Use of pharmacogenetic data to guide individualized opioid prescribing after surgery.

Surgery. 2019 Jul 15;:

Authors: Rocco R, Thiels CA, Ubl DS, Moyer AM, Habermann EB, Cassivi SD

Abstract
BACKGROUND: Despite the current strategies aimed at avoiding opioid overprescription by implementing institutional guidelines, the use of opioids after surgical procedures remains highly variable. It is well known that opioids are activated by the cytochrome p450 CYP2D6 enzyme to exert pharmacologic effect. Individual variation in CYP2D6 activity affects drug metabolism, and genotyping can be performed to predict an individual's ability to metabolize CYP2D6 substrates. We postulate that the pharmacogenomic identification of patients with different opioid metabolism capacity may allow for the individualization of postsurgical opioid prescription.
METHODS: This study was generated by the unison of data from 2 prior initiatives taking place at our Institution. In the first study, patients undergoing 1 of 25 elective surgical procedures were prospectively identified as part of a quality initiative and surveyed by phone 21 to 35 days after hospital discharge to complete a 29-question survey regarding opioid utilization and pain experience. Additional chart abstraction was conducted to obtain prescribing data and pain scores during the hospitalization. The second study was the Mayo Clinic Right Drug, Right Dose, Right Time study protocol, in which 5 pharmacogenes, including CYP2D6, were genotyped for 1,000 Mayo Clinic Biobank participants. The goal of this study was to implement preemptive pharmacogenomics in an academic health care setting and to generate data for further pharmacogenomic research. Patients were classified by their predicted CYP2D6 activity based on their CYP2D6 genotype.
RESULTS: Of the 2,486 patients with prospective opioid utilization data, 21 had pharmacogenetic data available and were included in the analysis. These patients were classified according to their activity as opioid metabolizers, with 10 patients (48%) classified as intermediate, 4 patients (19%) as intermediate to normal, and 7 patients (33%) as normal or extensive. Compared with the intermediate to normal and intermediate phenotypes, normal or extensive patients had the highest percentages of preoperative opioid naivety and recorded pain scores throughout the surgical experience. The percentage of unused opioids for intermediate, intermediate to normal, and normal or extensive categories was 79%, 63%, and 46%, respectively. Moreover, of the 14 patients declaring the highest level of satisfaction for their pain control after discharge, 60% belonged to intermediate, 100% to intermediate to normal, and 57% to the normal or extensive group.
CONCLUSION: This study outlines a possible correlation between genetically controlled metabolism and opioid requirements after surgery. In this setting, an increased CYP2D6 enzymatic activity was associated to a greater opioid consumption, lesser amount of unused opioids, and a lower satisfaction level from opioid prescription.

PMID: 31320226 [PubMed - as supplied by publisher]

Integrative genomic analysis for the functional roles of ITPKC in bone mineral density.

Biosci Rep. 2018 12 21;38(6):

Authors: Lu HF, Wong HS, Chen BK, Liao HT, Hsu YW, Ikegawa S, Cho EC, Hung KS, Chang WC

Abstract
Osteoporosis is defined by low bone mineral density (BMD), which is mainly due to the imbalances in osteoclast and osteoblast activity. Previous studies indicated that early activation of osteoclasts relies on calcium entry through store-operated calcium (SOC) entry, and several genes, including STIM1, ORAI1, and ITPKC, are known as key regulators of SOC entry. However, the relationships between STIM1, ORAI1, ITPKC, and human BMD are still unclear. In order to investigate the plausible associations between these genes and BMD, we conducted a meta-analysis of genes expression and BMD using the publicly available GEO database. We further recruited 1044 subjects and tested associations between polymorphisms in these genes and BMD. Clinical information (including age, sex, and BMI) was collected and used for the analysis. Our results indicated that ITPKC gene expression was significantly associated with BMD. Furthermore, we found that one ITPKC SNP (rs2607420) was significantly associated with lumbar spine BMD. Through bioinformatics analysis, rs2607420 was found to be very likely to participate in the regulation of ITPKC expression. Our findings suggest that ITPKC is a susceptibility gene for BMD, and rs2607420 may play an important role in the regulation of this gene.

PMID: 30355649 [PubMed - indexed for MEDLINE]

Frequency and clinical outcomes of CYP2C19 genotype-guided escalation and de-escalation of antiplatelet therapy in a real-world clinical setting.

Genet Med. 2019 Jul 18;:

Authors: Martin J, Williams AK, Klein MD, Sriramoju VB, Madan S, Rossi JS, Clarke M, Cicci JD, Cavallari LH, Weck KE, Stouffer GA, Lee CR

Abstract
PURPOSE: To evaluate the frequency and clinical impact of switches in antiplatelet therapy following implementation of CYP2C19 genotyping after percutaneous coronary intervention (PCI).
METHODS: The frequency of escalation (clopidogrel switched to prasugrel/ticagrelor) and de-escalation (prasugrel/ticagrelor switched to clopidogrel) was evaluated in 1063 PCI patients who underwent CYP2C19 genotyping. Risk of major adverse cardiovascular or cerebrovascular (MACCE) and bleeding events over one year was evaluated.
RESULTS: Antiplatelet therapy switches were common (19%), with escalation (101/115: 88%) and de-escalation (77/84: 92%) occurring predominantly in patients with and without a CYP2C19 nonfunctional allele, respectively. Nonfunctional allele carriers initiated and continued on clopidogrel had a significantly higher risk of experiencing either a MACCE or bleeding event compared with those escalated to prasugrel/ticagrelor (52 vs. 19 events/100 patient-years; adjusted hazard ratio [HR] 2.89 [1.44-6.13], p = 0.003). Patients without a nonfunctional allele de-escalated to clopidogrel had no difference in risk compared with those initiated and continued on prasugrel/ticagrelor (21 vs. 19 events/100 patient-years; adjusted HR 1.13 [0.51-2.34], p = 0.751).
CONCLUSION: CYP2C19-guided escalation and de-escalation is common in a real-world setting. Continuation of clopidogrel in nonfunctional allele carriers is associated with adverse outcomes. De-escalation to clopidogrel in patients without a nonfunctional allele appears safe and warrants prospective study.

PMID: 31316169 [PubMed - as supplied by publisher]

SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication.

Nat Commun. 2019 Jul 17;10(1):3142

Authors: Halder S, Torrecilla I, Burkhalter MD, Popović M, Fielden J, Vaz B, Oehler J, Pilger D, Lessel D, Wiseman K, Singh AN, Vendrell I, Fischer R, Philipp M, Ramadan K

Abstract
The SPRTN metalloprotease is essential for DNA-protein crosslink (DPC) repair and DNA replication in vertebrate cells. Cells deficient in SPRTN protease exhibit DPC-induced replication stress and genome instability, manifesting as premature ageing and liver cancer. Here, we provide a body of evidence suggesting that SPRTN activates the ATR-CHK1 phosphorylation signalling cascade during physiological DNA replication by proteolysis-dependent eviction of CHK1 from replicative chromatin. During this process, SPRTN proteolyses the C-terminal/inhibitory part of CHK1, liberating N-terminal CHK1 kinase active fragments. Simultaneously, CHK1 full length and its N-terminal fragments phosphorylate SPRTN at the C-terminal regulatory domain, which stimulates SPRTN recruitment to chromatin to promote unperturbed DNA replication fork progression and DPC repair. Our data suggest that a SPRTN-CHK1 cross-activation loop plays a part in DNA replication and protection from DNA replication stress. Finally, our results with purified components of this pathway further support the proposed model of a SPRTN-CHK1 cross-activation loop.

PMID: 31316063 [PubMed - in process]

Genomics education in nursing in Hong Kong, Taiwan and Mainland China.

Int Nurs Rev. 2019 Jul 17;:

Authors: Chair SY, Waye MMY, Calzone K, Chan CWH

Abstract
AIM: To identify issues and challenges of genomics education in Hong Kong, Taiwan and Mainland China.
BACKGROUND: The use of genetics/genomics in health care, such as genetic testing, pharmacogenomics and tumour profiling in the context of cancer, is increasing. The rapid application of genetics/genomics in clinical practice requires healthcare providers to be competent to practise genetics-related patient care.
SOURCES OF EVIDENCE: We reviewed current practices in genomics education in nursing in Hong Kong, Taiwan and Mainland China, including the opportunities for nurses to advance their knowledge and recommendations to incorporate genomics education in the nursing curriculum in these regions.
FINDINGS: While many citizens and health professionals recognize the importance of new and exciting research areas of genomics/genetics, there are still many gaps in the translation of genetic/genomic medicine into clinical practice. There is also a similar lack of genetics professionals in China.
CONCLUSION: Hong Kong, Taiwan and Mainland China face challenges in promoting genetic education in nursing. A strategic approach in a coordinated effort ineffectively translating genomic knowledge into healthcare practice should be established in these three regions.
IMPLICATIONS FOR NURSING AND POLICY: Nursing educators in Hong Kong, Taiwan and Mainland China should link with the international nursing community (e.g. Global Genomics Nursing Alliance) and form closer networks to improve education in the area of genetics and genomics. From a policy level, genomics education is suggested to be incorporated in nursing curriculum to enhance nurses' competency in incorporating genetics/genomics service into patient care.

PMID: 31313831 [PubMed - as supplied by publisher]

Phthalate plasticizer di(2-ethyl-hexyl) phthalate induces cyclooxygenase-2 expression in gastric adenocarcinoma cells.

Environ Toxicol. 2019 Jul 16;:

Authors: Wong JH, Wang YS, Nam S, Ho KH, Chang CM, Chen KC, Chen YF, Chang WC

Abstract
The phthalate plasticizer, di(2-ethyl-hexyl) phthalate (DEHP), and its derived metabolites are common anthropogenic environmental toxins, which are known to act as endocrine disruptors. Numerous studies have associated DEHP with disruption of sex hormones, abnormal development of reproductive organs, allergies, and inflammation. Its role in promoting inflammation has been reported by both human epidemiological and animal studies. In stomach tissue, chronic inflammation is known to accompany mucosal damage, and pave the way to gastritis, stomach ulcers, and ultimately gastric cancer. Eastern Asian populations possess the highest gastric cancer incidences in the world. Coincidentally, East Asia is one of the world's major sites for plastics manufacture and export. Thus, possible correlations between DEHP, a common plasticizer, and gastric cancer are of great interest. Our study revealed several critical findings. First, even at very low dosage, mimicking the residual plasticizer exposure, detrimental effects of DEHP on gastric cells can be detected. Second, gastric cells treated with DEHP increased cyclooxygenase-2 (COX-2) in a time-dependent manner. Third, promoter deletion studies revealed a critical role of nuclear factor-kappa B (NF-κB) for COX-2 gene responses. Finally, our results indicated that a low concentration of DEHP is able to trigger COX-2 activation via the extracellular signal-regulated kinase (ERK1/2) and NF-κB signaling pathway. Taken together, we demonstrate that very low doses of DEHP enhance the expression of the prototypical inflammatory gene, COX-2, in gastric cancer cells via ERK1/2 and NF-κB activation. This study provides important insights into the inflammatory process and damages associated with phthalate plasticizers exposure.

PMID: 31313480 [PubMed - as supplied by publisher]

Use of Pharmacogenetic Drugs by the Dutch Population.

Front Genet. 2019;10:567

Authors: Alshabeeb MA, Deneer VHM, Khan A, Asselbergs FW

Abstract
Introduction: The Dutch Pharmacogenetics Working Group (DPWG) indicated a list of actionable genotypes that affect patients' response to more 50 drugs; these drugs which show variable effects based on patients' genetic traits were named as pharmacogenetics (PGX) drugs. Preemptive genetic testing before using these drugs may protect certain patients from serious adverse reactions and could help in avoiding treatment failures. The objectives of this study include identifying the rate of PGX drug usage among Dutch population, estimating the level of users who carry the actionable genotypes and determining the main genes involved in drug's effect variability.
Methods: Usage of PGX drugs over 2011-2017 by the insured population (an average of 11.4 million) in outpatient clinics in Netherlands was obtained from the publically available GIP databank. The data of 45 drugs were analyzed and their interactions with selected pharmacogenes were estimated. Frequency of actionable genotypes of 249 Dutch parents was obtained from the public database: Genome of Netherlands (GoNL), to identify the pattern of genetic characteristics of Dutch population.
Results: Over a 7 year period, 51.3 million exposures of patients to PGX drugs were reported with an average of 5.3 exposures per each drug user. One quarterof the exposures (12.4 million) are predicted to be experienced by individuals with actionable genotypes (risky exposures). Up to 60% of the risky exposures (around 7.5 million) were related to drugs metabolized by CYP2D6. SLCO1B1, and CYP2C19 were also identified among the top genes affecting response of drugs users (involved in about 22 and 12.4% of the risky exposures, respectively). Cardiovascular medications were the top prescribed PGX drug class (43%), followed by gastroenterology (29%) and psychiatry/neurology medications (15%). Women use more PGX drugs than men (55.8 vs. 44.2%, respectively) with the majority (84%) of users in both sexes are above 45 years.
Conclusion: PGX drugs are commonly used in Netherlands. Preemptive panel testing for CYP2D6, SLCO1B1, and CYP2C19 only could be useful to predict 95% of vulnerable patients' exposures to PGX drugs. Future studies to assess the economic impact of preemptive panel testing on patients of older age are suggested.

PMID: 31312209 [PubMed]

Population diversity in oncology drug responses and implications to drug development.

Chin Clin Oncol. 2019 Jun;8(3):24

Authors: Walsh R, Goh BC

Abstract
Cancer drug development is proceeding at a rapid pace, with drug approvals in oncology outpacing the other disease indications. With high population growth and economic development of Asian countries, access to cancer drugs becomes a paramount necessity. Approval of these drugs is dependent on establishing their safety and efficacy in populations living in these countries. Ethnic and racial differences in drug pharmacokinetics, or drug receptor sensitivities may lead to differences in drug responses between populations. These differences may be due to intrinsic or extrinsic factors, and understanding of the magnitude of these differences and their etiologies is important. One key pharmacogenetic reason for ethnic variability of drug response arises from the different allelic frequencies of polymorphic drug-metabolising enzyme genes, resulting in altered drug disposition. Using race or ethnicity as a "biomarker" for pharmacotherapeutics is fraught with issues as they are difficult to define scientifically, and are considered more social constructs. Nonetheless, studying the genetics of ethno-geographical variability of drug response will allow genetic biomarkers to be uncovered, which would greatly facilitate precision medicine, and should justify broadening the involvement and accrual of patients from global diverse populations during the early phases of drug development for an oncology drug.

PMID: 31311278 [PubMed - in process]

Update on the pharmacogenomics of pain management.

Pharmgenomics Pers Med. 2019;12:125-143

Authors: Kaye AD, Garcia AJ, Hall OM, Jeha GM, Cramer KD, Granier AL, Kallurkar A, Cornett EM, Urman RD

Abstract
Pharmacogenomics is the study of genetic variants that impact drug effects through changes in a drug's pharmacokinetics and pharmacodynamics. Pharmacogenomics is being integrated into clinical pain management practice because variants in individual genes can be predictive of how a patient may respond to a drug treatment. Pain is subjective and is considered challenging to treat. Furthermore, pain patients do not respond to treatments in the same way, which makes it hard to issue a consistent treatment regimen for all pain conditions. Pharmacogenomics would bring consistency to the subjective nature of pain and could revolutionize the field of pain management by providing personalized medical care tailored to each patient based on their gene variants. Additionally, pharmacogenomics offers a solution to the opioid crisis by identifying potentially opioid-vulnerable patients who could be recommended a nonopioid treatment for their pain condition. The integration of pharmacogenomics into clinical practice creates better and safer healthcare practices for patients. In this article, we provide a comprehensive history of pharmacogenomics and pain management, and focus on up to date information on the pharmacogenomics of pain management, describing genes involved in pain, genes that may reduce or guard against pain and discuss specific pain management drugs and their genetic correlations.

PMID: 31308726 [PubMed]

Inconsistency in race and ethnic classification in pharmacogenetics studies and its potential clinical implications.

Pharmgenomics Pers Med. 2019;12:107-123

Authors: Zhang F, Finkelstein J

Abstract
Introduction: Racial and ethnic categories are frequently used in pharmacogenetics literature to stratify patients; however, these categories can be inconsistent across different studies. To address the ongoing debate on the applicability of traditional concepts of race and ethnicity in the context of precision medicine, we aimed to review the application of current racial and ethnic categories in pharmacogenetics and its potential impact on clinical care.
Methods: One hundred and three total pharmacogenetics papers involving the CYP2C9, CYP2C19, and CYP2D6 genes were analyzed for their country of origin, racial, and ethnic categories used, and allele frequency data. Correspondence between the major continental racial categories promulgated by National Institutes of Health (NIH) and those reported by the pharmacogenetics papers was evaluated.
Results: The racial and ethnic categories used in the papers we analyzed were highly heterogeneous. In total, we found 66 different racial and ethnic categories used which fall under the NIH race category "White", 47 different racial and ethnic categories for "Asian", and 62 different categories for "Black". The number of categories used varied widely based on country of origin: Japan used the highest number of different categories for "White" with 17, Malaysia used the highest number for "Asian" with 24, and the US used the highest number for "Black" with 28. Significant variation in allele frequency between different ethnic subgroups was identified within 3 major continental racial categories.
Conclusion: Our analysis showed that racial and ethnic classification is highly inconsistent across different papers as well as between different countries. Evidence-based consensus is necessary for optimal use of self-identified race as well as geographical ancestry in pharmacogenetics. Common taxonomy of geographical ancestry which reflects specifics of particular countries and is accepted by the entire scientific community can facilitate reproducible pharmacogenetic research and clinical implementation of its results.

PMID: 31308725 [PubMed]

Patient-reported outcomes in schizophrenia patients treated with once-monthly extended-release risperidone in a long-term clinical study.

Patient Prefer Adherence. 2019;13:1037-1050

Authors: Dhanda R, Varghese D, Nadipelli VR, Fava M, Joshi N, Solem CT, Graham JA, Learned SM, Heidbreder C

Abstract
Purpose: RBP-7000 (PERSERIS™) is a once-monthly subcutaneous extended-release risperidone formulation approved by the United States Food and Drug Administration for the treatment of schizophrenia in adults. The objective of this study was to describe the long-term impact of RBP-7000 on health-related quality of life (HRQoL), subjective well-being, treatment satisfaction and medication preference in patients with schizophrenia.
Patients and methods: HRQoL was derived from a 52-week multicentre Phase III single-arm open-label outpatient study that assessed the safety and efficacy of RBP-7000 (120 mg) in patients with schizophrenia. HRQoL was measured using the EuroQol EQ-5D-5L and Short-Form Survey SF-36 version 2; well-being using the Subjective Well-being Under Neuroleptic Treatment - Short Version (SWN-S); satisfaction using the Medication Satisfaction Questionnaire and medication preference using the Preference of Medication questionnaire.
Results: Of 482 participants at baseline, 234 remained through the end of study (EOS; week 52). Mean HRQoL and well-being scores remained stable between baseline (EQ-5D-5L index: 0.83; SF-36v2 Physical Component Score: 50; SF-36v2 Mental Component Score: 46; total SWN-S score: 89) and EOS (EQ-5D-5L index: 0.86; SF-36v2 Physical Component Score: 49; SF-36v2 Mental Component Score: 47; total SWN-S score: 90). The proportion of participants reporting satisfaction increased between week 4 (66%) and EOS (81%), with a similar trend for the preference of RBP-7000 over previous treatment (week 4: 66%; EOS: 72%). Sensitivity analyses suggested a minor effect of dropout on characterization of change over time in patient-reported outcomes (PRO) measures.
Conclusion: Study participants attained mean HRQoL scores near that of the general US population. Over two-thirds reported high satisfaction with and preference for RBP-7000 across the study period. Additional research is needed to confirm whether these PRO translate into improved outcomes such as adherence and ultimately fewer relapses in patients with schizophrenia.

PMID: 31308636 [PubMed]

Acid Sphingomyelinase - a Regulator of TRPC6 Channel Activity.

J Neurochem. 2019 Jul 16;:

Authors: Zeitler S, Ye L, Andreyeva A, Schumacher F, Monti J, Nürnberg B, Nowak G, Kleuser B, Reichel M, Fejtová A, Kornhuber J, Rhein C, Friedland K

Abstract
Recent investigations propose the acid sphingomyelinase (ASM)/ceramide system as a novel target for antidepressant action. ASM catalyzes the breakdown of the abundant membrane lipid sphingomyelin to the lipid messenger ceramide. This ASM-induced lipid modification induces a local shift in membrane properties, which influences receptor clustering and downstream signaling. Canonical transient receptor potential channels 6 (TRPC6) are non-selective cation channels located in the cell membrane that play an important role in dendritic growth, synaptic plasticity and cognition in the brain. They can be activated by hyperforin, an ingredient of the herbal remedy St. John's wort for treatment of depression disorders. Due to their role in the context of major depression, we investigated the crosstalk between the ASM/ceramide system and TRPC6 ion channels in a PC12 neuronal cell model (rat pheochromocytoma cell line). Ca2+ imaging experiments indicated that hyperforin-induced Ca2+ influx through TRPC6 channels is modulated by ASM activity. While antidepressants, known as functional inhibitors of ASM activity (FIASMAs), reduced TRPC6-mediated Ca2+ influx, extracellular application of bacterial sphingomyelinase rebalanced TRPC6 activity in a concentration-related way. This effect was confirmed in whole cell patch clamp electrophysiology recordings. Lipidomic analyses revealed a decrease in very long chain ceramide/sphingomyelin molar ratio after ASM inhibition, which was connected with changes in the abundance of TRPC6 channels in flotillin-1-positive lipid rafts as visualized by Western blotting. Our data provide evidence that the ASM/ceramide system regulates TRPC6 channels likely by controlling their recruitment to specific lipid subdomains and thereby fine-tuning their physical properties. This article is protected by copyright. All rights reserved.

PMID: 31310676 [PubMed - as supplied by publisher]

Management of adverse events associated with tyrosine kinase inhibitors: Improving outcomes for patients with hepatocellular carcinoma.

Cancer Treat Rev. 2019 Jul;77:20-28

Authors: Rimassa L, Danesi R, Pressiani T, Merle P

Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Sorafenib, regorafenib, lenvatinib and cabozantinib are tyrosine kinase inhibitors (TKIs) that target, in part, vascular endothelial growth factor receptors, and are approved in various regions of the world for the treatment of advanced HCC. All these agents are associated with a range of adverse events (AEs) that can have a substantial impact on patients' health-related quality of life. Fatigue, diarrhoea, hand-foot skin reaction, nausea, vomiting, decreased appetite, hypertension and weight loss are among the most common AEs experienced with these four TKIs. In this review, we discuss strategies for the management of these AEs in patients with advanced HCC, with the aim of maximizing treatment benefits and minimizing the need for TKI treatment discontinuation. We also consider potential TKI-drug interactions and discuss the use of TKIs in patients with liver dysfunction or who have experienced tumour recurrence after liver transplantation. Use of appropriate AE management strategies and avoidance of contraindicated drugs should help patients with advanced HCC to achieve optimal outcomes with TKIs.

PMID: 31195212 [PubMed - indexed for MEDLINE]

Going to the negative: genomics for optimized medical prescription.

Nat Rev Genet. 2019 01;20(1):1-2

Authors: Gibson G

Abstract
Personalized medicine promises to advance and improve health by targeting the right medication to the right person at the right time, thus maximizing the proportion of treated patients who achieve an effective response to therapy. This Comment article makes the complementary argument that equally important benefits will derive from negative prediction, namely by identifying those individuals who are either not actually in need of, or unlikely to respond to, a drug. Reduction of unnecessary prescription could conceivably save health-care systems many billions of dollars with very little detrimental impact on outcomes.

PMID: 30348998 [PubMed - indexed for MEDLINE]

Pharmacogenomics Clinical Annotation Tool (PharmCAT).

Clin Pharmacol Ther. 2019 Jul 15;:

Authors: Sangkuhl K, Whirl-Carrillo M, Whaley RM, Woon M, Lavertu A, Altman RB, Carter L, Verma A, Ritchie MD, Klein TE

Abstract
Pharmacogenomics (PGx) decision support and return of results is an active area of precision medicine. One challenge of implementing PGx is extracting genomic variants and assigning haplotypes in order to apply prescribing recommendations and information from CPIC, FDA, PharmGKB, etc. PharmCAT (1) extracts variants specified in guidelines from a genetic dataset derived from sequencing or genotyping technologies; (2) infers haplotypes and diplotypes; and (3) generates a report containing genotype/diplotype-based annotations and guideline recommendations. We describe PharmCAT and a pilot validation project comparing results for 1000 Genomes sequences of Coriell samples with corresponding Genetic Testing Reference Materials Coordination Program (GeT-RM) sample characterization. PharmCAT was highly concordant with the GeT-RM data. PharmCAT is available in GitHub to evaluate, test and report results back to the community. As precision medicine becomes more prevalent, our ability to consistently, accurately, and clearly define and report PGx annotations and prescribing recommendations is critical. This article is protected by copyright. All rights reserved.

PMID: 31306493 [PubMed - as supplied by publisher]

A pharmacokinetic and pharmacogenetic evaluation of contraceptive implants and antiretroviral therapy among women in Kenya and Uganda.

AIDS. 2019 Jul 10;:

Authors: Patel RC, Stalter RM, Thomas KK, Tamraz B, Blue SW, Erikson DW, Kim CJ, Kelley EJ, Nanda K, Kourtis AP, Lingappa JR, Mugo N, Baeten JM, Scarsi KK, Partners PrEP Study Team

Abstract
OBJECTIVES: To evaluate pharmacokinetics and pharmacogenetics of contraceptive implant progestin concentrations in HIV-positive women initiating efavirenz- or nevirapine-containing antiretroviral therapy (ART).
DESIGN: We analyzed stored samples from women self-reporting implant use in the Partners PrEP Study.
METHODS: Plasma samples collected every six months were analyzed for levonorgestrel and etonogestrel concentrations. Progestin concentrations from samples collected after ART initiation were compared to pre-ART concentrations for intraindividual comparisons. We used adjusted linear mixed models to compare hormone concentrations between individuals on efavirenz and nevirapine to a no ART group. We then evaluated whether possessing certain alleles with known or possible influences on efavirenz, nevirapine, or progestin metabolism were associated with changes in progestin concentrations or modified the association between ART use and progestin concentrations.
RESULTS: Our analysis included 11 women who initiated efavirenz, 13 who initiated nevirapine, and 36 who remained ART-naïve. In the efavirenz group, the adjusted geometric mean ratio (aGMR) of levonorgestrel was 0.39 (90% confidence intervals (0.31, 0.49); p < 0.001) and the etonogestrel aGMR was 0.51 (0.34, 0.76); p = 0.006) compared to the control group. No difference was observed in the nevirapine group compared to controls (levonorgestrel 0.93 (0.74, 1.18); p = 0.64; etonogestrel 1.07 (0.77, 1.50); p = 0.73). Possession of four allele variants were found to result in further reductions in progestin concentrations among those receiving efavirenz.
CONCLUSIONS: Concomitant use of efavirenz significantly reduces levonorgestrel or etonogestrel concentrations by 61% and 49%, respectively, compared to no ART use. We also report allelic variants in hepatic enzymes that influenced the extent of the observed drug-interaction between progestins and efavirenz.

PMID: 31306173 [PubMed - as supplied by publisher]

SNPs Within the MTOR Gene Are Associated With an Increased Risk of Developing De Novo Diabetes Mellitus Following the Administration of Everolimus in Liver Transplant Recipients.

Transplant Proc. 2019 Jul 11;:

Authors: Husen P, Straub K, Willuweit K, Hagemann A, Wedemeyer H, Bachmann HS, Herzer K

Abstract
BACKGROUND: The impact of immunosuppressive drugs in patients following liver transplantation (LT) is very individual. Despite the multiple beneficial effects of the mammalian target of rapamycin (mTOR) inhibitor everolimus (EVR) in LT recipients, some patients do not benefit from EVR administration. We investigated whether the presence of common single-nucleotide polymorphisms (SNPs) in the mTOR gene are predictive for adverse events following the introduction of EVR after LT.
MATERIALS AND METHODS: The feasibility and efficacy of EVR in 127 liver transplant recipients who were converted to EVR-based immunosuppression was documented retrospectively. Blood samples of these patients were analyzed for the occurrence of 4 SNPs in the mTOR promoter region (mTOR3099/rs2295079 C>G, mTOR3162/rs2295080 A>C) and the mTOR 3' untranslated regio (mTOR8167/rs12139042 C>T, mTOR8600/rs2536 A>G); the specific allele variants were also associated with the incidence of adverse events (AEs).
RESULTS: Of all patients, 21 (16.5%) did not tolerate the medication and had to discontinue. Of those patients who continued, 37% developed signs of reduced tolerance within the first 6 months, resolving after 12 months. When the cohort was divided according to genotype and allele frequency, patients with the mTOR3162/rs2295080 CC variant had a significantly higher risk (odds ratio = 5.89; 95% confidence interval = 1.48-23.40; P = .012) of developing new-onset diabetes mellitus following EVR treatment than AA or AC genotype carriers.
CONCLUSION: Our results suggest that the SNP mTOR3162/rs2295080 CC genotype is associated with the development of new-onset diabetes mellitus following EVR treatment.

PMID: 31303410 [PubMed - as supplied by publisher]

[Pharmacogenomics of sevoflurane: role in emergence delirium].

Rev Bras Anestesiol. 2019 Jul 11;:

Authors: Nair A

PMID: 31303310 [PubMed - as supplied by publisher]

Machine learning algorithm-based risk prediction model of coronary artery disease.

Mol Biol Rep. 2018 Oct;45(5):901-910

Authors: Naushad SM, Hussain T, Indumathi B, Samreen K, Alrokayan SA, Kutala VK

Abstract
In view of high mortality associated with coronary artery disease (CAD), development of an early predicting tool will be beneficial in reducing the burden of the disease. The database comprising demographic, conventional, folate/xenobiotic genetic risk factors of 648 subjects (364 cases of CAD and 284 healthy controls) was used as the basis to develop CAD risk and percentage stenosis prediction models using ensemble machine learning algorithms (EMLA), multifactor dimensionality reduction (MDR) and recursive partitioning (RP). The EMLA model showed better performance than other models in disease (89.3%) and stenosis prediction (82.5%). This model depicted hypertension and alcohol intake as the key predictors of CAD risk followed by cSHMT C1420T, GCPII C1561T, diabetes, GSTT1, CYP1A1 m2, TYMs 5'-UTR 28 bp tandem repeat and MTRR A66G. MDR and RP models are in agreement in projecting increasing age, hypertension and cSHMTC1420T as the key determinants interacting in modulating CAD risk. Receiver operating characteristic curves exhibited clinical utility of the developed models in the following order: EMLA (C = 0.96) > RP (C = 0.83) > MDR (C = 0.80). The stenosis prediction model showed that xenobiotic pathway genetic variants i.e. CYP1A1 m2 and GSTT1 are the key determinants of percentage of stenosis. Diabetes, diet, alcohol intake, hypertension and MTRR A66G are the other determinants of stenosis. These eleven variables contribute towards 82.5% stenosis. To conclude, the EMLA model exhibited higher predictability both in terms of disease prediction and stenosis prediction. This can be attributed to higher number of iterations in EMLA model that can increase the prediction accuracy.

PMID: 29995270 [PubMed - indexed for MEDLINE]

Beneficial Effects of Sideritis scardica and Cichorium spinosum against Amyloidogenic Pathway and Tau Misprocessing in Alzheimer's Disease Neuronal Cell Culture Models.

J Alzheimers Dis. 2018;64(3):787-800

Authors: Chalatsa I, Arvanitis DA, Mikropoulou EV, Giagini A, Papadopoulou-Daifoti Z, Aligiannis N, Halabalaki M, Tsarbopoulos A, Skaltsounis LA, Sanoudou D

Abstract
BACKGROUND: Natural products are a significantly underutilized source of potential treatments against human disease. Alzheimer's disease (AD) is a prime example of conditions that could be amenable to such treatments as suggested by recent findings.
OBJECTIVE: Aiming to identify novel potentially therapeutic approaches against AD, we assessed the effects of Cichorium spinosum and Sideritis scardica extracts, both distinct components of the Mediterranean diet.
METHODS/RESULTS: After the detailed characterization of the extracts' composition using LC-HRMS methods, they were evaluated on two AD neuronal cell culture models, namely the AβPP overexpressing SH-SY5Y-AβPP and the hyperphosphorylated tau expressing PC12-htau. Initially their effect on cell viability of SH-SY5Y and PC12 cells was examined, and subsequently their downstream effects on AβPP and tau processing pathways were investigated in the SH-SY5Y-AβPP and PC12-htau cells. We found that the S. scardica and C. spinosum extracts have similar effects on tau, as they both significantly decrease total tau, the activation of the GSK3β, ERK1 and/or ERK2 kinases of tau, as well as tau hyperphosphorylation. Furthermore, both extracts appear to promote AβPP processing through the alpha, non-amyloidogenic pathway, albeit through partly different mechanisms.
CONCLUSIONS: These findings suggest that C. spinosum and S. scardica could have a notable potential in the prevention and/or treatment of AD, and merit further investigations at the in vivo level.

PMID: 29914017 [PubMed - indexed for MEDLINE]