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The Pharmacogenomics Journal Dec 2022The successful implementation of pharmacogenetics (PGx) into clinical practice requires patient genomic data to be shared between stakeholders in multiple settings. This...
The successful implementation of pharmacogenetics (PGx) into clinical practice requires patient genomic data to be shared between stakeholders in multiple settings. This creates a number of barriers to widespread adoption of PGx, including privacy concerns related to the storage and movement of identifiable genomic data. Informatic solutions that support secure and equitable data access for genomic data are therefore important to PGx. Here we propose a methodology that uses smart contracts implemented on a blockchain-based framework, PGxChain, to address this issue. The design requirements for PGxChain were identified through a systematic literature review, identifying technical challenges and barriers impeding the clinical implementation of pharmacogenomics. These requirements included security and privacy, accessibility, interoperability, traceability and legal compliance. A proof-of-concept implementation based on Ethereum was then developed that met the design requirements. PGxChain's performance was examined using Hyperledger Caliper for latency, throughput, and transaction success rate. The findings clearly indicate that blockchain technology offers considerable potential to advance pharmacogenetic data sharing, particularly with regard to PGx data security and privacy, large-scale accessibility of PGx data, PGx data interoperability between multiple health care providers and compliance with data-sharing laws and regulations.
Topics: Humans; Blockchain; Pharmacogenetics; Computer Security; Information Dissemination; Pharmacogenomic Testing
PubMed: 35869255
DOI: 10.1038/s41397-022-00285-5 -
Predicting drug response and toxicity in metastatic colorectal cancer: the role of germline markers.Expert Review of Clinical Pharmacology Jun 2022Despite the introduction of targeted agents leading to therapeutic advances, clinical management of patients with metastatic colorectal cancer (mCRC) is still challenged...
INTRODUCTION
Despite the introduction of targeted agents leading to therapeutic advances, clinical management of patients with metastatic colorectal cancer (mCRC) is still challenged by significant interindividual variability in treatment outcomes, both in terms of toxicity and therapy efficacy. The study of germline genetic variants could help to personalize and optimize therapeutic approaches in mCRC.
AREAS COVERED
A systematic review of pharmacogenetic studies in mCRC patients published on PubMed between 2011 and 2021, evaluating the role of germline variants as predictive markers of toxicity and efficacy of drugs currently approved for treatment of mCRC, was perfomed.
EXPERT OPINION
Despite the large amount of pharmacogenetic data published to date, only a few genetic markers (i.e. and variants) reached the clinical practice, mainly to prevent the toxic effects of chemotherapy. The large heterogeneity of available studies represents the major limitation in comparing results and identifying potential markers for clinical use, the role of which remains exploratory in most cases. However, the available published findings are an important starting point for future investigations. They highlighted new promising pharmacogenetic markers within the network of inflammatory and immune response signaling. In addition, the emerging role of previously overlooked rare variants has been pointed out.
Topics: Antineoplastic Agents; Colorectal Neoplasms; Germ Cells; Humans; Pharmacogenetics
PubMed: 35829762
DOI: 10.1080/17512433.2022.2101447 -
European Child & Adolescent Psychiatry Jun 2024The global prevalence of attention-deficit/hyperactivity disorder (ADHD) is estimated to be between 6% and 7% in children worldwide. The pathophysiology of this... (Review)
Review
The global prevalence of attention-deficit/hyperactivity disorder (ADHD) is estimated to be between 6% and 7% in children worldwide. The pathophysiology of this heterogeneous neurodevelopmental disorder remains unknown. Mitochondrial dysfunction has been proposed as a possible contributing factor to the etiology of ADHD. There is limited literature available to help our understanding of this hypothesis, and thus we conducted a systematic review of the number and quality of studies pertaining to mitochondrial genetic alterations in ADHD. A systematic search was conducted in the relevant databases Medline (PubMed) and Embase up to March 2021. Inclusion criteria included randomized control trials, cross-sectional studies, and case-control studies. This search resulted in a total of 507 articles that emerged from the search criteria. Of these results, 10 primary research articles were selected for in depth review based on the inclusion and exclusion criteria. These studies all reported on mitochondrial genetic variation in ADHD cases such as increased copy number, single-nucleotide polymorphisms, and haplogroup associations. This initial review of the experimental literature suggests mitochondrial genetic variation, in both the mitochondrial DNA and nuclear-encoded mitochondrial genes, may indeed contribute to ADHD pathophysiology. The studies reviewed here provide promising evidence for future research to further examine the mitochondrial genetics contributing to ADHD pathophysiology. We suggest that expansion of investigations into mitochondrial mechanisms may have potential to inform new treatment options for ADHD.
Topics: Humans; Attention Deficit Disorder with Hyperactivity; DNA, Mitochondrial; Genetic Variation; Mitochondria; Child; Polymorphism, Single Nucleotide
PubMed: 35796884
DOI: 10.1007/s00787-022-02030-6 -
Pharmacogenomics and Personalized... 2022In neonates, pharmacogenetics has an additional layer of complexity. This is because in addition to genetic variability in genes that code for proteins relevant to... (Review)
Review
In neonates, pharmacogenetics has an additional layer of complexity. This is because in addition to genetic variability in genes that code for proteins relevant to clinical pharmacology, there are rapidly maturational changes in these proteins. Consequently, pharmacotherapy in neonates has unique challenges. To provide a contemporary overview on pharmacogenetics in neonates, we conducted a systematic review to identify, describe and quantify the impact of pharmacogenetics on pharmacokinetics and -dynamics in neonates and infants (PROSPERO, CRD42022302029). The search was performed in Medline, Embase, Web of Science and Cochrane, and was extended by a PubMed search on the 'top 100 Medicines' (medicine + newborn/infant + pharmacogen*) prescribed to neonates. Following study selection (including data in infants, PGx related) and quality assessment (Newcastle-Ottawa scale, Joanna Briggs Institute tool), 55/789 records were retained. Retained records relate to metabolizing enzymes involved in phase I [cytochrome P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C8/C9/C18, CYP2C19, CYP2D6, CYP3A5, CYP2E1)], phase II [glutathione-S-transferases, N-acetyl transferases, UDP-glucuronosyl-transferase], transporters [ATP-binding cassette transporters, organic cation transporters], or receptor/post-receptor mechanisms [opioid related receptor and post-receptor mechanisms, tumor necrosis factor, mitogen-activated protein kinase 8, vitamin binding protein diplotypes, corticotrophin-releasing hormone receptor-1, nuclear receptor subfamily-1, vitamin K epoxide reductase complex-1, and angiotensin converting enzyme variants]. Based on the available overview, we conclude that the majority of reported pharmacogenetic studies explore and extrapolate observations already described in older populations. Researchers commonly try to quantify the impact of these polymorphisms in small datasets of neonates or infants. In a next step, pharmacogenetic studies in neonatal life should go beyond confirmation of these associations and explore the impact of pharmacogenetics as a covariate limited to maturation of neonatal life (ie, fetal malformations, breastfeeding or clinical syndromes). The challenge is to identify the specific factors, genetic and non-genetic, that contribute to the best benefit/risk balance.
PubMed: 35795337
DOI: 10.2147/PGPM.S350205 -
Pharmaceutics Jun 2022This systematic review summarizes the impact of pharmacogenetics on the effect and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressants when used... (Review)
Review
BACKGROUND
This systematic review summarizes the impact of pharmacogenetics on the effect and safety of non-steroidal anti-inflammatory drugs (NSAIDs) and antidepressants when used for pain treatment.
METHODS
A systematic literature search was performed according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines regarding the human in vivo efficacy and safety of NSAIDs and antidepressants in pain treatment that take pharmacogenetic parameters into consideration. Studies were collected from PubMed, Scopus, and Web of Science up to the cutoff date 18 October 2021.
RESULTS
Twenty-five articles out of the 6547 initially detected publications were identified. Relevant medication-gene interactions were noted for drug safety. Interactions important for pain management were detected for (1) ibuprofen/; (2) celecoxib/; (3) piroxicam/, ; (4) diclofenac/, , , ; (5) meloxicam/; (6) aspirin/, , and ; (7) amitriptyline/ and ; (8) imipramine/; (9) nortriptyline/, , ; and (10) escitalopram/, , and .
CONCLUSIONS
Overall, a lack of well powered human in vivo studies assessing the pharmacogenetics in pain patients treated with NSAIDs or antidepressants is noted. Studies indicate a higher risk for partly severe side effects for the poor metabolizers and NSAIDs. Further in vivo studies are needed to consolidate the relevant polymorphisms in NSAID safety as well as in the efficacy of NSAIDs and antidepressants in pain management.
PubMed: 35745763
DOI: 10.3390/pharmaceutics14061190 -
The Pharmacogenomics Journal Jul 2022Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the... (Meta-Analysis)
Meta-Analysis
Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the occurrence of a potentially fatal adverse reaction, clozapine-induced agranulocytosis (CIA). Identifying genetic variations contributing to CIA would help predict patient risk of developing CIA and personalize treatment. Here, we (1) review existing pharmacogenomic studies of CIA, and (2) conduct meta-analyses to identify targets for clinical implementation. A systematic literature search identified studies that included individuals receiving clozapine who developed CIA and controls who did not. Results showed that individuals carrying the HLA-DRB1*04:02 allele had nearly sixfold (95% CI 2.20-15.80, p = 0.03) higher odds of CIA with a negative predictive value of 99.3%. Previously unreplicated alleles, TNFb5, HLA-B*59:01, TNFb4, and TNFd3 showed significant associations with CIA after multiple-testing corrections. Our findings suggest that a predictive HLA-DRB1*04:02-based pharmacogenomic test may be promising for clinical implementation but requires further investigation.
Topics: Agranulocytosis; Alleles; Antipsychotic Agents; Clozapine; Humans; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 35710824
DOI: 10.1038/s41397-022-00281-9 -
Pharmacogenomics and Personalized... 2022Rifamycins are a novel class of antibiotics clinically approved for tuberculosis chemotherapy. They are characterized by high inter-individual variation in... (Review)
Review
BACKGROUND
Rifamycins are a novel class of antibiotics clinically approved for tuberculosis chemotherapy. They are characterized by high inter-individual variation in pharmacokinetics. This systematic review aims to present the contribution of genetic variations in drug-metabolizing enzymes and transporter proteins to the inter-individual variation of rifamycin pharmacokinetics.
METHOD
We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. The search for relevant studies was done through PubMed, Embase, Web of Science, and Scopus databases. Studies reporting single nucleotide polymorphism in drug transporters and metabolizing enzymes' influence on rifamycin pharmacokinetics were solely included. Two reviewers independently performed data extraction.
RESULTS
The search identified 117 articles of which 15 fulfilled the eligibility criteria and were included in the final data synthesis. The single nucleotides polymorphism in the drug transporters rs4149032, rs2306283, rs11045819, and rs1045642 for rifampicin, drug metabolizing enzyme rs1803155 for rifapentine and for rifampicin partly contributes to the variability of pharmacokinetic parameters in tuberculosis patients.
CONCLUSION
The pharmacokinetics of rifamycins is influenced by genetic variation of drug-metabolizing enzymes and transporters. Controlled clinical studies are, however, required to establish these relationships.
PubMed: 35693129
DOI: 10.2147/PGPM.S363058 -
Journal of Clinical Medicine Apr 2022In recent years, antioxidant supplements have become popular to counteract the effects of oxidative stress in fibromyalgia and one of its most distressing symptoms,... (Review)
Review
In recent years, antioxidant supplements have become popular to counteract the effects of oxidative stress in fibromyalgia and one of its most distressing symptoms, pain. The aim of this systematic review was to summarize the effects of antioxidant supplementation on pain levels perceived by patients diagnosed with fibromyalgia. The words used respected the medical search terms related to our objective including antioxidants, fibromyalgia, pain, and supplementation. Seventeen relevant articles were identified within Medline (PubMed), Scopus, Web of Science (WOS), the Cochrane Database of Systematic Review, and the Cochrane Central Register of Controlled Trials. This review found that antioxidant supplementation is efficient in reducing pain in nine of the studies reviewed. Studies with a duration of supplementation of at least 6 weeks showed a benefit on pain perception in 80% of the patients included in these studies. The benefits shown by vitamins and coenzyme Q10 are remarkable. Further research is needed to identify the effects of other types of antioxidants, such as extra virgin olive oil and turmeric. More homogeneous interventions in terms of antioxidant doses administered and duration would allow the effects on pain to be addressed more comprehensively.
PubMed: 35566585
DOI: 10.3390/jcm11092462 -
Pharmaceutics Apr 2022Antineoplastic uptake by blast cells in acute myeloid leukemia (AML) could be influenced by influx and efflux transporters, especially solute carriers (SLCs) and... (Review)
Review
Antineoplastic uptake by blast cells in acute myeloid leukemia (AML) could be influenced by influx and efflux transporters, especially solute carriers (SLCs) and ATP-binding cassette family (ABC) pumps. Genetic variability in and could produce interindividual differences in clinical outcomes. A systematic review was performed to evaluate the influence of and polymorphisms and their combinations on efficacy and safety in AML cohorts. Anthracycline intake was especially influenced by polymorphisms, associated with lower hepatic uptake, showing higher survival rates and toxicity in AML studies. The variant alleles of were related to anthracycline intracellular accumulation, increasing complete remission, survival and toxicity. Similar findings have been suggested with and polymorphisms. Polymorphisms of , responsible for cytarabine uptake, demonstrated significant associations with survival and response in Asian populations. Promising results were observed with and combinations regarding anthracycline toxicities. Knowledge of the role of transporter pharmacogenetics could explain the differences observed in drug disposition in the blast. Further studies including novel targeted therapies should be performed to determine the influence of genetic variability to individualize chemotherapy schemes.
PubMed: 35456712
DOI: 10.3390/pharmaceutics14040878 -
Pharmaceuticals (Basel, Switzerland) Apr 2022Platinum-based chemotherapy regimens have been proven to be effective in various cancers; however, considerable toxicities may develop and can even lead to treatment... (Review)
Review
Platinum-based chemotherapy regimens have been proven to be effective in various cancers; however, considerable toxicities may develop and can even lead to treatment discontinuation. Diverse factors may influence adverse treatment events, with pharmacogenetic variations being one prime example. Polymorphisms within the glutathione S-transferase pi 1 (GSTP1) gene may especially alter enzyme activity and, consequently, various toxicities in patients receiving platinum-based chemotherapy. Due to a lack of consistency in the degree of elevated complication risk, we performed a systematic literature review and meta-analysis to determine the level of platinum-associated toxicity in patients with the GSTP1 rs1695 polymorphism. We conducted a systematic search for eligible studies published before January 2022 from PubMed, Web of Science, and EMBASE based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between the rs1695 polymorphism and various toxicities. Ten eligible studies met the inclusion criteria. The pooled ORs for hematological toxicity and neutropenia in the patients with the variant (G) allele were 1.7- and 2.6-times higher than those with the AA genotype (95% CI 1.06-2.73 and 1.07-6.35), respectively. In contrast, the rs1695 polymorphism resulted in a 44% reduced gastrointestinal toxicity compared to wild-type homozygotes. Our study found that the GSTP1 rs1695 polymorphism was significantly correlated with platinum-induced toxicities. The study also revealed that rs1695 expression exhibited tissue-specific patterns and thus yielded opposite effects in different tissues. A personalized chemotherapy treatment based on these polymorphisms may be considered for cancer patients in the future.
PubMed: 35455437
DOI: 10.3390/ph15040439