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International Journal of Molecular... Aug 2023Improper drug prescription is a main cause of both drug-related harms (inefficacy and toxicity) and ineffective spending and waste of the healthcare system's resources....
Improper drug prescription is a main cause of both drug-related harms (inefficacy and toxicity) and ineffective spending and waste of the healthcare system's resources. Nowadays, strategies to support an improved, informed prescription process may benefit from the adequate use of pharmacogenomic testing. Using next-generation sequencing, we analyzed the genomic profile for three major cytochromes P450 (CYP2C9, CYP2C19, CYP2D6) and studied the frequencies of dysfunctional isozymes (e.g., poor, intermediate, or rapid/ultra-rapid metabolizers) in a cohort of 298 Italian subjects. We found just 14.8% of subjects with a fully normal set of cytochromes, whereas 26.5% of subjects had combined cytochrome dysfunction (more than one isozyme involved). As improper drug prescription is more frequent, and more burdening, in polytreated patients, since drug-drug interactions also cause patient harm, we discuss the potential benefits of a more comprehensive PGX testing approach to support informed drug selection in such patients.
Topics: Humans; Cytochrome P-450 CYP2C9; Drug Prescriptions; Cytochrome P-450 CYP2D6; Genetic Profile; High-Throughput Nucleotide Sequencing
PubMed: 37628884
DOI: 10.3390/ijms241612696 -
Pharmacy (Basel, Switzerland) Aug 2023There is a paucity of evidence to inform the value of pharmacogenomic (PGx) results in patients after kidney transplant and how these results differ between Indigenous...
BACKGROUND
There is a paucity of evidence to inform the value of pharmacogenomic (PGx) results in patients after kidney transplant and how these results differ between Indigenous Americans and Whites. This study aims to identify the frequency of recommended medication changes based on PGx results and compare the pharmacogenomic (PGx) results and patients' perceptions of the findings between a cohort of Indigenous American and White kidney transplant recipients.
METHODS
Thirty-one Indigenous Americans and fifty White kidney transplant recipients were studied prospectively. Genetic variants were identified using the OneOme RightMed PGx test of 27 genes. PGx pharmacist generated a report of the genetic variation and recommended changes. Pre- and post-qualitative patient surveys were obtained.
RESULTS
White and Indigenous American subjects had a similar mean number of medications at the time of PGx testing (mean 13 (SD 4.5)). In the entire cohort, 53% received beta blockers, 30% received antidepressants, 16% anticoagulation, 47% pain medication, and 25% statin therapy. Drug-gene interactions that warranted a clinical action were present in 21.5% of patients. In 12.7%, monitoring was recommended. Compared to the Whites, the Indigenous American patients had more normal CYP2C19 ( = 0.012) and CYP2D6 ( = 0.012) activities. The Indigenous American patients had more normal CYP4F2 ( = 0.004) and lower VKORC ( = 0.041) activities, phenotypes for warfarin drug dosing, and efficacy compared to the Whites. SLC6A4, which affects antidepressant metabolism, showed statistical differences between the two cohorts ( = 0.017); specifically, SLC6A4 had reduced expression in 45% of the Indigenous American patients compared to 20% of the White patients. There was no significant difference in patient perception before and after PGx.
CONCLUSIONS
Kidney transplant recipients had several drug-gene interactions that were clinically actionable; over one-third of patients were likely to benefit from changes in medications or drug doses based on the PGx results. The Indigenous American patients differed in the expression of drug-metabolizing enzymes and drug transporters from the White patients.
PubMed: 37624080
DOI: 10.3390/pharmacy11040125 -
BioRxiv : the Preprint Server For... Aug 2023Hantaviruses - dichotomized into New World (i.e. Andes virus, ANDV; Sin Nombre virus, SNV) and Old-World viruses (i.e. Hantaan virus, HTNV) - are zoonotic viruses...
BACKGROUND
Hantaviruses - dichotomized into New World (i.e. Andes virus, ANDV; Sin Nombre virus, SNV) and Old-World viruses (i.e. Hantaan virus, HTNV) - are zoonotic viruses transmitted from rodents to humans. Currently, no FDA-approved vaccines against hantaviruses exist. Given the recent breakthrough to human-human transmission by the ANDV, an essential step is to establish an effective pandemic preparedness infrastructure to rapidly identify cell tropism, infective potential, and effective therapeutic agents through systematic investigation.
METHODS
We established human cell model systems in lung (airway and distal lung epithelial cells), heart (pluripotent stem cell-derived (PSC-) cardiomyocytes), and brain (PSC-astrocytes) cell types and subsequently evaluated ANDV, HTNV and SNV tropisms. Transcriptomic, lipidomic and bioinformatic data analyses were performed to identify the molecular pathogenic mechanisms of viruses in different cell types. This cell-based infection system was utilized to establish a drug testing platform and pharmacogenomic comparisons.
RESULTS
ANDV showed broad tropism for all cell types assessed. HTNV replication was predominantly observed in heart and brain cells. ANDV efficiently replicated in human and mouse 3D distal lung organoids. Transcriptomic analysis showed that ANDV infection resulted in pronounced inflammatory response and downregulation of cholesterol biosynthesis pathway in lung cells. Lipidomic profiling revealed that ANDV-infected cells showed reduced level of cholesterol esters and triglycerides. Further analysis of pathway-based molecular signatures showed that, compared to SNV and HTNV, ANDV infection caused drastic lung cell injury responses. A selective drug screening identified STING agonists, nucleoside analogues and plant-derived compounds that inhibited ANDV viral infection and rescued cellular metabolism. In line with experimental results, transcriptome data shows that the least number of total and unique differentially expressed genes were identified in urolithin B- and favipiravir-treated cells, confirming the higher efficiency of these two drugs in inhibiting ANDV, resulting in host cell ability to balance gene expression to establish proper cell functioning.
CONCLUSIONS
Overall, our study describes advanced human PSC-derived model systems and systems-level transcriptomics and lipidomic data to better understand Old and New World hantaviral tropism, as well as drug candidates that can be further assessed for potential rapid deployment in the event of a pandemic.
PubMed: 37577539
DOI: 10.1101/2023.08.04.552083 -
Pharmacogenomic testing for antidepressant treatment selection: lessons learned and roadmap forward.Neuropsychopharmacology : Official... Jan 2024Pharmacogenomic technology is a developing field with enthusiastic interest and broad application potential. Three large, controlled studies have been published... (Review)
Review
Pharmacogenomic technology is a developing field with enthusiastic interest and broad application potential. Three large, controlled studies have been published exploring the benefit of pharmacogenomically guided antidepressant treatment selection. Though all three studies did not show significant benefit of using this technology, these studies laid the foundation for further research that should address the limitations of this previous research and currently available commercial platforms. Future research needs to include large scale pharmacogenomic trials with GWAS analytics across diverse groups with attention to cost-effectiveness models, particularly for cases of treatment resistance and polypharmacy. The application of results from these large scale pharmacogenomic trials must also include exploring optimal EHR user interface design.
Topics: Pharmacogenomic Testing; Pharmacogenetics; Antidepressive Agents; Research Design
PubMed: 37550439
DOI: 10.1038/s41386-023-01667-4 -
JAMA Network Open Jul 2023Although the clinical utility of genome sequencing for critically ill children is well recognized, its utility for proactive pediatric screening is not well explored.
IMPORTANCE
Although the clinical utility of genome sequencing for critically ill children is well recognized, its utility for proactive pediatric screening is not well explored.
OBJECTIVE
To evaluate molecular findings from screening ostensibly healthy children with genome sequencing compared with a gene panel for medically actionable pediatric conditions.
DESIGN, SETTING, AND PARTICIPANTS
This case series study was conducted among consecutive, apparently healthy children undergoing proactive genetic screening for pediatric disorders by genome sequencing (n = 562) or an exome-based panel of 268 genes (n = 606) from March 1, 2018, through July 31, 2022.
EXPOSURES
Genetic screening for pediatric-onset disorders using genome sequencing or an exome-based panel of 268 genes.
MAIN OUTCOMES AND MEASURES
Molecular findings indicative of genetic disease risk.
RESULTS
Of 562 apparently healthy children (286 girls [50.9%]; median age, 29 days [IQR, 9-117 days]) undergoing screening by genome sequencing, 46 (8.2%; 95% CI, 5.9%-10.5%) were found to be at risk for pediatric-onset disease, including 22 children (3.9%) at risk for high-penetrance disorders. Sequence analysis uncovered molecular diagnoses among 32 individuals (5.7%), while copy number variant analysis uncovered molecular diagnoses among 14 individuals (2.5%), including 4 individuals (0.7%) with chromosome scale abnormalities. Overall, there were 47 molecular diagnoses, with 1 individual receiving 2 diagnoses; of the 47 potential diagnoses, 22 (46.8%) were associated with high-penetrance conditions. Pathogenic variants in medically actionable pediatric genes were found in 6 individuals (1.1%), constituting 12.8% (6 of 47) of all diagnoses. At least 1 pharmacogenomic variant was reported for 89.0% (500 of 562) of the cohort. In contrast, of 606 children (293 girls [48.3%]; median age, 26 days [IQR, 10-67 days]) undergoing gene panel screening, only 13 (2.1%; 95% CI, 1.0%-3.3%) resulted in potential childhood-onset diagnoses, a significantly lower rate than those screened by genome sequencing (P < .001).
CONCLUSIONS AND RELEVANCE
In this case series study, genome sequencing as a proactive screening approach for children, due to its unrestrictive gene content and technical advantages in comparison with an exome-based gene panel for medically actionable childhood conditions, uncovered a wide range of heterogeneous high-penetrance pediatric conditions that could guide early interventions and medical management.
Topics: Female; Child; Humans; Infant, Newborn; Genetic Testing; Genomics; Penetrance; Exome
PubMed: 37523181
DOI: 10.1001/jamanetworkopen.2023.26445 -
Journal of Experimental & Clinical... Jul 2023Approximately 20-50% of patients presenting with localized colorectal cancer progress to stage IV metastatic disease (mCRC) following initial treatment and this is a...
BACKGROUND
Approximately 20-50% of patients presenting with localized colorectal cancer progress to stage IV metastatic disease (mCRC) following initial treatment and this is a major prognostic determinant. Here, we have interrogated a heterogeneous set of primary colorectal cancer (CRC), liver CRC metastases and adjacent liver tissue to identify molecular determinants of the colon to liver spreading. Screening Food and Drug Administration (FDA) approved drugs for their ability to interfere with an identified colon to liver metastasis signature may help filling an unmet therapeutic need.
METHODS
RNA sequencing of primary colorectal cancer specimens vs adjacent liver tissue vs synchronous and asynchronous liver metastases. Pathways enrichment analyses. The Library of Integrated Network-based Cellular Signatures (LINCS)-based and Connectivity Map (CMAP)-mediated identification of FDA-approved compounds capable to interfere with a 22 gene signature from primary CRC and liver metastases. Testing the identified compounds on CRC-Patient Derived Organoid (PDO) cultures. Microscopy and Fluorescence Activated Cell Sorting (FACS) based analysis of the treated PDOs.
RESULTS
We have found that liver metastases acquire features of the adjacent liver tissue while partially losing those of the primary tumors they derived from. We have identified a 22-gene signature differentially expressed among primary tumors and metastases and validated in public databases. A pharmacogenomic screening for FDA-approved compounds capable of interfering with this signature has been performed. We have validated some of the identified representative compounds in CRC-Patient Derived Organoid cultures (PDOs) and found that pentoxyfilline and, to a minor extent, dexketoprofen and desloratadine, can variably interfere with number, size and viability of the CRC -PDOs in a patient-specific way. We explored the pentoxifylline mechanism of action and found that pentoxifylline treatment attenuated the 5-FU elicited increase of ALDHhigh cells by attenuating the IL-6 mediated STAT3 (tyr705) phosphorylation.
CONCLUSIONS
Pentoxifylline synergizes with 5-Fluorouracil (5-FU) in attenuating organoid formation. It does so by interfering with an IL-6-STAT3 axis leading to the emergence of chemoresistant ALDHhigh cell subpopulations in 5-FU treated PDOs. A larger cohort of CRC-PDOs will be required to validate and expand on the findings of this proof-of-concept study.
Topics: Humans; Colorectal Neoplasms; Interleukin-6; Pentoxifylline; Fluorouracil; Liver Neoplasms; Organoids
PubMed: 37460938
DOI: 10.1186/s13046-023-02754-6 -
Pharmacogenomics Jul 2023To understand how attitudes toward pharmacogenomic (PGx) testing among healthcare providers varies by specialty. Providers reported comfort ordering PGx testing and...
To understand how attitudes toward pharmacogenomic (PGx) testing among healthcare providers varies by specialty. Providers reported comfort ordering PGx testing and its perceived utility on web-based surveys before and after genetics education. Primary quantitative analyses compared primary care providers (PCPs) to specialty providers at both timepoints. PCPs were more likely than specialty care providers to rate PGx testing as useful at both timepoints. Education increased comfort ordering PGx tests, with larger improvements among PCPs than specialty providers. Over 90% of cardiology and internal medicine providers rated PGx testing as useful at pre- and post-education. PCPs overwhelmingly perceive PGx to be useful, and provider education is particularly effective for improving PCPs' confidence. Education for all specialties will be essential to ensure appropriate integration into routine practice.
Topics: Humans; Pharmacogenomic Testing; Attitude; Delivery of Health Care; Pharmacogenetics; Health Personnel
PubMed: 37458095
DOI: 10.2217/pgs-2023-0039 -
Frontiers in Pediatrics 2023Flecainide is a class IC antiarrhythmic utilized in prophylaxis of refractory paroxysmal supraventricular tachycardias in pediatric populations. Despite being a highly...
Case report: Use of therapeutic drug monitoring and pharmacogenetic testing as opportunities to individualize care in a case of flecainide toxicity after fetal supraventricular tachycardia.
Flecainide is a class IC antiarrhythmic utilized in prophylaxis of refractory paroxysmal supraventricular tachycardias in pediatric populations. Despite being a highly effective agent, its narrow therapeutic index increases the risk of toxicity and proarrhythmic events, including wide-complex tachycardia. In the absence of direct plasma sampling in the fetus to quantitate flecainide systemic concentrations, clinicians typically make drug dosing decisions from maternal plasma concentrations and QRS duration on maternal ECGs. There remains a paucity of standard guidelines and data to inform the timing and frequency of the aforementioned test in pregnancy and timing of flecainide discontinuation prior to childbirth. Flecainide primarily undergoes metabolism via cytochrome P450 (CYP). Given the variance of CYP-mediated metabolism at the level of the individual patient, pharmacogenomics can be considered in patients who present with flecainide toxicity to determine the maternal vs. fetal factors as an etiology for the event. Finally, pharmacogenetic testing can be utilized as an adjunct to guide flecainide dosing decisions, but must be done with caution in neonates <2 weeks of age. This case report highlights utilization of pharmacogenomic testing and therapeutic drug monitoring as adjuncts to guide therapy for a newborn with refractory supraventricular tachycardia, who experienced flecainide toxicity immediately post-partum and was trialed unsuccessfully on multiple alternative antiarrhythmics without rhythm control.
PubMed: 37449265
DOI: 10.3389/fped.2023.1168619 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Jun 2023To evaluate the value of pharmacogenetic testing for improving the efficacy and safety of treatment with cyclosporine, tacrolimus, and cyclophosphamide (CTX) for...
OBJECTIVE
To evaluate the value of pharmacogenetic testing for improving the efficacy and safety of treatment with cyclosporine, tacrolimus, and cyclophosphamide (CTX) for PLA2R-related membranous nephropathy and for determing individualized and precise treatment plans for the patients.
METHODS
A total of 63 patients with PLA2R-related membranous nephropathy hospitalized in the Department of Nephrology at our hospital from January, 2019 to October, 2021 were enrolled in this study. Thirty-three of the patients underwent pharmacogenetic testing before taking the immunosuppressive drugs selected based on the results of genetic screening for sensitive targets, and the other 30 patients were empirically given immunosuppressive drugs according to the guidelines (control group). The clinical efficacy and adverse effects of the immunosuppressive drugs were analyzed for all the patients. The two groups of patients were compared for demographic and biochemical parameters including 24-h urine protein, serum albumin, renal function, and serum anti-phospholipase A2 receptor antibody both before and at 3 months after the beginning of the treatment.
RESULTS
Among the 33 patients undergoing pharmacogenetic testing, 51.5% showed a GG genotype for cyclosporine, and 61.6% had an AG genotype for tacrolimus; for CTX, 51.5% of the patients showed a homozygous deletion and 63.6% had an AA genotype. After treatment for 3 months, serum anti-phospholipase A2 receptor antibody, 24-h urine protein, and serum albumin levels were significantly improved in pharmacogenetic testing group as compared with the control group ( < 0.05).
CONCLUSION
Individualized and precise administration of immunosuppressive drugs based on pharmacogenetic testing better controls proteinuria and serum antiphospholipase A2 receptor antibodies and increases serum albumin level in patients with PLA2R-related membranous nephropathy.
Topics: Humans; Autoantibodies; Cyclosporine; Glomerulonephritis, Membranous; Homozygote; Immunosuppressive Agents; Pharmacogenomic Testing; Receptors, Phospholipase A2; Sequence Deletion; Serum Albumin; Tacrolimus
PubMed: 37439180
DOI: 10.12122/j.issn.1673-4254.2023.06.23 -
Military Medicine Jan 2024Response to medications can differ widely among individual patients. Adverse drug reactions can lead to serious morbidity and mortality. Pharmacogenetic (PGx) testing...
INTRODUCTION
Response to medications can differ widely among individual patients. Adverse drug reactions can lead to serious morbidity and mortality. Pharmacogenetic (PGx) testing can predict responses to medications and increased risks of adverse events where the genetic basis is understood. Several published manuscripts suggest positive impacts of systematic preemptive PGx testing. However, few studies have been conducted on PGx implementation in the Military Health System (MHS).
MATERIAL AND METHODS
A cross-sectional study of adult beneficiaries in a primary care clinic at a large military treatment facility was conducted in 2022. Participants underwent PGx genotyping of CYP2C19 and CYP2D6 genes at the Defense Health Agency Genetics Reference Laboratory. Participant medication lists were compared to the current Clinical Pharmacogenetic Implementation Consortium (CPIC) PGx gene-drug guidelines to assess potential actionability of these results.
RESULTS
Genotyping of CYP2C19 and CYP2D6 in 165 MHS beneficiaries (mean age: 65 years) revealed that 81.2% of participants had at least one abnormal PGx finding. Among those with an abnormal PGx result, 65% were taking a medication listed on the CPIC website with an association with the particular gene in which the finding was identified. In addition, 78% of all of the participants in the study were taking at least one medication that is metabolized by CYP2C19 or CYP2D6 with associated CPIC guidelines.
CONCLUSIONS
Pharmacogenetic testing for CYP2C19 and CYP2D6 identified a substantial proportion of MHS patients at a single center who could benefit from evaluation of current medication regimens based on the CPIC guidelines. Individualized medical management may be warranted to a greater degree than previously recognized based on the findings given possible differences in medication metabolism. Many MHS beneficiaries already take medications metabolized by CYP2C19 and CYP2D6, and a substantial proportion may be at risk for preventable adverse events for medications metabolized by these enzymes. While preliminary, a large number of actionable polymorphisms among a relatively small set of individuals taking at-risk medications suggest that implementing PGx testing in clinical practice may be beneficial in the MHS with appropriate clinical infrastructure.
Topics: Adult; Humans; Aged; Cytochrome P-450 CYP2D6; Pharmacogenomic Testing; Cytochrome P-450 CYP2C19; Cross-Sectional Studies; Military Health Services
PubMed: 37436924
DOI: 10.1093/milmed/usad254