory states; for example, allergy, heart failure and renal failure. Previously, we demonstrated that the application of adenoviral mediated β2-AR gene delivery to enhance renal β2-AR activity afforded the kidney protection against endotoxin-induced acute renal failure. These observations would suggest the possibility that the level of β2-AR activity might be associated with β2-AR polymorphisms which may pre-determine the increased risk of organ dysfunction following severe sepsis. At present it seems that β2-AR polymorphisms do not play a role as sepsiscausing genes; however, they might be risk factors, might modify sepsis, and/or might influence the progression of sepsis. Thus, genomic information on β2-AR polymorphisms has a potential use to identify groups of patients with a raised risk of developing severe sepsis and multiple organ dysfunctions.

US Senator Barack Obama recently proposed the Genomics and Personalized Medicine Act of 2006, which should it be enacted, would establish a Genomics and Personalized Medicine Interagency Working Group to coordinate personalized medicine efforts, fund genomics research to improve drug safety and establish a US Biobanking Research Initiative similar to efforts deployed in other countries. But what impact could personalized medicine have on the drug development process, the pharmaceutical industry and international health, including that in developing countries? Can personalized medicines support innovation, sustainability and growth in the pharmaceutical industry and also respond to changing world realities, emerging public demands for safer and more efficacious medicines and equitable access to pharmaceuticals? The present paper examines these socio-ethical and science policy questions by first elucidating their intrinsic and often complex interactions with other economic and policy issues (and the often divergent interests of stakeholders). We then present some examples from other industries (e.g., the case of hybrid cars and attendant growth of consumer interest and confidence in high quality sustainable products), with a view to identifying the factors that might contribute to a successful integration of pharmacogenomics and related biomarker technologies in patient care, international health and public policy. In particular, we propose ways to integrate the concept of sustainability into corporate and investor models of pharmaceutical industry development. While the power of pharmacogenomics to serve as a driver for the pharmaceutical industry remains to be evaluated, we submit that biomedical innovation and economic prosperity can co-exist with ethical drug development and the sustainable commercialization of customized drug therapies.

Pharmacogenomics is an evolving research discipline within ophthalmology. An early application appears to involve open-angle glaucoma, a common cause of worldwide preventable blindness. Primary open-angle glaucoma is primarily treated with medications, and the two most common classes of drugs are β-adrenergic receptor antagonists and prostaglandin analogs. One small clinical trial has documented a pharmacogenomic relationship between polymorphisms in the β1-adrenergic receptor with the selective β1-antagonist betaxolol. A second small clinical trial has documented a pharmacogenomic relationship between polymorphisms in the prostaglandin F2α receptor and the prostaglandin analog latanoprost. A small pilot study has not found any significant pharmacogenomic relationship between polymorphisms in the glucocorticoid receptor and intraocular pressure elevation following treatment with intravitreal triamcinolone acetonide. Pharmacogenomics may explain some of the well-documented variability in response to common glaucoma medications.

Mood disorders, such as major depressive disorder and bipolar disorder, are common, severe and chronic psychiatric diseases. There is an increasing recognition that the pathophysiology of mood disorders could be the result of dysregulation of synaptic plasticity with alterations in the levels of neurotrophins. Brain-derived neurotrophic factor (BDNF), the most abundant neurotrophin in the brain, has been investigated extensively in mood disorder. BDNF is important for neuronal growth, development, differentiation and survival. In addition, BDNF can modulate synaptic plasticity and its molecular mediators across multiple neurotransmitter systems, as well as the intracellular signal-transduction pathway. From findings in animal as well as clinical studies, the BDNF gene is considered an attractive candidate for predicting mood disorders or antidepressant/mood stabilizer therapeutic response. In this review, we summarize the findings of recent investigations of the effects of the BDNF gene on therapeutic response and the risk for mood disorders. Although the general conclusion to be drawn from the findings of these genetic studies, is that BDNF genetic variants have implications for the pathogenesis and treatment of mood disorders, the findings of these studies are sometimes inconsistent. Several recommendations are proposed for future genetic studies of BDNF signaling pathways in mood disorders.

Inter-individual variations in response to pharmacotherapy such as adverse effects, treatment resistance and toxicities affect all patient populations. Multidrug resistance associated proteins (MRPs) work as efflux pumps for many xenobiotics and endogenous substances and hence, can affect the drug concentration at the target site which governs therapeutic response. Genetic polymorphisms of the MRPs can lead to an over- or under-expression of these transporter proteins. These polymorphisms can therefore play an integral role in drug disposition and therapeutic outcomes via pharmacokinetic and pharmacodynamic changes. These changes may cause drug-drug interactions, treatment resistance and/or toxicity. Overexpression of certain MRPs is thought to correlate with multidrug resistance in pharmacotherapy, especially with anticancer drugs. It is also evident that some genetic variants linked with MRP genes can lead to disease states such as pseudoxanthoma elasticum. With further research, more definitive functional characterization of MRPs and the understanding of this relationship with genetic polymorphisms can be achieved. This article highlights the genetic polymorphisms of MRPs and their clinical implications with an emphasis on MRP1-4. It also provides an insight into the role that these proteins can play in disease states and toxicities as well as the implications for future research and patient management.