Tacrolimus-induced nephrotoxicity and genetic variability:A review

Background: Calcineurin inhibition (CNI) is the mainstay of immunosuppressant therapy for most solid organ transplant patients. High tacrolimus levels are related with acute nephrotoxicity, but the relationship with chronic toxicity is less clear. Variation in disposition of tacrolimus is associated with genetic variation in CYP3A5. Hence, could genetic variation in CYP3A5 or other genes involved in tacrolimus disposition and effect be associated with a risk for tacrolimus-induced nephrotoxicity? To perform a review of the literature and to identify if genetic variation in CYP3A5 or other genes involved in tacrolimus disposition or effect may be associated with tacrolimus-induced nephrotoxicity and/or renal dysfunction in solid organ transplant recipients. Material/Methods: Pubmed/Medline, Embase and Google were searched from their inception till November 8th 2010 with the search terms 'tacrolimus', 'genetics', and 'nephrotoxicity' or 'renal dysfunction'. References of relevant articles were screened as well. Results: We identified 13 relevant papers. In kidney recipients, associations between donor ABCB1, recipient CCR5 genotype and tacrolimus-induced nephrotoxicity were found. CYP3A5 genotype studies in kidney recipients yielded contradictory results. In liver recipients, a possible association between recipient ACE, CYP3A5, ABCB1 and CYP2C8 genetic polymorphisms and tacrolimus-induced nephrotoxicity was suggested. In heart recipients, TGF-β genetic polymorphisms were associated with tacrolimus-induced nephrotoxicity. The quality of the studies varied considerably. Conclusions: Limited evidence suggests that variation in genes involved in pharmacokinetics (ABCB1 and CYP3A5) and pharmacodynamics (TGF-β, CYP2C8, ACE, CCR5) of tacrolimus may impact a transplant recipients' risk to develop tacrolimus-induced nephrotoxicity across different transplant organ groups.</p

Clinical Practice Recommendations for the Management and Prevention of Cisplatin-Induced Hearing Loss Using Pharmacogenetic Markers

Currently no pharmacogenomics-based criteria exist to guide clinicians in identifying individuals who are at risk of hearing loss from cisplatin-based chemotherapy. This review summarizes findings from pharmacogenomic studies that report genetic polymorphisms associated with cisplatin-induced hearing loss and aims to (1) provide up-to-date information on new developments in the field, (2) provide recommendations for the use of pharmacogenetic testing in the prevention, assessment, and management of cisplatin-induced hearing loss in children and adults, and (3) identify knowledge gaps to direct and prioritize future research. These practice recommendations for pharmacogenetic testing in the context of cisplatin-induced hearing loss reflect a review and evaluation of recent literature, and are designed to assist clinicians in providing optimal clinical care for patients receiving cisplatin-based chemotherapy

Characteristics of opioid-users whose death was related to opioid-toxicity: a population-based study in Ontario, Canada.

The impact of the prescription opioid public health crisis has been illustrated by the dramatic increase in opioid-related deaths in North America. We aimed to identify patterns and characteristics amongst opioid-users whose cause of death was related to opioid toxicity.This was a population-based study of Ontarians between the years 2006 and 2008. All drug-related deaths which occurred during this time frame were reviewed at the Office of the Chief Coroner of Ontario, and opioid-related deaths were identified. Medical, toxicology, pathology, and police reports were comprehensively reviewed. Narratives, semi-quantitative, and quantitative variables were extracted, tabulated, and analyzed.Out of 2330 drug-related deaths in Ontario, 58% were attributed either in whole or in part, to opioids (n = 1359). Oxycodone was involved in approximately one-third of all opioid-related deaths. At least 7% of the entire cohort used opioids that were prescribed for friends and/or family, 19% inappropriately self-administered opioids (injection, inhalation, chewed patch), 3% were recently released from jail, and 5% had been switched from one opioid to another near the time of death. Accidental deaths were significantly associated with personal history of substance abuse, enrollment in methadone maintenance programs, cirrhosis, hepatitis, and cocaine use. Suicides were significantly associated with mental illness, previous suicide attempts, chronic pain, and a history of cancer.These results identify novel, susceptible groups of opioid-users whose cause of death was related to opioids in Ontario and provide the first evidence to assist in quantifying the contribution of opioid misuse and diversion amongst opioid-related mortality in Canada. Multifaceted prevention strategies need to be developed based on subpopulations of opioid users

Thiopurine Dosing using Thiopurine Methyltransferase Status: A Systematic Review of Clinical Guidance

Produced by Technology Assessment at SickKids, Hospital for Sick Children.The objective of this study was to conduct a systematic review of clinical guidance documents that recommend TPMT testing prior to the administration of thiopurine drugs. The specific aims were to 1) review the breadth of guidance documents and their sources, and 2) critically appraise the quality of the guidance documents by evaluating the quality of evidence used to support the preferential use of one method (genotyping versus phenotyping) over another and used to guide dose adjustments based on TPMT status.Supported by a program grant from the Ontario Ministry of Health and Long-Term Care Drug Innovation Fun

Manner of death per opioid type.

<p>This graph illustrates the relative proportion of accidental, suicide, or undetermined manners of death per opioid type. The graph represents all single opioid-related deaths in Ontario, Canada between the years 2006 and 2008 (n = 1040 decedents).</p

Comparison of demographic characteristics between opioid-related mortalities and non-opioid drug related mortalities in Ontario for the years 2006, 2007, and 2008.

a<p>Two values not available. All tests were performed by Pearson's Chi-square unless otherwise indicated. ⁺Mann-Whitney U-test. Note: 20 files were not available for assessment or contained missing information.</p

Opioid-related deaths in Ontario which were temporally associated with release from a correctional institution or under custody (n = 46).

*<p>These values are reported as median (inter-quartile range).</p>+<p>Based on seven cases in which information pertaining to the length of detainment was available.</p