@article {10831, title = {Pharmacogenetics of treatments for inflammatory bowel disease.}, journal = {Expert Opin Drug Metab Toxicol}, volume = {14}, year = {2018}, month = {2018 Dec}, pages = {1209-1223}, abstract = {

INTRODUCTION: Inflammatory bowel disease is a chronic inflammation of the gut whose pathogenesis is still unclear. Although no curative therapy is currently available, a number of drugs are used in induction and maintenance therapy; however, for most of these drugs, a high inter-individual variability in response is observed. Among the factors of this variability, genetics plays an important role. Areas covered: This review summarizes the results of pharmacogenetic studies, considering the most important drugs used and in particular aminosalycilates, glucocorticoids, thiopurines, monoclonal antibodies and thalidomide. Most studies used a candidate gene approach, even if significant breakthroughs have been obtained recently from applying genome-wide studies. When available, also investigations considering epigenetics and pharmacogenetic dosing guidelines have been included. Expert opinion: Only for thiopurines, genetic markers identified as predictors of efficacy or adverse events have allowed the development of dosing guidelines. For the other drugs, encouraging results are available and great expectations rely on the study of epigenetics and integration with pharmacokinetic information, especially useful for biologics. However, to improve therapy of IBD patients with these drugs, for implementation in the clinics of pharmacogenetics, informatic clinical decision support systems and training about pharmacogenetics of health providers are needed.

}, keywords = {Dose-Response Relationship, Drug, Epigenesis, Genetic, Gastrointestinal Agents, Genetic Markers, Genetic Predisposition to Disease, Humans, Inflammatory Bowel Diseases, Pharmacogenetics}, issn = {1744-7607}, doi = {10.1080/17425255.2018.1551876}, author = {Lucaf{\`o}, Marianna and Franca, Raffaella and Selvestrel, Davide and Curci, Debora and Pugnetti, Letizia and Decorti, Giuliana and Stocco, Gabriele} } @article {8075, title = {Patients{\textquoteright} Induced Pluripotent Stem Cells to Model Drug Induced Adverse Events: A Role in Predicting Thiopurine Induced Pancreatitis?}, journal = {Curr Drug Metab}, volume = {17}, year = {2015}, month = {2015}, pages = {91-8}, abstract = {

Induced pluripotent stem cells (iPSC) can be produced from adult cells by transfecting them with a definite set of pluripotency-associated genes. Under adequate growth conditions and stimulation iPSC can differentiate to almost every somatic lineage in the body. Patients{\textquoteright} derived iPSC are an innovative model to study mechanisms of adverse drug reactions in individual patients and in cell types that cannot be easily obtained from human subjects. Proof-of concept studies with known toxicants have been performed for liver, cardiovascular and central nervous system cells: neurons obtained from iPSC have been used to elucidate the mechanism of chemotherapy-induced peripheral neuropathy by evaluating the effects of neurotoxic drugs such as vincristine. However, no study has been performed yet on pancreatic tissue and drug induced pancreatitis. Thiopurines (azathioprine and mercaptopurine) are immunosuppressive antimetabolite drugs, commonly used to treat Crohn{\textquoteright}s disease. About 5\% of Crohn{\textquoteright}s disease patients treated with thiopurines develop pancreatitis, a severe idiosyncratic adverse event; these patients have to stop thiopurine administration and may require medical treatment, with significant personal and social costs. Molecular mechanism of thiopurine induced pancreatitis (TIP) is currently unknown and no fully validated biomarker is available to assist clinicians in preventing this adverse event. Hence, in this review we have reflected upon the probable research applications of exocrine pancreatic cells generated from patient specific iPS cells. Such pancreatic cells can provide excellent insights into the molecular mechanism of TIP. In particular three hypotheses on the mechanism of TIP could be explored: drug biotransformation, innate immunity and adaptative immunity.

}, issn = {1875-5453}, author = {Stocco, Gabriele and Lanzi, Gaetana and Yue, Fengming and Giliani, Silvia and Sasaki, Katsunori and Tommasini, Alberto and Pelin, Marco and Martelossi, Stefano and Ventura, Alessandro and Decorti, Giuliana} } @article {3516, title = {Pharmacogenetics of azathioprine in inflammatory bowel disease: a role for glutathione-S-transferase?}, journal = {World J Gastroenterol}, volume = {20}, year = {2014}, month = {2014 Apr 7}, pages = {3534-41}, abstract = {

Azathioprine is a purine antimetabolite drug commonly used to treat inflammatory bowel disease (IBD). In vivo it is active after reaction with reduced glutathione (GSH) and conversion to mercaptopurine. Although this reaction may occur spontaneously, the presence of isoforms M and A of the enzyme glutathione-S-transferase (GST) may increase its speed. Indeed, in pediatric patients with IBD, deletion of GST-M1, which determines reduced enzymatic activity, was recently associated with reduced sensitivity to azathioprine and reduced production of azathioprine active metabolites. In addition to increase the activation of azathioprine to mercaptopurine, GSTs may contribute to azathioprine effects even by modulating GSH consumption, oxidative stress and apoptosis. Therefore, genetic polymorphisms in genes for GSTs may be useful to predict response to azathioprine even if more in vitro and clinical validation studies are needed.

}, keywords = {6-Mercaptopurine, Animals, Apoptosis, Azathioprine, Glutathione, Glutathione Transferase, Humans, Immunosuppressive Agents, Inflammatory Bowel Diseases, Oxidative Stress, Pharmacogenetics, Polymorphism, Genetic}, issn = {2219-2840}, doi = {10.3748/wjg.v20.i13.3534}, author = {Stocco, Gabriele and Pelin, Marco and Franca, Raffaella and De Iudicibus, Sara and Cuzzoni, Eva and Favretto, Diego and Martelossi, Stefano and Ventura, Alessandro and Decorti, Giuliana} } @article {1933, title = {Personalized therapies in pediatric inflammatory and autoimmune diseases.}, journal = {Curr Pharm Des}, volume = {18}, year = {2012}, month = {2012}, pages = {5766-75}, abstract = {

Pediatric inflammatory and autoimmune diseases are a wide array of systemic or organ-specific conditions, characterized by an exaggerated immune reactivity, which generally occurs in immunogenetically predisposed children. Among the most important ones, in terms of their diffusion and morbidity in the population worldwide, pediatric inflammatory bowel disease (IBD) and juvenile rheumatoid arthritis (JRA) have to be considered. The aim of personalized therapy is to give to each patient the most appropriate drug and dose regimen, in order to maximize treatment response and reduce the risk of adverse events. In general, several therapeutic options exist for pediatric inflammatory and autoimmune conditions, therefore the perspective of pharmacological tools that allow identification of patients with increased risk of treatment issues related to a particular medication, in terms of lack of efficacy or increased probability of adverse events, is particularly desirable and promising. The present review will be focused on the personalized therapy approaches already available or in development for pediatric patients with IBD or JRA, comprising pharmacokinetic, pharmacodynamic and pharmacogenetic assays.

}, keywords = {Arthritis, Rheumatoid, Autoimmune Diseases, Child, Genetic Predisposition to Disease, Humans, Immunogenetic Phenomena, Individualized Medicine, Inflammation, Inflammatory Bowel Diseases, Pharmacogenetics}, issn = {1873-4286}, author = {Stocco, Gabriele and De Iudicibus, Sara and Franca, Raffaella and Addobbati, Riccardo and Decorti, Giuliana} } @article {1686, title = {Pharmacogenomics in pediatric leukemia.}, journal = {Curr Opin Pediatr}, volume = {22}, year = {2010}, month = {2010 Dec}, pages = {703-10}, abstract = {

PURPOSE OF REVIEW: The therapeutic index of many medications, especially in children, is very narrow with substantial risk for toxicity at doses required for therapeutic effects. This is particularly relevant to cancer chemotherapy, when the risk of toxicity must be balanced against potential suboptimal (low) systemic exposure that can be less effective in patients with higher rates of drug clearance. The purpose of this review is to discuss genetic factors that lead to interpatient differences in the pharmacokinetics and pharmacodynamics of these medications.

RECENT FINDINGS: Genome-wide agonistic studies of pediatric patient populations are revealing genome variations that may affect susceptibility to specific diseases and that influence the pharmacokinetic and pharmacodynamic characteristics of medications. Several genetic factors with relatively small effect may be combined in the determination of a pharmacogenomic phenotype and considering these polygenic models may be mandatory in order to predict the related drug response phenotypes. These findings have potential to yield new insights into disease pathogenesis, and lead to molecular diagnostics that can be used to optimize the treatment of childhood cancers.

SUMMARY: Advances in genome technology, and their comprehensive and systematic deployment to elucidate the genomic basis of interpatient differences in drug response and disease risk, hold great promise to ultimately enhance the efficacy and reduce the toxicity of drug therapy in children.

}, keywords = {Antineoplastic Agents, Child, Genetic Predisposition to Disease, Genetic Testing, Humans, Individualized Medicine, Pharmacogenetics, Phenotype, Precursor Cell Lymphoblastic Leukemia-Lymphoma}, issn = {1531-698X}, doi = {10.1097/MOP.0b013e32833fde85}, author = {Paugh, Steven W and Stocco, Gabriele and Evans, William E} }