From Personalized Medicine to Personalized Justice: The Promises of Translational Pharmacogenomics in the Justice System
2010; Future Medicine; Volume: 11; Issue: 6 Linguagem: Inglês
10.2217/pgs.10.63
ISSN1744-8042
AutoresSteven Wong, Christopher Happy, Dan Blinka, S. B. Gock, Jeffrey M. Jentzen, Joseph Donald Hon., Howard Coleman, Saeed A. Jortani, Yolande Lucire, Cynthia L. Morris-Kukoski, Manuela G. Neuman, Paul J. Orsulak, Tara L. Sander, Michael Wagner, Jennifer Wynn, Alan H.B. Wu, Kiang-Teck J. Yeo,
Tópico(s)Biosimilars and Bioanalytical Methods
ResumoPharmacogenomicsVol. 11, No. 6 EditorialFree AccessFrom personalized medicine to personalized justice: the promises of translational pharmacogenomics in the justice systemSteven HY Wong, Christopher Happy, Dan Blinka, Susan Gock, Jeffrey M Jentzen, Joseph Donald Hon., Howard Coleman, Saeed A Jortani, Yolande Lucire, Cynthia L Morris-Kukoski, Manuela G Neuman, Paul J Orsulak, Tara Sander, Michael A Wagner, Jennifer R Wynn, Alan HB Wu & Kiang-Teck J YeoSteven HY Wong† Author for correspondenceProfesssor of Pathology, Psychiatry and Behavioral Medicine, and Population Health-Epidemiology and Director of Toxicology and TDM, Medical College of Wisconsin, Milwaukee, WI 53226–0509, USA and Scientific Director, Toxicology Department and Pharmacogenomics, Milwaukee County Medical Examiner's Office, WI, USA. , Christopher HappyMedical Examiner of Milwaukee County and Assistant Professor of Pathology, Medical College of Wisconsin, Milwaukee, WI 53233, USA, Dan BlinkaProfessor, Marquette Law School, Milwaukee, WI 53233, USA, Susan GockTechnical Director, Toxicology Department, Milwaukee County Medical Examiner's Office, WI, USA and Instructor of Pathology, Medical College of Wisconsin, Milwaukee, WI 53233, USA, Jeffrey M JentzenProfessor of Pathology and Director of Autopsy Services, University of Michigan, Ann Arbor, MI, USA, Joseph Donald Hon.Milwaukee County Circuit Court – Branch 2, Milwaukee County Safety Building, Room 423, Milwaukee, WI 53233, USA, Howard ColemanGenelex Corporation, 3000 First Avenue, Suite One, Seattle, WA 98121, USA, Saeed A JortaniAssociate Professor, Department of Pathology and Laboratory Medicine, University of Louisville, 511 S. Floyd Street (Room 217A), Louisville, KY 40202, USA, Yolande LucireForensic and Medico-Legal Psychiatry, Level 5, 203–233 New South Head Road, NSW 2027, Australia, Cynthia L Morris-KukoskiForensic Examiner Toxicology, FBI Laboratory, Quantico, VA, USA and Clinical Pharmacologist/Toxicologist, United States Navy Reserves, USA, Manuela G NeumanAssociate Professor of Pharmacology, Biophysics and International Health, Department of Pharmacology & Institute of Drug Research, USA and Director of In vitro Drug Safety & BioTechnology, MaRS Discovery District, 101 College Street, Suite 300, Laboratory 351, Toronto, ON, M5G 1L7, Canada, Paul J OrsulakConsultant Clincal and Forensic Toxicology, Minneapolis, MN, USA, Tara SanderAssociate Professor of Pathology, Medical College of Wisconsin, USA and Director, Molecular Diagnostics of Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA, Michael A WagnerAssociate Professor, Department of Pharmacology and Toxicology and Department of Pathology, Indiana University School of Medicine, USA and Director, Indiana State Department of Toxicology, 550 W. 16th Street, Indianapolis, IN 46202, USA, Jennifer R WynnAssistant Professor of Criminal Justice, Coordinator, Joint Criminal Justice Program, Department of Law, Police Science and Criminal Justice Administration, LaGuardia Community College and John Jay College of Criminal Justice, 899 10th Avenue, New York, NY 10019, USA, Alan HB WuProfessor of Pathology and Laboratory Medicine, University of California San Francisco, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, CA 94110, USA & Kiang-Teck J YeoProfessor of Pathology, Director, Clinical Chemistry, UC Med Laboratory, and Pharmacogenomics Program, University of Chicago, Chicago, IL 60637, USAPublished Online:27 May 2010https://doi.org/10.2217/pgs.10.63AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Figure 1. Complementary relationship of personalized medicine and personalized justice.Reproduced and modified with permission from [8].Enabled by pharmacogenomics (PGx), molecular imaging and other molecular biomarkers, personalized medicine (PM) promises to optimize therapy while minimizing side effects. It may also dramatically impact the justice system in ways we are only beginning to understand.Personalized medicine has already entered the curricula of well-regarded medical schools such as that of Johns Hopkins University (MD, USA) [1], but law schools offer no analog. Although clinical acceptance of PM has proved slow even with US FDA support [2,101], PM's legal ramifications are evident. Recently, for example, the FDA relabeled some drugs with companion PGx [2], such as warfarin withCYP2C9 and vitamin K epoxide reductase complex 1 to reduce bleeding [3,4,101]. If PGx retrospectively reveals that the warfarin patient was at high risk and testing was not initially performed, litigation may follow. Indeed, some lawyers advertise on the internet for cases involving warfarin-related errors [102]. Consequently, PGx may become part of defensive medicine.Personalized justice (PJ) complements PM and the overlapping practice of translational medicine [5–8], which holds that individual differences are caused primarily by genetic and environmental factors. The acronym 'TSPB' captures its elements in relation to adverse drug reactions (ADRs): toxicity, sensitivity, impaired performance (e.g., driving under the influence of drugs) and behavioral changes. Future legal applications may include molecular imaging and analyses – genomic, proteomic, metabolomics and epigenetics/imprintomics. By comparison, molecular DNA fingerprinting for identity testing is well accepted [9]. Conceptually, Figure 1 proposes a social-balance relationship for PM and PJ [8].In assessing PJ, consider two index scenarios: ▪ Drug toxicity: a 9-year old boy, diagnosed with attention-deficit hyperactivity disorder, obsessive–compulsive disorder, and Tourette's syndrome, was treated with methylphenidate, clonidine and fluoxetine [10]. Over a 10-month period, he developed gastrointestinal toxicity, incoordination and disorientation, and seizures. He died from a cardiac arrest. Postmortem toxicology showed high fluoxetine and norfluoxetine concentrations, and PGx revealed a poor CYP2D6 metabolizer genotype, resulting in fluoxetine accumulation and toxicity. Subsequently, the boy's parent were absolved from involvement in fluoxetine intoxication. Another example is genotyping uridine 5´-diphosphate-glucuronyltransferase 1A1 for patients medicated with irinotecan to avoid hematopoietic toxicity [11];▪ Drug sensitivity: in addition to warfarin, one should genotype HLA-B*5701[12] and HLA-B*1502[13] for patients medicated with abacavir [12] and some antiepileptics [13], respectively, to avoid Stevens–Johnson syndrome. Lawyers use internet advertising to reach persons who may be affected [103].In establishing PJ, a firm foundation should be based on sound legal principles as well as reliable and valid evidence-based studies, not on 'junk' science and unsubstantiated case reports. This lesson resonates in the deficiencies that beset various forensic sciences recently reported by the National Academy of Science [14,104]. The American Academy of Forensic Sciences supports the National Academy of Science's 13 recommendations and the following principles: the need for strong scientific foundations; laboratory accreditation; certification of technicians; the standardization of terminology; ethical protocols; governmental oversight; and the education of legal professionals, including judges, in forensic scientific methods and principles [15,16,105]. It is imperative that PJ heeds these recommendations, including the study of the relationship of PGx biomarkers to TSPB and the education of interested parties, including forensic pathologists and toxicologists, those engaged in molecular diagnostics and, of course, the legal community. Based on the aforementioned assessment, this article ushers in the practice of PJ by differentiating between science and myth, proposing a legal framework, updating the reader on rapidly developing technological advances, and illustrating scenarios and published cases.Legal frameworkWhile personalized medicine is rapidly taking root among the medical sciences, one may reasonably expect a slower, more begrudging acceptance by the legal profession. Law is innately conservative and reluctant to accommodate dramatic change. 'Cutting-edge' developments of all sorts often take decades to gain a foothold [17]. It will be important then to educate judges, lawyers and legal academics about the explanatory power of PJ and PM. The law's incredibly rich experience with DNA developments may, however, facilitate this task [18].One set of barriers consists of evidence rules, particularly those involving expert opinion testimony. The vaunted 'Daubert standard', pioneered by the federal courts and adopted by many states, demands that judges serve as gatekeepers who will ensure that only 'reliable' science is admitted [19]. Although courts have been distressingly inconsistent in how they scrutinize most sciences [20], DNA evidence has become the 'gold standard' for forensic sciences. Thus, the DNA channel may provide a helpful port of entry for PJ.The prime questions though will relate to the role PJ will play in the legal system. DNA evidence thus far is narrowly confined to trace evidence: was this biological evidence left by the defendant or someone else? A thornier problem occurs when we attempt to apply biological evidence to moral culpability, which pertains to an accused's personal blameworthiness. The Supreme Court recognized in Penry v. Lynaugh that punishment for a criminal offense should be directly related to the defendant's personal culpability [21]. The concept of personal culpability acknowledges that human choices are shaped by many factors: genetic, neurological, intellectual, educational, social and environmental. It follows then that an individual's blameworthiness for criminal conduct may vary depending on the factors that shaped his moral development or compromised his choices.Thus, from a PJ perspective, the question becomes something like this: should courts consider identifiable biological conditions that predispose a person to criminal behavior in weighing moral culpability? Legal precedent suggests that it should. Consider Roper v. Simmons, where the Supreme Court held that persons under the age of 18 years could not be subjected to the death penalty because their brains were not yet fully developed [22]. MRIs and neuroimaging showed that neuronal changes in the brain continued to develop into the early twenties. Since the brain affects behavior, the justices ruled that punishing a person for behavior caused by an underdeveloped brain (of which the defendant had no choice) violated the prohibition against cruel and unusual punishment. Similar logic was applied in Atkins v. Virginia, which prohibited subjecting the mentally retarded defendants to the death penalty [23]. Roper and Atkins illustrate the principle that criminal defendants with brain-based deficits are not as morally culpable as those without. As such, they deserve a lesser penalty. This is a legal springboard for PJ.Forensic pathology perspectivesFor several medical examiner/coroner offices in the USA and Europe, PGx has served as an adjunct for drug death certification – an emerging practice of molecular autopsy [7,8]. Previous studies showed a higher prevalence of CYP2D6 genetic variations, corresponding to intermediate and slow metabolizers with decreased or without enzymatic activity, in the decedents intoxicated with methadone, oxycodone and antidepressants [7,8,24,25]. Thus, PGx might aid in the interpretation of the effect of impaired drug metabolism due to genetic variations. If potentially lethal medications are identified at the scene of a crime with correspondingly toxic drug concentrations of the decedent, and subsequent PGx testing confirms an 'extensive' (normal) metabolizer, death is certified as a suicide. If the deceased's genotype is a variant – resulting in decreased drug metabolism – death is certified as accident. Recent indications of PJ for forensic pathology include a PGx section in the forensic toxicology texts for medical examiners by Molina [26] and Karch [27]. Future molecular diagnostic biomarkers of interest might include epigenetics/imprintomics and gene expression in understanding suicide [28,29], metabolomics and proteomics [8].Molecular diagnosticsThe detection of individual genetic variants is at the heart of PM and PJ. SNPs, the most common type of genetic variation, might affect drug metabolism [30]. Several SNP genotyping technologies facilitate rapid PGx testing in clinical laboratories. The three main steps, DNA extraction, amplification and detection, may be performed by automated platforms. Biotechnology companies offering PGx testing platforms, some with FDA approval, include: Luminex xTag® (Luminex Corporation, TK, USA), Roche AmpliChip® (Roche, Basel, Switzerland), Affymetrix DMET® chip (Affymetrix, CA, USA), Autogenomics INFINITI™ Analyzer (Autogenomics, CA, USA), Osmetech eSensors® (WA, USA), ParagonDx (NC, USA), and ABI PRISM® SNaPshot™ (Applied Biosystems, CA, USA) and TaqMan® assays (Applied Biosystems). Thus, the laboratory can rapidly develop, validate and perform PGx testing in-house within months, further enhanced by readily available quality-control products and survey programs. The limitations include existing evidence to demonstrate significant and medically relevant correlations for many disease-causing genes and variants, limited detection of genetic variants within the context of each testing platform, clinical interpretation of genotype results including environmental factors, and transplanted organs interfering with testing.▪ Drug hypersensitivity in vitro diagnosticsIn vitro lymphocyte toxicity assays (LTAs) compares the peripheral blood lymphocytes of patients with a history of an ADR with control individuals who take the same drug in the same dose and do not present any ADR [31]. LTA is based upon the dysfunction of mitochondria in people hypersensitive to certain drugs, such as sulfonamides, NSAIDs, protease inhibitors and antiepileptics. This test can also detect possible drug–drug interactions. Dysfunction of mitochondria has severe cellular consequences and is linked to a lack of detoxification of drugs in humans. Several surveillance strategies have evolved that limit mitochondrial damage and ensure cellular integrity. Intra-organellar proteases conduct protein quality control and exert regulatory functions, allowing the mitochondria to protect against apoptosis. LTA can be used in PJ when several drugs are implicated in an ADR in order to enable a distinction between the drug that produced the reaction and the other drugs, which were taken in the same period of time but did not contribute to the ADR.Illustrative cases & scenarios▪ AlcoholAlcoholism, with up to 30–40% inheritability, is a complex and controversial disease with both environmental and genetic components. Genetic variations influence alcohol's pharmacokinetics/metabolism and pharmacodynamics. Alcohol dehydrogenase and acetaldehyde dehydrogenase are two main polymorphic enzymes involved in alcohol metabolism, with a minor contribution from CYP2E1. Pharmacodynamic systems influenced by PGx are: GABA A/B receptors, glutamate (NMDA and a-amino-3-hydroxyl-5-methyl-isoxazole-propionate), serotonin, voltage-activated calcium channels, dopamine/norepinepherine/acetylcholine and opioid systems. For example, naltrexone, used for detoxification, binds to opioid receptor µ1, and the variants of the candidate gene of this receptor may affect addiction treatment [32,33].▪ Antidepressants & antipsychoticsPersonalized justice might address the effect of antidepressant and/or antipsychotics on behavioral changes. A recent review examined the relationship of violent behavior to the antidepressants: paroxetine, sertraline and fluoxetine. Different verdicts in a series of medicolegal cases reflected the different judicial processes, without considering drug-induced violence [34]. Incidentally, co-author Lucire studied patients medicated with antidepressants and antipsychotics metabolized by polymorphic CYPs, and assessed the development of akathisic, suicidal and/or homicidal ideations, and their relationship to CYP gene variations [Lucire Y, Pers. Comm.]. The validity of these preliminary observations are pending publication in peer-reviewed journals and validation by other investigators.▪ WarfarinOral warfarin anticoagulation is widely used to prevent thromboembolic events. Dosing selection is due to a narrow therapeutic range with a large interindividual variation (20-fold) affected by genetic and nongenetic factors [35,36]. Approximately 10–17% of patients experience bleeding [35]. Genotyping of CYP2C9, CYP4F2, VKORC1 and relevant clinical factors account for up to approximately 56% of dosing variability [37,38]. In 2007, the FDA relabeled warfarin to suggest genotyping, followed by the 22 January 2010 relabeling [4]:"The patient's CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose."Previously, in May 2009, the Centers for Medicare and Medicaid Services recommended against reimbursement [106]. Potential legal culpability was addressed in the introduction.▪ Pain managementIn addressing pain management with safety, Dr Woodcock of the FDA discussed the balance of providing patients with efficacious analgesics and the associated risks [39]. For example, in ultrarapid metabolizers, greater CYP2D6 activity can lead to poisoning after opioid administration. A 2007 case report detailed a breast-feeding infant who suffered respiratory depression and died as a result of toxic amounts of morphine being present in the milk [40]. The mother, later identified with multiple copies of CYP2D6 genes corresponding to an ultrarapid metabolizer, 'overconverted' codeine to a 'high' amount of morphine. This was excreted into breast milk, resulting in the baby's high morphine concentrations, which was identified in postmortem analysis. Consequently, guidelines were developed for breast-feeding mothers medicated with codeine.ConclusionIn recognizing the complementary, check and balance relationship of PM and PJ, translational PGx may serve the promising role of an adjunct biomarker for interpreting drug-related toxicity and sensitivity. Currently, robust, scientific and clinical studies substantiating the relationship between PGx and behavioral and/or performance changes are lacking [34]. These desired PJ studies are challenging to perform because of ethical and legal considerations and a lack of funding. Consequently, interpretations may be extrapolated from case reports, or clinical behavioral and performance studies; for example, studies related to 'driving under the influence of drug'. Other advances include automated platforms and the potential use of oral fluid for toxicology and PGx. Oral fluid, currently being evaluated for forensic drug testing [41–44] and therapeutic drug monitoring, is easily collected for PM and PJ pending outcome studies to demonstrate efficacy comparable to blood samples. In considering PGx for PJ, advantages and disadvantages are listed in Box 1.In ushering PJ practice in with PGx, a working group should consist of colleagues from inter-related disciplines in order to probe and keep abreast of recent developments, to grade evidence of case reports and outcome studies, and to develop inclusion and exclusion criteria. With sound scientific and legal principles and correct interpretation, a firm and lasting foundation could support the emerging concept of PJ becoming a reality to enhance patient safety and maintain social justice.Box 1. Advantages and disadvantages of using pharmacogenomics as an adjunct biomarker in personalized justice.Advantages:▪ DNA is stable in postmortem settings▪ It provides a personalized approach for assessing drug response▪ It can assist in the interpretation of drug concentrations in postmortem toxicology and drug death certification▪ It can assess patient compliance▪ The turnaround time is suitable for medicolegal and/or forensic applications▪ The cost of pharmacogenomics is 'low' in comparison with the legal settlement▪ It might differentiate between chronic versus acute toxicityDisadvantages:▪ Data are available in clinical cases but are limited in postmortem cases▪ Legal interpretation is challenging owing to its complexity▪ Drug inhibitors, inducers of enzymes and environmental factors complicate interpretation▪ It does not account for post-translational modifications▪ Multiple enzyme systems are involved in metabolismDisclosureThis article reflects the consensus of the co-authors and not the official position of opinion of their respective employers.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interestBibliography1 Miller ED: A bold leap into the future – personalized medicine is key to the new genes to society curriculum. In: Hopkins Medicine. Pasquale SE (Ed.). Johns Hopkins Medicine, Baltimore, MD, USA, 48 (2009).Google Scholar2 Wu AHB, Babic N, Yeo KTJ: Implementation of pharmacogenomics into the clinical practice of therapeutics: issues for the clinician and the laboratorian. Per. Med.6,315–327 (2009).Link, CAS, Google Scholar3 Wadelius M, Pirmohamed M: Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J.8(7),99–111 (2007).Crossref, Google Scholar4 Ray T: FDA updates warfarin labeling with PGx-guided dosing ranges. Pharmacogenomics Reporter 3 February 2010.Google Scholar5 Wong SH: Pharmacogenomics and personalized medicine for drug addiction and toxicology: towards personalized justice? Presented at: 11th Asian Pacific Congress of Clinical Biochemistry. Beijing, China, 14–19 October 2007.▪▪ Introduces for the first time the concept of personalized justice at an international scientific congress.Google Scholar6 Wong SHY, Happy C: Personalized justice, translational pharmacogenomics and personalized medicine – relevant to the forensic sciences? Tox. Talk33,22–23 (2009).Google Scholar7 Wong SH, JM Jentzen, RZ Shi; the Forensic Pathology/Toxicology Methadone Pharmacogenomics Study Group (FPTMPGxSG): Personalized medicine enabling personalized justice: methadone pharmacogenomics as an adjunct – for molecular autopsy, and for addiction and driving under the influence of drugs (DUID). Clin. Chem. Lab. Med.46,A118 (2008).Medline, Google Scholar8 Wong SHY: Pharmacogenomics as molecular autopsy – an adjunct to forensic pathology/toxicology: from Gregor Mendel to personalized medicine and personalized justice. In: Clarke's Analysis of Drugs and Poisons (4th Edition). Moffat AC, Osselton DM, Widdop B (Eds). Royal Pharmaceutical Society Publishing, London, UK (2010) (In Press).▪ First publication of the concept of personalized justice.Google Scholar9 Jeffreys AJ, Wilson V, Thein SL: Individual-specific 'fingerprints' of human DNA. Nature316(6023),76–79 (1985).▪▪ Beginning of the practice of DNA fingerprinting.Crossref, Medline, CAS, Google Scholar10 Sallee FR, DeVane CL, Ferrell RE: Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic deficiency. J. Child. Adolesc. Psychopharmacol.10,327–334 (2000).▪ Published index case that included pharmacogenetics for interpreting fluoxetine toxicity.Crossref, Medline, Google Scholar11 Cote JF, Kirzin S, Kramar A et al.: UGT1A1 polymorphism can predict hematologic toxicigy inpatients treated with irinotecan. Clin. Cancer Res.13,3269–3275 (2007).Crossref, Medline, CAS, Google Scholar12 Mallal S, Phillips E, Carosi G et al.: HLA-B*5701 screening for hypersensitivity to abacavir. N. Engl. J. Med.358,568–579 (2008).Crossref, Medline, Google Scholar13 Chung WH, Hung SI, Hong HS et al.: Medical genetics: a marker for Stevens–Johnson syndrome. Nature428,486 (2004).▪▪ Reports the association of Stevens–Johnson syndrome with the HLA-*B1502 allele.Crossref, Medline, CAS, Google Scholar14 Committee on Identifying the Needs of the Forensic Science Community – National Research Council of the National Academies: Strengthening Forensic Science in the United States: A Path Forward. National Academy of Sciences. The National Academies Press, Washington, DC, USA, 1–352 (2009).▪▪ National Academy of Science identified deficiencies in several areas of forensic sciences and offered recommendations for the future.Google Scholar15 American Academy of Forensic Sciences: The American Academy of Forensic Sciences approved position statement in response to National Academy of Sciences' "Forensic Needs" Report. American Academy Of Forensic Sciences, CO, USA (2009).Google Scholar16 Bohan TL: President's message. Academy News39(1),34–35 (2009).Google Scholar17 Gianelli P: Understanding Evidence (3rd Edition). 323 (2003).Google Scholar18 Federal Judicial Center: Reference Manual on Scientific Evidence (2nd Edition). Washington, DC, USA, 487 (2000).Google Scholar19 Federal Rule of Evidence, 702, Testimony by Experts.Google Scholar20 Kassirer JP, Cecil JS: Inconsistency in evidentiary standards for medical testimony: disorder in the courts. JAMA288,1382–1387 (2002).Crossref, Medline, Google Scholar21 Penry v. Lynaugh, 429 US 302 (1989).Google Scholar22 Roper v. Simmons, 543 US 551 (2005).Google Scholar23 Atkins v. Virginia, 536 US 304 (2002).Google Scholar24 Wong SHY, Wagner MA, Jentzen JM et al.: Pharmacogenomics as an adjunct of molecular autopsy for forensic pathology/toxicology: does genotyping CYP 2D6 serve as an adjunct for certifying methadone toxicity? J. Forensic Sci.48,1406–1415 (2003).Crossref, Medline, CAS, Google Scholar25 Wong SHY, Gock SB, Shi RZ et al.: Pharmacogenomics as an aspect of molecular autopsy for forensic pathology/toxicology. In: Pharmacogenomics and Proteomics: Enabling the Practice of Personalized Medicine. Wong SHY, Linder M, Valdes R Jr (Eds). AACC Press, Washington, DC, USA, 311–320 (2006).Google Scholar26 Molina DK: Handbook of Forensic Toxicology for Medical Examiners. CRC Press, Boca Raton, FL, USA, 1–370 (2010) (Appendix C – PGXs, 343–347).Google Scholar27 Karch SB: Karch's Pathology of Drug Abuse (4th Edition). CRC Press, Boca Raton, FL, USA, 1–709 (2009).Google Scholar28 Ernst C, Mechawar N, Turecki G: Suicide neurobiology. Prog. Neurobiol.89,315–333 (2009).Crossref, Medline, CAS, Google Scholar29 Golgin E: Epigenetic suicide note. The Scientist, 18–19 August (2009).Google Scholar30 Kim S, Misra A: SNP genotyping technologies and biomedical applications. Annu. Rev. Biomed. Eng.9,289–320 (2007).Crossref, Medline, CAS, Google Scholar31 Neuman MG, Malkiewicz IM, Shear NH: A novel lymphocyte toxicity assay to assess drug hypersensitivity syndromes. Clin. Biochem.33,517–524 (2000).Crossref, Medline, CAS, Google Scholar32 King AC, Volpicelli JR, Frazer A, O'Brien CP: Effect of naltrexone on subjective alcohol response in subjects at high and low risk for future alcohol dependence. Psychopharmacology129,15–22 (1997).Crossref, Medline, CAS, Google Scholar33 Wang JB, Imai Y, Eppler CM, Gregor P, Spivak CE, Uhl GR: µ-opiate receptor: cDNA cloning and expression. Proc. Natl Acad. Sci. USA90(21),10230–10234 (1993).Crossref, Medline, CAS, Google Scholar34 Healy D, Herxheimer A, Menkes DB: Antidepressants and violence: problems at the interface of medicine and law. PloS3,1478–1487 (2006).▪ Comprehensive review of candidate antidepressant cases that showed potential legal implications.Google Scholar35 Stehle S, Kirchheiner U, Lazar A, Fuhr U: PGXs of oral anticoagulants. Clin. Pharmacokin.47,565–594 (2008).Crossref, Medline, CAS, Google Scholar36 Kangelaris KN, Bent S, Nussbaum RL, Garcia DA, Tice JA: Genetic testing before anticoagulation? A systematic review of PGX dosing of warfarin. J. Gen. Intern. Med.24,656–664 (2009).Crossref, Medline, Google Scholar37 Caldwell MD, Awad T, Johnson JA et al.: CYP4F2 genetic variant alters required warfarin dose. Blood111,4106–4112 (2008).Crossref, Medline, CAS, Google Scholar38 Gage BF, Eby C, Johnson JA et al.: Use of PGX and clinical factors to predict the therapeutic dose of warfarin. Clin. Pharmacol. Ther.84,326–331 (2008).Crossref, Medline, CAS, Google Scholar39 Woodcock J: A difficult balance – pain management, drug safety and the FDA. N. Engl. J. Med.361,2105–2107 (2009).▪ US FDA perspective centered around pain management and drug safety.Crossref, Medline, CAS, Google Scholar40 Madadi P, Koren G, Cairns J et al.: Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Can. Fam. Phys.53,33–35 (2007).Medline, Google Scholar41 Bosker WM, Huestis MA: Oral fluid testing for drugs of abuse. Clin. Chem.55,1910–1931 (2009).Crossref, Medline, CAS, Google Scholar42 Cone EJ, Huestis MA: Interpretation of oral fluid tests for drugs of abuse. Ann. NY Acad. Sci.1098,51–103 (2007).Crossref, Medline, CAS, Google Scholar43 Pil K, Verstraete AZ: Current developments in drug testing in oral fluids. Ther. Drug Monit.30,196–202 (2008).Crossref, Medline, CAS, Google Scholar44 Bush DM: The U.S. Mandatory Guidelines for Federal Workplace Drug Testing Programs: current status and future considerations. Forensic Sci. Int.174,111–119 (2008).Crossref, Medline, Google Scholar101 Coumadin® Tablets (Warfarin Sodium Tablets, USP) Crystalline Coumadin® For Injection (Warfarin Sodium for Injection, USP) www.accessdata.fda.gov/drugsatfda_docs/label/2010/009218s108lbl.pdfGoogle Scholar102 Coumadin Overdose, Warfarin Overdose, Law Examples www.spanglaw.com/medical-malpractice/medication-errors/coumadinGoogle Scholar103 SSJ Law http://ssjlaw.mobiGoogle Scholar104 Strengthening Forensic Science in the United States: A Path Forward www.nap.edu/catalog/12589.htmlGoogle Scholar105 The American Academy of Forensic Sciences Approves Position Statement in Response to the National Academy of Sciences' "Forensic Needs" Report www.aafs.org/pdf/AAFS_Position_Statement_for_Press_Distribution_ 090409.pdfGoogle Scholar106 Centers for Medicare and Medicaid Services www.cms.hhs.gov/mcd/viewdraftdecisionmemo.asp?from2=viewdraftdecisionmemo.asp&id=224&Google ScholarFiguresReferencesRelatedDetailsCited ByPsychoactive Medication, Violence, and Variant Alleles for Cytochrome P450 Genes18 May 2021 | Journal of Personalized Medicine, Vol. 11, No. 5Pharmacogenomics14 August 2020Personalized justice: the potential use of genotyping in wrongful death investigationsAlan HB Wu7 December 2016 | Personalized Medicine, Vol. 14, No. 1Post-modern Medicolegal and Forensic Toxicology28 March 2018The relevance of cytochrome P450 polymorphism in forensic medicine and akathisia-related violence and suicideJournal of Forensic and Legal Medicine, Vol. 41Interpretación de resultados toxicológicos post-mórtem: criterios de garantía de calidadRevista Española de Medicina Legal, Vol. 41, No. 1Medicolegal Autopsies and Pharmacogenetics10 July 2013Risk, Reward, and the Double-Edged Sword: Perspectives on Pharmacogenetic Research and Clinical Testing Among Alaska Native PeopleAmerican Journal of Public Health, Vol. 103, No. 12Pain management in the 21st century: utilization of pharmacogenomics and therapeutic drug monitoring18 May 2011 | Expert Opinion on Drug Metabolism & Toxicology, Vol. 7, No. 6Pharmacogenomics, Personalized Medicine and Personalized Justice Influencing the Quality and Practice of Forensic Science28 February 2011Issues in Translation of Pharmacogenomics into Clinical Practice2 November 2010Pharmacogenetics raises new legal questionsNature Medicine, Vol. 16, No. 7 Vol. 11, No. 6 Follow us on social media for the latest updates Metrics History Published online 27 May 2010 Published in print June 2010 Information© Future Medicine LtdDisclosureThis article reflects the consensus of the co-authors and not the official position of opinion of their respective employers.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download
Referência(s)