Pharmacogenomics
In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids of <em>Holarrhena pubescens</em> Wall. ex G. Don to Guanylyl Cyclase C: Implications in Designing of Novel Antidiarrheal Therapeutic Strategies
Molecules. 2021 Jul 8;26(14):4147. doi: 10.3390/molecules26144147.
ABSTRACT
The binding of heat stable enterotoxin (STa) secreted by enterotoxigenic Escherichia coli (ETEC) to the extracellular domain of guanylyl cyclase c (ECDGC-C) causes activation of a signaling cascade, which ultimately results in watery diarrhea. We carried out this study with the objective of finding ligands that would interfere with the binding of STa on ECDGC-C. With this view in mind, we tested the biological activity of a alkaloid rich fraction of Holarrhena pubescens against ETEC under in vitro conditions. Since this fraction showed significant antibacterial activity against ETEC, we decided to test the screen binding affinity of nine compounds of steroidal alkaloid type from Holarrhena pubescens against extracellular domain (ECD) by molecular docking and identified three compounds with significant binding energy. Molecular dynamics simulations were performed for all the three lead compounds to establish the stability of their interaction with the target protein. Pharmacokinetics and toxicity profiling of these leads demonstrated that they possessed good drug-like properties. Furthermore, the ability of these leads to inhibit the binding of STa to ECD was evaluated. This was first done by identifying amino acid residues of ECDGC-C binding to STa by protein-protein docking. The results were matched with our molecular docking results. We report here that holadysenterine, one of the lead compounds that showed a strong affinity for the amino acid residues on ECDGC-C, also binds to STa. This suggests that holadysenterine has the potential to inhibit binding of STa on ECD and can be considered for future study, involving its validation through in vitro assays and animal model studies.
PMID:34299422 | DOI:10.3390/molecules26144147
Performance Comparisons of AlexNet and GoogLeNet in Cell Growth Inhibition IC50 Prediction
Int J Mol Sci. 2021 Jul 19;22(14):7721. doi: 10.3390/ijms22147721.
ABSTRACT
Drug responses in cancer are diverse due to heterogenous genomic profiles. Drug responsiveness prediction is important in clinical response to specific cancer treatments. Recently, multi-class drug responsiveness models based on deep learning (DL) models using molecular fingerprints and mutation statuses have emerged. However, for multi-class models for drug responsiveness prediction, comparisons between convolution neural network (CNN) models (e.g., AlexNet and GoogLeNet) have not been performed. Therefore, in this study, we compared the two CNN models, GoogLeNet and AlexNet, along with the least absolute shrinkage and selection operator (LASSO) model as a baseline model. We constructed the models by taking drug molecular fingerprints of drugs and cell line mutation statuses, as input, to predict high-, intermediate-, and low-class for half-maximal inhibitory concentration (IC50) values of the drugs in the cancer cell lines. Additionally, we compared the models in breast cancer patients as well as in an independent gastric cancer cell line drug responsiveness data. We measured the model performance based on the area under receiver operating characteristic (ROC) curves (AUROC) value. In this study, we compared CNN models for multi-class drug responsiveness prediction. The AlexNet and GoogLeNet showed better performances in comparison to LASSO. Thus, DL models will be useful tools for precision oncology in terms of drug responsiveness prediction.
PMID:34299341 | DOI:10.3390/ijms22147721
Influence of Cannabinoid Receptor 1 Genetic Variants on the Subjective Effects of Smoked Cannabis
Int J Mol Sci. 2021 Jul 9;22(14):7388. doi: 10.3390/ijms22147388.
ABSTRACT
As many jurisdictions consider relaxing cannabis legislation and usage is increasing in North America and other parts of the world, there is a need to explore the possible genetic differences underlying the subjective effects of cannabis. This pilot study investigated specific genetic variations within the cannabinoid receptor 1 (CNR1) gene for association with the subjective effects of smoked cannabis. Data were obtained from a double-blinded, placebo-controlled clinical trial studying the impact of cannabis intoxication on driving performance. Participants randomized to the active cannabis group who consented to secondary genetic analysis (n = 52) were genotyped at the CNR1 rs1049353 and rs2023239 polymorphic areas. Maximum value and area under the curve (AUC) analyses were performed on subjective measures data. Analysis of subjective effects by genotype uncovered a global trend towards greater subjective effects for rs1049353 T-allele- and rs2023239 C-allele-carrying subjects. However, significant differences attributed to allelic identity were only documented for a subset of subjective effects. Our findings suggest that rs1049353 and rs2023239 minor allele carriers experience augmented subjective effects during acute cannabis intoxication.
PMID:34299009 | DOI:10.3390/ijms22147388
Disease Differentiation and Monitoring of Anti-TNF Treatment in Rheumatoid Arthritis and Spondyloarthropathies
Int J Mol Sci. 2021 Jul 9;22(14):7389. doi: 10.3390/ijms22147389.
ABSTRACT
Rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) are comprehensive immunological disorders. The treatment of these disorders is limited to ameliorating the symptoms and improving the quality of life of patients. In this study, serum samples from RA, AS, and PsA patients were analyzed with metabolomic tools employing the 1H NMR method in combination with univariate and multivariate analyses. The results obtained in this study showed that the changes in metabolites were the highest for AS > RA > PsA. The study demonstrated that the time until remission or until low disease activity is achieved is shortest (approximately three months) for AS, longer for RA and longest for PsA. The statistically common metabolite that was found to be negatively correlated with the healing processes of these disorders is ethanol, which may indicate the involvement of the gut microflora and/or the breakdown of malondialdehyde as a cell membrane lipid peroxide product.
PMID:34299006 | DOI:10.3390/ijms22147389
Contribution of "Omic" Studies to the Understanding of Cadasil. A Systematic Review
Int J Mol Sci. 2021 Jul 8;22(14):7357. doi: 10.3390/ijms22147357.
ABSTRACT
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor β (TGFβ) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets.
PMID:34298974 | DOI:10.3390/ijms22147357
Developmental Pharmacogenetics of CYP2D6 in Chinese Children: Loratadine as a Substrate Drug
Front Pharmacol. 2021 Jul 6;12:657287. doi: 10.3389/fphar.2021.657287. eCollection 2021.
ABSTRACT
Objective: The elucidation of CYP2D6 developmental pharmacogenetics in children has improved, however, these findings have been largely limited to studies of Caucasian children. Given the clear differences in CYP2D6 pharmacogenetic profiles in people of different ancestries, there remains an unmet need to better understand the developmental pharmacogenetics in populations of different ancestries. We sought to use loratadine as a substrate drug to evaluate the effects of ontogeny and pharmacogenetics on the developmental pattern of CYP2D6 in Chinese pediatric patients. Methods: Chinese children receiving loratadine treatment were enrolled in the present study. The metabolite-to-parent ratio (M/P ratio), defined as the molar ratio of desloratadine to loratadine of trough concentrations samples at steady-state condition, was used as a surrogate of CYP2D6 activity. Loratadine and desloratadine were determined by LC/MS/MS method. Variants of CYP2D6 were genotyped by polymerase chain reaction for CYP2D6 *4, *10, *41 and long polymerase chain reaction for CYP2D6 *5. Results: A total of 40 patients were available for final analysis. The mean age was 4.50 (range 0.50-9.00) years and the mean weight was 19.64 (range 7.00-42.00) kg. The M/P ratio was significantly lower in intermediate metabolizers (IMs) compared to normal metabolizers (NMs) (10.18 ± 7.97 vs. 18.80 ± 15.83, p = 0.03). Weight was also found to be significantly associated with M/P ratio (p = 0.03). Conclusion: The developmental pharmacogenetics of CYP2D6 in Chinese children was evaluated using loratadine as a substrate drug. This study emphasizes the importance of evaluating the developmental pharmacogenetics in populations of different ancestries.
PMID:34295246 | PMC:PMC8292113 | DOI:10.3389/fphar.2021.657287
Metabolomic signatures associated with depression and predictors of antidepressant response in humans: A CAN-BIND-1 report
Commun Biol. 2021 Jul 22;4(1):903. doi: 10.1038/s42003-021-02421-6.
ABSTRACT
One of the biggest challenges in treating depression is the heterogeneous and qualitative nature of its clinical presentations. This highlights the need to find quantitative molecular markers to tailor existing treatment strategies to the individual's biological system. In this study, high-resolution metabolic phenotyping of urine and plasma samples from the CAN-BIND study collected before treatment with two common pharmacological strategies, escitalopram and aripiprazole, was performed. Here we show that a panel of LDL and HDL subfractions were negatively correlated with depression in males. For treatment response, lower baseline concentrations of apolipoprotein A1 and HDL were predictive of escitalopram response in males, while higher baseline concentrations of apolipoprotein A2, HDL and VLDL subfractions were predictive of aripiprazole response in females. These findings support the potential of metabolomics in precision medicine and the possibility of identifying personalized interventions for depression.
PMID:34294869 | DOI:10.1038/s42003-021-02421-6
Magnetic Resonance Imaging is a valuable tool to evaluate the therapeutic efficacy of burosumab in children with X-linked hypophosphatemia
Eur J Endocrinol. 2021 Jul 1:EJE-21-0429.R1. doi: 10.1530/EJE-21-0429. Online ahead of print.
ABSTRACT
PURPOSE: to examine the MRI diagnostic performance in assessment of therapeutic response to burosumab in children with X-linked hypophosphatemia (XLH).
DESIGN: prospective longitudinal open cohort.
PATIENTS: 17 children with XLH, average age of 10.2±2.7 years, had a knee MRI at baseline and after one year of burosumab.
INTERVENTION: Children received burosumab at average dose of 1.4±0.5 mg/kg during one year for the treatment of severe rickets [the target serum phosphate >1.2 mmol/l (>3.7 mg/dl)]. The primary endpoint was the change from baseline to 12 months in rachitic lesions on knee MRI. Secondary endpoints were changes in biochemical parameters of phosphate and alkaline phosphatase (ALP).
RESULTS: One year of treatment with burosumab significantly reduced radiological disease activity on knee MRI (by 44±29% in transverse extent of widening) which was accompanied by a significant reduction in biochemical activity, namely in serum ALP activity, by 28±17%. Additionally, MRI parameters after one year of treatment with burosumab (the maximum width of medial physis at 12 months and the change from baseline in the maximum width of lateral physis) were associated with ALP activity at 12 months.
CONCLUSION: We suggest that MRI is a valuable and quantitative tool to evaluate the therapeutic response to burosumab. MRI could be an excellent alternative to standard bone radiographs for evaluation of the rachitic lesions in clinical setting avoiding repeated exposition to ionizing radiation. Number of registration with ClinicalTrials.gov: NCT04419363, https://clinicaltrials.gov/ct2/show/NCT04419363.
PMID:34292170 | DOI:10.1530/EJE-21-0429
Toward predicting CYP2D6-mediated variable drug response from <em>CYP2D6</em> gene sequencing data
Sci Transl Med. 2021 Jul 21;13(603):eabf3637. doi: 10.1126/scitranslmed.abf3637.
ABSTRACT
Pharmacogenomics is a key component of personalized medicine that promises safer and more effective drug treatment by individualizing drug choice and dose based on genetic profiles. In clinical practice, genetic biomarkers are used to categorize patients into *-alleles to predict CYP450 enzyme activity and adjust drug dosages accordingly. However, this approach leaves a large part of variability in drug response unexplained. Here, we present a proof-of-concept approach that uses continuous-scale (instead of categorical) assignments to predict enzyme activity. We used full CYP2D6 gene sequences obtained with long-read amplicon-based sequencing and cytochrome P450 (CYP) 2D6-mediated tamoxifen metabolism data from a prospective study of 561 patients with breast cancer to train a neural network. The model explained 79% of interindividual variability in CYP2D6 activity compared to 54% with the conventional *-allele approach, assigned enzyme activities to known alleles with previously reported effects, and predicted the activity of previously uncharacterized combinations of variants. The results were replicated in an independent cohort of tamoxifen-treated patients (model R 2 adjusted = 0.66 versus *-allele R 2 adjusted = 0.35) and a cohort of patients treated with the CYP2D6 substrate venlafaxine (model R 2 adjusted = 0.64 versus *-allele R 2 adjusted = 0.55). Human embryonic kidney cells were used to confirm the effect of five genetic variants on metabolism of the CYP2D6 substrate bufuralol in vitro. These results demonstrate the advantage of a continuous scale and a completely phased genotype for prediction of CYP2D6 enzyme activity and could potentially enable more accurate prediction of individual drug response.
PMID:34290055 | DOI:10.1126/scitranslmed.abf3637
Genistein as a regulator of signaling pathways and microRNAs in different types of cancers
Cancer Cell Int. 2021 Jul 21;21(1):388. doi: 10.1186/s12935-021-02091-8.
ABSTRACT
Cancers are complex diseases orchestrated by a plethora of extrinsic and intrinsic factors. Research spanning over several decades has provided better understanding of complex molecular interactions responsible for the multifaceted nature of cancer. Recent advances in the field of next generation sequencing and functional genomics have brought us closer towards unravelling the complexities of tumor microenvironment (tumor heterogeneity) and deregulated signaling cascades responsible for proliferation and survival of tumor cells. Phytochemicals have begun to emerge as potent beneficial substances aimed to target deregulated signaling pathways. Isoflavonoid genistein is an essential phytochemical involved in regulation of key biological processes including those in different types of cancer. Emerging preclinical evidence have shown its anti-cancer, anti-inflammatory and anti-oxidant properties. Testing of this substance is in various phases of clinical trials. Comprehensive preclinical and clinical trials data is providing insight on genistein as a modulator of various signaling pathways both at transcription and translation levels. In this review we have explained the mechanistic regulation of several key cellular pathways by genistein. We have also addressed in detail various microRNAs regulated by genistein in different types of cancer. Moreover, application of nano-formulations to increase the efficiency of genistein is also discussed. Understanding the pleiotropic potential of genistein to regulate key cellular pathways and development of efficient drug delivery system will bring us a step towards designing better chemotherapeutics.
PMID:34289845 | DOI:10.1186/s12935-021-02091-8
Patient-led Remote IntraCapillary pharmacoKinetic Sampling (fingerPRICKS) for therapeutic drug monitoring in patients with inflammatory bowel disease
J Crohns Colitis. 2021 Jul 21:jjab128. doi: 10.1093/ecco-jcc/jjab128. Online ahead of print.
ABSTRACT
BACKGROUND & AIMS: Because of COVID-19 public health restrictions, telemedicine has replaced conventional outpatient follow up for most patients with chronic immune-mediated inflammatory disorders treated with biologic drugs. Innovative solutions to facilitate remote therapeutic drug monitoring are therefore required. Low-volume intracapillary blood sampling can be undertaken by patients at home and samples returned by post to central laboratories. We sought to report the effect of the COVID-19 pandemic on requests for therapeutic drug monitoring and the equivalence, acceptability and effectiveness of low volume Patient-led Remote IntraCapillary pharmacoKinetic Sampling (fingerPRICKS) compared to conventional venepuncture.
METHODS: We undertook a cross-sectional blood sampling methods comparison study and compared sample types using linear regression models. Drug and antidrug antibody levels were measured using standard ELISAs. Acceptability was assessed using a purpose-designed questionnaire.
RESULTS: Therapeutic drug monitoring requests for adalimumab (96.5 [70.5 - 106] per week to 52 [33.5 - 57.0], p < 0.001) but not infliximab (184.5 [161.2 - 214.2] to 161 [135 - 197.5], p = 0.34) reduced during the first UK stay-at-home lockdown compared with the preceding six months.Fingerprick sampling was equivalent to conventional venepuncture for adalimumab, infliximab, vedolizumab, and ustekinumab drug, and anti-adalimumab and -infliximab antibody levels. The median (IQR) volume of serum obtained using intracapillary sampling was 195µL (130-210). More than 87% (90/103) patients agreed that intracapillary testing was easy and 69% (71/103) preferred it to conventional venepuncture.In routine care, 75.3% (58/77) patients returned two blood samples within 14 days to permit remote assessment of biologic therapeutic drug monitoring.
CONCLUSIONS: Therapeutic drug monitoring can be undertaken using patient-led remote intracapillary blood sampling and has the potential to be a key adjunct to telemedicine in patients with immune-mediated inflammatory diseases.
PMID:34289028 | DOI:10.1093/ecco-jcc/jjab128
Pharmacogenomics in Older Adults: An Integrative Review
Res Gerontol Nurs. 2021 Jul-Aug;14(4):211-220. doi: 10.3928/19404921-20210428-01. Epub 2021 May 19.
ABSTRACT
Through pharmacogenomics testing, identifying genetic variants that influence how individuals respond to medications could potentially decrease the "trial and error" approach to prescribing medications, maximize beneficial effects, and reduce risks of adverse drug events. Yet, pharmacogenomics testing is still subject to an ongoing debate over its clinical validity and utility. The purpose of the current integrative review was to examine and synthesize evidence on the clinical application of pharmacogenomics in medication management among older adults. Gaps were found, such as lack of studies investigating the prospective use of pharmacogenomics testing to improve clinical outcomes and lack of strong evidence on the clinical validity and utility of pharmacogenomics testing in the medication management of older adults. However, the review identified evidence for the potential benefits of pharmacogenomics testing to improve older adults' clinical outcomes that warrant further investigation. [Research in Gerontological Nursing, 14(4), 211-220.].
PMID:34288783 | DOI:10.3928/19404921-20210428-01
Thiopurine pharmacogenomics and pregnancy in inflammatory bowel disease
J Gastroenterol. 2021 Jul 21. doi: 10.1007/s00535-021-01805-z. Online ahead of print.
ABSTRACT
The thiopurine drugs azathioprine and 6-mercaptopurine are widely used for the maintenance of clinical remission in steroid-dependent inflammatory bowel disease (IBD). Thiopurines are recommended to be continued throughout pregnancy in IBD patients, but conclusive safety data in pregnant patients remain still insufficient. On the other hand, a strong association between a genetic variant of nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15 p.Arg139Cys) and thiopurine-induced myelotoxicity has been identified. Pharmacokinetic studies have revealed that thiopurine metabolism is altered in pregnant IBD patients and suggested that the fetus may be exposed to the active-thiopurine metabolite, 6-thioguaninetriphosphate, in the uterus. A recent study using knock-in mice harboring the p.Arg138Cys mutation which corresponds to human p.Arg139Cys showed that oral administration of 6-MP at clinical dose induces a severe toxic effect on the fetus harboring the homozygous or heterozygous risk allele. This suggests that NUDT15 genotyping may be required in both women with IBD who are planning pregnancy (or pregnant) and their partner to avoid adverse outcomes for their infant. The risk to the fetus due to maternal thiopurine use is minimal but there are some concerns that are yet to be clarified. In particular, a pharmacogenomic approach to the fetus is considered necessary.
PMID:34287682 | DOI:10.1007/s00535-021-01805-z
Research into ageing and frailty
Future Healthc J. 2021 Jul;8(2):e237-e242. doi: 10.7861/fhj.2021-0088.
ABSTRACT
Research into ageing covers opportunities and challenges posed by an older population, and research to understand the ageing processes across the lifespan. The evidence base for Comprehensive Geriatric Assessment (CGA) is well established and efforts should now shift to understanding how to implement its principles across different healthcare contexts. Research around syndromes common in older people has progressed with variable success; while effective therapies for falls and cognitive impairment have been identified, older people with advanced frailty have commonly been excluded from Parkinson's disease and continence research. Research to understand the mechanisms of ageing has potential to mitigate against or treat emerging sarcopenia and cognitive impairment, and thus modify frailty trajectories. Pharmacogenetics could individualise therapeutics to reduce polypharmacy. These issues can only be addressed with development of infrastructure, capacity and expertise in ageing research. Commonly used research methodologies must be adapted to take account of frailty, cognitive impairment and functional dependency.
PMID:34286191 | PMC:PMC8285138 | DOI:10.7861/fhj.2021-0088
Tabula Rasa HealthCare company profile: involvement on pharmacogenomic and personalized medicine research
Pharmacogenomics. 2021 Jul 21. doi: 10.2217/pgs-2021-0085. Online ahead of print.
NO ABSTRACT
PMID:34284600 | DOI:10.2217/pgs-2021-0085
Personal DNA Testing Increases Pharmacy Students' Confidence and Competence in Pharmacogenomics
Am J Pharm Educ. 2021 Apr;85(4):8249. doi: 10.5688/ajpe8249. Epub 2020 Dec 31.
ABSTRACT
Objective. Pharmacogenomics, a key tool in personalized medicine, and therapeutic drug management is projected to become an integral part of pharmacy practice. This study describes an innovative pedagogy that used several interactive learning methods to increase learners' competence and perceptions in pharmacogenomics.Methods. First-year student pharmacists at the Medical College of Wisconsin participated in lectures, discussions, and patient care laboratory training on the topic of pharmacogenomics. These students were given the opportunity to undergo personal pharmacogenomics testing. Before and after these activities, participants were surveyed about their attitudes towards the use of pharmacogenomics in current and future practice.Results. Forty-five students participated in this voluntary personal pharmacogenomics testing and completed pre-course and post-course surveys. Significant improvements were seen in 22 of the 27 surveys questions responses from the pre-course to the post-course surveys. Student learning outcomes, competencies, and attitudes towards pharmacogenomics improved from a relatively neutral perception of pharmacogenomics to one of more confidence.Conclusion. This study demonstrated that participation in a novel pedagogy that included voluntarily individual pharmacogenomics testing was beneficial to student pharmacists by improving knowledge, interest, and confidence in pharmacogenomics and its incorporation into their future pharmacy practice.
PMID:34283790 | DOI:10.5688/ajpe8249
Advanced Pharmacy Practice Experiences in Pharmacogenomics Offered by US Pharmacy Programs
Am J Pharm Educ. 2020 Dec;84(12):ajpe8031. doi: 10.5688/ajpe8031. Epub 2020 Oct 2.
ABSTRACT
Objective. To characterize advanced pharmacy practice experiences (APPEs) with a primary focus in pharmacogenomics at schools and colleges of pharmacy in the United States.Methods. This was a cross-sectional, multicenter, observational study of pharmacogenomics APPEs at US pharmacy schools. Directors of experiential education at 146 accredited schools of pharmacy were contacted by phone and asked if their school offered a pharmacogenomics APPE. The preceptors of pharmacogenomics APPEs identified by this phone screen were sent an email with a link to an online survey that asked about their APPE offerings.Results. Of the 142 schools of pharmacy that were successfully reached via phone, 40 (28%) offered an APPE with a primary focus in pharmacogenomics. Thirty unique APPEs with pharmacogenomics as a primary focus were identified. The total number of preceptors involved in the pharmacogenomics APPEs was 33: 19 (58%) faculty preceptors and 14 (42%) non-faculty preceptors. Twenty-three of the 30 pharmacogenomics APPEs completed the survey (77% response rate). The APPE sites were diverse and included academic medical centers, community health systems, pharmacogenomic testing laboratories, and schools of pharmacy. Each pharmacogenomics APPE accommodated an average of six students per year. The APPE activities varied across sites.Conclusion. Only a small number of US pharmacy schools offer an APPE with a primary focus in pharmacogenomics. These rotations are diverse in scope and precepted by faculty or non-faculty pharmacists. The Academy should pursue opportunities to increase experiential education in pharmacogenomics.
PMID:34283786 | DOI:10.5688/ajpe8031
Multisite investigation of strategies for the clinical implementation of pre-emptive pharmacogenetic testing
Genet Med. 2021 Jul 19. doi: 10.1038/s41436-021-01269-9. Online ahead of print.
ABSTRACT
PURPOSE: The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Pre-emptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear.
METHODS: In this report, we compare and contrast implementation strategies for pre-emptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates.
RESULTS: We found that while pre-emptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Finally, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for pre-emptive PGx testing remain low.
CONCLUSION: These findings should inform the establishment of future implementation efforts at institutions considering a pre-emptive PGx testing program.
PMID:34282303 | DOI:10.1038/s41436-021-01269-9
Resistance to platinum-based cancer drugs: a special focus on epigenetic mechanisms
Pharmacogenomics. 2021 Jul 20. doi: 10.2217/pgs-2021-0020. Online ahead of print.
ABSTRACT
Chemoresistance is a significant clinical challenge, limiting the drug response in cancer. Several mechanisms associated with drug resistance have been characterized, and the role of epigenetics in generating resistance to platinum-based drugs has been clarified. Epigenetic mechanisms such as DNA methylation, histone modification, long noncoding RNA, and microRNA affect the expression of genes implicated in absorption, distribution, metabolism and excretion (ADME) of drugs, and other non-ADME genes that encode enzymes involved in the processes of cell proliferation, DNA repair, apoptosis and signal transduction key in the development of chemoresistance in cancer, specifically in platinum-based drugs. This review summarizes current discoveries in epigenetic regulation implicated in platinum drug resistance in cancer and the main clinical trials based on epigenetic therapy, evaluating their potential synergy with platinum-based drugs.
PMID:34281355 | DOI:10.2217/pgs-2021-0020
A Systematic Review of Parkinson's Disease Pharmacogenomics: Is There Time for Translation into the Clinics?
Int J Mol Sci. 2021 Jul 5;22(13):7213. doi: 10.3390/ijms22137213.
ABSTRACT
BACKGROUND: Parkinson's disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson's disease.
METHODS: We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson's disease treatment, along with a manual search, and finally included a total of 116 publications in the review.
RESULTS: We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings.
CONCLUSIONS: This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient.
PMID:34281267 | DOI:10.3390/ijms22137213