Γενετική και Ανεπιθύμητες Ενέργειες φαρμάκων
Keywords:
Ανεπιθύμητες ενέργειες, Φαρμακογονιδιωματική, μεταβολισμός φαρμάκων, τοξικότητα φαρμάκων, γονοτυπική ανάλυση
Abstract
Τα τελευταία χρόνια παρατηρείται ολοένα και μεγαλύτερη αύξηση του ενδιαφέροντος της επιστημονικής κοινότητας αναφορικά με τις ανεπιθύμητες ενέργειες από φάρμακα (ΑΕ). Αν και οι περισσότερες από αυτές είναι δοσοεξαρτώμενες και προβλέψιμες (τύπος Α), υπάρχει άλλη μια κατηγορία αντιδράσεων σε φάρμακα οι οποίες είναι πιο σπάνιες, ιδιόμορφες και χαρακτηρίζονται από αυξημένο ποσοστό θνησιμότητας (τύπος Β). Οι αντιδράσεις τύπου Β έχουν έντονο γενετικό χαρακτήρα και η εμφάνιση τους σχετίζεται με αλληλόμορφα γονιδίων ιστοσυμβατότητας (HLA, Human Leukocyte Antigen) με γονίδια ενζύμων που συμμετέχουν στον μεταβολισμό φαρμάκων, με γονίδια μεταφορέων φαρμάκων και με διάφορους επιγενετικούς παράγοντες. Η σοβαρότητα των ΑΕ που εντάσσονται στον τύπο Β, όπως η φαρμακευτική ηπατοτοξικότητα και η τοξική επιδερμική νεκρόλυση, τονίζει την ανάγκη άμεσης αντιμετώπισης του προβλήματος. Το συγκεκριμένο άρθρο εστιάζει στην παρουσίαση του γενετικού υπόβαθρου των ανεπιθύμητων ενεργειών τύπου Β καθώς και στον ρόλο της επιστήμης της φαρμακογονιδιωματικής, η οποία βασιζόμενη στη γενετική δομή κάθε ατόμου και με την αξιοποίηση σύγχρονων μεθόδων μοριακής βιολογίας θα συμβάλλει σε μεγάλο βαθμό, στην μείωση των περιστατικών ΑΕ.
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10. Daly AK. Pharmacogenomics of adverse drug reactions. Genome Med 2013; 5(1): 5.
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20. White KD, Chung WH, Hung SI, Mallal S, Philips EJ. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: The role of host, pathogens, and drug response. J Allergy Clin Immunol 2015; 136(2): 219-234; quiz 235.
21. Li Y, Liu M, Zhang X, Lu Y, Meng J. Switching from allopurinol to febuxostat: efficacy and safety in the treatment of hyperuricemia in renal transplant recipients. Ren Fail 2019; 41(1): 595-599.
22. Yu KH, Yu CY, Fang YF. Diagnostic utility of HLA-B*5801 screening in severe allopurinol hypersensitivity syndrome: an updated systematic review and meta-analysis. Int J Rheum Dis 2017; 20(9): 1057-1071.
23. Jung JW, Song WJ, Kim YS, et al. HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency. Nephrol Dial Transplant 2011; 26(11): 3567-3572.
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26. Phillips EJ, Mallal SA. Active suppression rather than ignorance: tolerance to abacavir-induced HLA-B*57:01 peptide repertoire alteration. J Clin Invest. 2018; 128(7): 2746-2749.
27. Monshi MM, Faulkner L, Gibson A, et al. Human leukocyte antigen (HLA)‐B*57:01‐restricted activation of drug‐specific T cells provides the immunological basis for flucloxacillin‐induced liver injury. Hepatology 2013; 57(2): 727-739.
28. Wuillemin N, Adam J, Fontana S, Krähenbühl S, Pichler WJ, Yerly D. HLA Haplotype Determines Hapten or p-i T Cell Reactivity to Flucloxacillin. J Immunol 2013; 190(10): 4956-4964.
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30. Lucena MI, Molokhia M, Shen Y, et al. Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury is Influenced by Multiple HLA Class I and II Alleles. Gastroenterology 2011; 141(1): 338–347.
31. Stephens C, López-Nevot MA, Ruiz-Cabello F, et. al. HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity. PLoS One 2013; 8(7): e68111.
32. Singer JB, Lewitzky S, Leroy E, et al. A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet 2010; 42(8): 711-714.
33. EMA. Επιστημονικά πορίσματα και λόγοι ανάκλησης της άδειας κυκλοφορίας που παρουσιάστηκαν από τον ΕΜΕΑ. Παράρτημα ΙΙ. Διαθέσιμο https://www.ema.europa.eu/en/documents/referral/lumiracoxib-article-107-procedures-annex-ii_el.pdf. Εκδόθηκε Δεκέμβριος 13, 2007. Επίσκεψη Δεκέμβριος 7, 2020.
34. Fan WL, Shiao MS, Hui RCY, et al. HLA Association with Drug-Induced Adverse Reactions. J Immunol Res 2017; 2017: 3186328.
35. Hung SI, Chung WH, Wen-Hungb C, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 2006; 16(4): 297-306.
36. Choo SY. The HLA System: Genetics, Immunology, Clinical Testing, and Clinical Implications. Yonsei Med J 2007; 48(1): 11–23.
37. Man CB, Kwan P, Baum L, et. al. Association between HLA‐B*1502 Allele and Antiepileptic Drug‐Induced Cutaneous Reactions in Han Chinese. Epilepsia 2007; 48(5): 1015-1018.
38. Brown HA, Pereira N. Pharmacogenomic Impact of CYP2C19 Variation on Clopidogrel Therapy in Precision Cardiovascular Medicine. J Pers Med 2018; 8(1): 8.
39. MedlinePlus. Cytochrome P450 family 2 subfamily C member 19. Available via https://medlineplus.gov/genetics/gene/cyp2c19/. Accessed June 9, 2020.
40. Iverson Genetics. Clopidogrel GenoSTAT. Available via http://www.iversongenetics.com/clopidogrel-genoSTAT.html. Accessed May 15, 2020.
41. Ellis KJ, Stouffer GA, McLeod HL, Lee CR. Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA recommendations. Pharmacogenomics 2009; 10(11): 1799-1817.
42. Βαλαβανίδης Α, Ευσταθίου Κ. Η χημική ένωση του μήνα. Βαρφαρίνη: από ποντικοφάρμακο σε θαυματουργό φάρμακο. Διαθέσιμο http://195.134.76.37/chemicals/chem_warfarin.htm. Εκδόθηκε Μάρτιος, 2013. Επίσκεψη Μάιος 15, 2020.
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45. MedlinePlus. Vitamin K epoxide reductase complex subunit 1. Available via https://medlineplus.gov/genetics/gene/vkorc1/. Accessed June 9, 2020.
46. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet 2009; 48(11): 689-723.
47. Μαρσέλος Μ, Λεονταρίτης Γ, Αντωνίου Α, και συν. Βιοχημική φαρμακολογία. Αθήνα: Σύνδεσμος Ελληνικών Ακαδημαϊκών Βιβλιοθηκών. 2015 Διαθέσιμο: http://hdl.handle.net/11419/4252.
48. Tirona RG, Kim RB. Introduction to Clinical Pharmacology, Robertson D, Williams G (ed) Clinical and Translational Science (2nd Edition), Academic Press, London, United Kingdom, 2017, pp. 365-388.
49. Goetz MP, Kamal A, Ammes MM. Tamoxifen Pharmacogenomics: The Role of CYP2D6 as a Predictor of Drug Response. Clin Pharmacol Ther 2008; 83(1): 160-166.
50. Paulík A , Nekvindová J, Filip S. Irinotecan toxicity during treatment of metastatic colorectal cancer: focus on pharmacogenomics and personalized medicine. Tumori 2020; 106(2): 87-94.
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