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International Journal of Molecular... May 2023Sickle cell anemia (SCA) is an inherited disease affecting the hemoglobin that is particularly common in sub-Saharan Africa. Although monogenic, phenotypes are markedly...
Sickle cell anemia (SCA) is an inherited disease affecting the hemoglobin that is particularly common in sub-Saharan Africa. Although monogenic, phenotypes are markedly heterogeneous in terms of severity and life span. Hydroxyurea is still the most common treatment for these patients, and the response to treatment is highly variable and seems to be an inherited trait. Therefore, identifying the variants that might predict hydroxyurea response is important for identifying patients who will have a poorer or non-response to treatment, and the ones that are more prone to suffer from severe side effects. In the present pharmacogenetic study, we analyzed the exons of 77 genes described in the literature as potentially associated with hydroxyurea metabolism in Angolan children treated with hydroxyurea and evaluated the drug response considering fetal hemoglobin levels, other hematological and biochemical parameters, hemolysis, number of vaso-occlusive crises and hospitalizations. Thirty variants were identified in 18 of those genes as possibly associated with drug response, five of them in gene DCHS2. Other polymorphisms in this gene were also associated with hematological, biochemical and clinical parameters. Further research examining the maximum tolerated dose and fixed dose with a larger sample size is necessary to corroborate these findings.
Topics: Humans; Hydroxyurea; Pharmacogenomic Testing; Anemia, Sickle Cell; Hemolysis; Fetal Hemoglobin
PubMed: 37240136
DOI: 10.3390/ijms24108792 -
Frontiers in Pharmacology 2023Research in the field of pharmacogenomics (PGx) aims to identify genetic variants that modulate response to drugs, through alterations in their pharmacokinetics (PK) or...
Research in the field of pharmacogenomics (PGx) aims to identify genetic variants that modulate response to drugs, through alterations in their pharmacokinetics (PK) or pharmacodynamics (PD). The distribution of PGx variants differs considerably among populations, and whole-genome sequencing (WGS) plays a major role as a comprehensive approach to detect both common and rare variants. This study evaluated the frequency of PGx markers in the context of the Brazilian population, using data from a population-based admixed cohort from Sao Paulo, Brazil, which includes variants from WGS of 1,171 unrelated, elderly individuals. The Stargazer tool was used to call star alleles and structural variants (SVs) from 38 pharmacogenes. Clinically relevant variants were investigated, and the predicted drug response phenotype was analyzed in combination with the medication record to assess individuals potentially at high-risk of gene-drug interaction. In total, 352 unique star alleles or haplotypes were observed, of which 255 and 199 had a frequency < 0.05 and < 0.01, respectively. For star alleles with frequency > 5% ( = 97), decreased, loss-of-function and unknown function accounted for 13.4%, 8.2% and 27.8% of alleles or haplotypes, respectively. Structural variants (SVs) were identified in 35 genes for at least one individual, and occurred with frequencies >5% for CYP2D6, CYP2A6, GSTM1, and UGT2B17. Overall 98.0% of the individuals carried at least one high risk genotype-predicted phenotype in pharmacogenes with PharmGKB level of evidence 1A for drug interaction. The Electronic Health Record (EHR) Priority Result Notation and the cohort medication registry were combined to assess high-risk gene-drug interactions. In general, 42.0% of the cohort used at least one PharmGKB evidence level 1A drug, and 18.9% of individuals who used PharmGKB evidence level 1A drugs had a genotype-predicted phenotype of high-risk gene-drug interaction. This study described the applicability of next-generation sequencing (NGS) techniques for translating PGx variants into clinically relevant phenotypes on a large scale in the Brazilian population and explores the feasibility of systematic adoption of PGx testing in Brazil.
PubMed: 37234706
DOI: 10.3389/fphar.2023.1178715 -
The Journal of Applied Laboratory... Jul 2023
Topics: Humans; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 37228092
DOI: 10.1093/jalm/jfad016 -
PEC Innovation Dec 2023To examine the impact of various presentations of pharmacogenomic testing results using a published, color-coded decision support tool (DST) format as a standard...
OBJECTIVE
To examine the impact of various presentations of pharmacogenomic testing results using a published, color-coded decision support tool (DST) format as a standard stimulus to list possible medications.
METHODS
Participants were randomly assigned to groups and asked to decide which psychotropic medication they would prefer if depressed. Three of the groups varied the color-coded category of fluoxetine and received a statement indicating that this was the most prescribed drug for depression. A fourth control condition omitted base rate information. Participants also provided detail about their decision-making processes through a qualitative interview.
RESULTS
Comparison of the first three groups indicated that significantly more participants selected medications from the highest category of likely effectiveness when fluoxetine appeared in this list. Comparison of the control group to its relevant analogue suggested no significant differences in selection strategy. Qualitative interview responses indicated participant comfort with genetic testing despite awareness of having very limited understanding of these techniques and their implications.
CONCLUSIONS
Both DST color-coding and base rates were influential in driving drug selection decisions, despite most participants indicating they did not understand this information.
INNOVATION
Efforts to standardize pharmacogenomic stimuli may lead to advances in methods of studying quantifiable healthcare decisions. Attention to the context for presenting test results may also be a useful source of understanding patient responses, particularly regarding complex tests that are likely to be interpreted heuristically.
PubMed: 37214496
DOI: 10.1016/j.pecinn.2022.100119 -
Frontiers in Genetics 2023Unexpected poor efficacy and intolerable adverse effects are medication-related problems that may result from genetic variation in genes encoding key proteins involved...
Unexpected poor efficacy and intolerable adverse effects are medication-related problems that may result from genetic variation in genes encoding key proteins involved in pharmacokinetics or pharmacodynamics. Pharmacogenomic (PGx) testing can be used in medical practice "pre-emptively" to avoid future patient harm from medications and "reactively" to diagnose medication-related problems following their occurrence. A structured approach to PGx consulting is proposed to calculate the pharmacogenomics benefit score (PGxBS), a patient-centered objective measure of congruency between medication-related problems and patient genotypes. An example case of poor efficacy with multiple medications is presented, together with comments on the potential benefits and limitations of using the PGxBS in medical practice.
PubMed: 37214415
DOI: 10.3389/fgene.2023.1152585 -
Trials May 2023The evidence for the clinical utility of pharmacogenomic (PGx) testing is growing, and guidelines exist for the use of PGx testing to inform prescribing of 13...
The PRESIDE (PhaRmacogEnomicS In DEpression) Trial: a double-blind randomised controlled trial of pharmacogenomic-informed prescribing of antidepressants on depression outcomes in patients with major depressive disorder in primary care.
BACKGROUND
The evidence for the clinical utility of pharmacogenomic (PGx) testing is growing, and guidelines exist for the use of PGx testing to inform prescribing of 13 antidepressants. Although previous randomised controlled trials of PGx testing for antidepressant prescribing have shown an association with remission of depression in clinical psychiatric settings, few trials have focused on the primary care setting, where most antidepressant prescribing occurs.
METHODS
The PRESIDE Trial is a stratified double-blinded randomised controlled superiority trial that aims to evaluate the impact of a PGx-informed antidepressant prescribing report (compared with standard prescribing using the Australian Therapeutic Guidelines) on depressive symptoms after 12 weeks, when delivered in primary care. Six hundred seventy-two patients aged 18-65 years of general practitioners (GPs) in Victoria with moderate to severe depressive symptoms, measured using the Patient Health Questionnaire-9 (PHQ-9), will be randomly allocated 1:1 to each arm using a computer-generated sequence. Participants and GPs will be blinded to the study arm. The primary outcome is a difference between arms in the change of depressive symptoms, measured using the PHQ-9 after 12 weeks. Secondary outcomes include a difference between the arms in change in PHQ-9 score at 4, 8 and 26 weeks, proportion in remission at 12 weeks, a change in side effect profile of antidepressant medications, adherence to antidepressant medications, change in quality of life and cost-effectiveness of the intervention.
DISCUSSION
This trial will provide evidence as to whether PGx-informed antidepressant prescribing is clinically efficacious and cost-effective. It will inform national and international policy and guidelines about the use of PGx to select antidepressants for people with moderate to severe depressive symptoms presenting in primary care.
TRIAL REGISTRATION
Australian and New Zealand Clinical Trial Registry ACTRN12621000181808. Registered on 22 February 2021.
Topics: Humans; Depressive Disorder, Major; Depression; Pharmacogenetics; Quality of Life; Selective Serotonin Reuptake Inhibitors; Australia; Antidepressive Agents; Primary Health Care; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 37208772
DOI: 10.1186/s13063-023-07361-6 -
Frontiers in Pharmacology 2023Methotrexate is an immunosuppressant and chemotherapeutic agent used in the treatment of a range of autoimmune disorders and cancers. Its main serious adverse effects,...
Methotrexate is an immunosuppressant and chemotherapeutic agent used in the treatment of a range of autoimmune disorders and cancers. Its main serious adverse effects, bone marrow suppression and gastrointestinal complications, arise from its antimetabolite effect. Nevertheless, hepatotoxicity and nephrotoxicity are two widely described adverse effects of methotrexate. Its hepatotoxicity has been studied mainly in the low-dose, chronic setting, where patients are at risk of fibrosis/cirrhosis. Studies of acute hepatoxicity of high dose methotrexate, such as during chemotherapy, are scarce. We present the case of a 14-year-old patient who received high-dose methotrexate and subsequently developed acute fulminant liver failure and acute kidney injury. Genotyping of (Methylene tetrahydrofolate reductase gene), (codes for P-glycoprotein, intestinal transport and biliary excretion), (codes for BCRP, intestinal transporter and renal excretion) and (codes for OATP1B1, hepatic transporter) identified variants in all the genes analysed that predicted a reduced rate of methotrexate elimination and thus may have contributed to the clinical situation of the patient. Precision medicine involving pharmacogenomic testing could potentially avoid such adverse drug effects.
PubMed: 37201023
DOI: 10.3389/fphar.2023.1130548 -
BMC Psychiatry May 2023Pharmacogenomic testing guided treatment have been developed to guide drug selection or conversion in major depressive disorder patients. Whether patients benefit from... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pharmacogenomic testing guided treatment have been developed to guide drug selection or conversion in major depressive disorder patients. Whether patients benefit from pharmacogenetic testing remains unclear. We aim to evaluates the effect of pharmacogenomic testing guiding on clinical outcomes of major depressive disorder.
METHODS
Pubmed, Embase, and Cochrane Library of Clinical Trials were searched from inception until August 2022. Key terms included pharmacogenomic and antidepressive. Odds ratios (RR) with 95% confidence intervals (95%CIs) were calculated using fixed-effects model for low or moderate heterogeneity or random-effects model for high heterogeneity.
RESULTS
Eleven studies (5347 patients) were included. Compared with usual group, pharmacogenomic testing guided group was associated with an increased response rate at week 8 (OR 1.32, 95%CI 1.15-1.53, 8 studies, 4328 participants) and week 12 (OR 1.36, 95%CI 1.15-1.62, 4 studies, 2814 participants). Similarly, guided group was associated with an increased rate of remission at week 8 (OR 1.58, 95%CI 1.31-1.92, 8 studies, 3971 participants) and week 12 (OR 2.23, 95%CI 1.23-4.04, 5 studies, 2664 participants). However, no significant differences were found between the two groups in response rate at week 4 (OR 1.12, 95%CI 0.89-1.41, 2 studies, 2261 participants) and week 24 (OR 1.16, 95%CI 0.96-1.41, 2 studies, 2252 participants), and remission rate at week 4 (OR 1.26, 95%CI 0.93-1.72, 2 studies, 2261 participants) and week 24 (OR 1.06, 95%CI 0.83-1.34, 2 studies, 2252 participants). Medication congruence in 30 days was significantly reduced in the pharmacogenomic guided group compared with the usual care group (OR 2.07, 95%CI 1.69-2.54, 3 studies, 2862 participants). We found significant differences between subgroups of target population in response and remission rate.
CONCLUSION
Patients with major depressive disorder may benefit from pharmacogenomic testing guided treatment by achieving target response and remission rates more quickly.
Topics: Humans; Depressive Disorder, Major; Pharmacogenetics; Antidepressive Agents; Pharmacogenomic Testing; Odds Ratio; Randomized Controlled Trials as Topic
PubMed: 37173736
DOI: 10.1186/s12888-023-04756-2 -
Journal of Psychiatry & Neuroscience :... 2023
Topics: Humans; Pharmacogenetics; Terminology as Topic; Drug-Related Side Effects and Adverse Reactions
PubMed: 37172962
DOI: 10.1503/jpn.230022-l