Arch Med Sci. 2023 May 24;19(3):810-813. doi: 10.5114/aoms/163259. eCollection 2023.

ABSTRACT

INTRODUCTION: To determine the impact of single nucleotide polymorphisms (SNPs) in MTHFR and MTRR genes on disease activity and the presence of MTX therapy adverse events in Polish children with juvenile idiopathic arthritis (JIA).

METHODS: SNP genotyping was performed using genomic DNA isolated from peripheral blood samples.

RESULTS: Patients with MTHFR rs1801133 CT/TT variant had higher values of inflammatory markers, number of joints with active arthritis, and JADAS-71 value at the baseline of MTX treatment. Children with MTRR rs1801394 AG/AA variant presented higher inflammatory marker values at JIA diagnosis.

CONCLUSIONS: MTHFR rs1801133 and MTRR rs1801394 polymorphisms are associated with higher disease activity at the moment of JIA diagnosis.

PMID:37313208 | PMC:PMC10259383 | DOI:10.5114/aoms/163259

J Thromb Thrombolysis. 2023 Jun 13. doi: 10.1007/s11239-023-02837-3. Online ahead of print.

ABSTRACT

Rivaroxaban is a direct factor Xa inhibitor, recently implemented as a favorable alternative to warfarin in anticoagulation therapy. Rivaroxaban effectively reduces thrombin generation, which plays a major role in the activation of thrombin activatable fibrinolysis inhibitor (TAFI) to TAFIa. Based on the antifibrinolytic role of TAFIa, we hypothesized that rivaroxaban would consequently induce more rapid clot lysis. In vitro clot lysis assays were used to explore this hypothesis and additionally determine the effects of varying TAFI levels and a stabilizing Thr325Ile polymorphism (rs1926447) in the TAFI protein on the effects of rivaroxaban. Rivaroxaban was shown to decrease thrombin generation, resulting in less TAFI activation, thus enhancing lysis. These effects were also shown to be less substantial in the presence of greater TAFI levels or the more stable Ile325 enzyme. These findings suggest a role for TAFI levels and the Thr325Ile polymorphism in the pharmacodynamics and pharmacogenomics of rivaroxaban.

PMID:37310666 | DOI:10.1007/s11239-023-02837-3

Acta Pharm. 2023 Jun 12;73(2):227-241. doi: 10.2478/acph-2023-0018. Print 2023 Jun 1.

ABSTRACT

More than half of patients with opioid use disorder for chronic non-cancer pain (CNCP) reduced their dose through a progressive opioid withdrawal supported by a rotation to buprenorphine and/or tramadol. The aim of this research is to analyse the long-term effectiveness of opioid deprescription taking into account the impact of sex and pharmacogenetics on the inter-individual variability. A cross-sectional study was carried out from October 2019 to June 2020 on CNCP patients who had previously undergone an opioid deprescription (n = 119 patients). Demographic, clinical (pain, relief and adverse events) and therapeutic (analgesic use) outcomes were collected. Effectiveness (< 50 mg per day of morphine equivalent daily dose without any aberrant opioid use behaviour) and safety (number of side-effects) were analysed in relation to sex differences and pharmacogenetic markers impact [OPRM1 genotype (rs1799971) and CYP2D6 phenotypes]. Long-term opioid deprescription was achieved in 49 % of the patients with an increase in pain relief and a reduction of adverse events. CYP2D6 poor metabolizers showed the lowest long-term opioid doses. Here, women showed a higher degree of opioid deprescription, but increased use of tramadol and neuromodulators, as well as an increased number of adverse events. Long-term deprescription was successful in half of the cases. Understanding sex and gender interaction plus a genetic impact could help to design more individualized strategies for opioid deprescription.

PMID:37307374 | DOI:10.2478/acph-2023-0018

Clin Pharmacol Ther. 2023 Jun 12. doi: 10.1002/cpt.2969. Online ahead of print.

ABSTRACT

During systemic inflammation, pro-inflammatory cytokines alter metabolism and transport of drugs affecting the clincal outcome. We used an in vivo like human 3D liver spheroid model to study the effects and mechanisms of pro-inflammatory cytokines on the expression of nine different genes encoding enzymes responsible for the metabolism of > 90% of clinically used drugs. Treatment of spheroids with pathophysiologically relevant concentrations of IL-1β, IL-6 or TNFα resulted in a pronounced decrease in mRNA expression of CYP3A4 and UGT2B10 within 5 h. The reduction of CYP1A2, CYP2C9, CYP2C19 and CYP2D6 mRNA expression was less pronounced, whereas the pro-inflammatory cytokines caused increased CYP2E1 and UGT1A3 mRNA expression. The cytokines did not influence expression of key nuclear proteins, nor the activities of specific kinases involved in the regulation of genes encoding drug metabolizing enzymes. However, ruxolitinib, a JAK1/2 inhibitor, inhibited the IL-6 dependent increase in CYP2E1 and the decrease in CYP3A4 and UGT2B10 mRNA expression. We evaluated the effect of TNFα in hepatocytes in 2D plates and found a rapid decrease in DME mRNA both in the absence or presence of the cytokines. Taken together, these data suggest that pro-inflammatory cytokines regulate multiple gene- and cytokine-specific events seen in in vivo and in 3D but not in 2D liver models. We propose that the 3D spheroid system is suitable for the prediction of drug metabolism under conditions of inflammation and constitutes a versatile system for short- and long-term pre-clinical and mechanistic studies of cytokine-induced changes in drug metabolism.

PMID:37307233 | DOI:10.1002/cpt.2969

Pharmacogenomics. 2023 Jun 12. doi: 10.2217/pgs-2023-0067. Online ahead of print.

ABSTRACT

Aim: Few genome-wide association studies (GWASs) have been conducted to identify predictors of drug concentrations. The authors therefore sought to discover the pharmacogenomic markers involved in metoprolol pharmacokinetics. Patients & methods: The authors performed a GWAS of a cross-sectional study of 993 patients from the Montreal Heart Institute Biobank taking metoprolol. Results: A total of 391 and 444 SNPs reached the significance threshold of 5 × 10-8 for metoprolol and α-OH-metoprolol concentrations, respectively. All were located on chromosome 22 at or near the CYP2D6 gene, encoding CYP450 2D6, metoprolol's main metabolizing enzyme. Conclusion: The results reinforce previous findings of the importance of the CYP2D6 locus for metoprolol concentrations and confirm that large biobanks can be used to identify genetic determinants of drug pharmacokinetics at a GWAS significance level.

PMID:37307170 | DOI:10.2217/pgs-2023-0067

J Peripher Nerv Syst. 2023 Jun 12. doi: 10.1111/jns.12572. Online ahead of print.

ABSTRACT

BACKGROUND: Mutations in the Early-Growth Response 2 (EGR2) gene cause various hereditary neuropathies, including demyelinating Charcot-Marie-Tooth (CMT) disease type 1D (CMT1D), congenital hypomyelinating neuropathy type 1 (CHN1), Déjerine-Sottas syndrome (DSS), and axonal CMT (CMT2).

METHODS: In this study, we identified 14 patients with heterozygous EGR2 mutations diagnosed between 2000 and 2022.

RESULTS: Mean age was 44 years (15-70), ten patients were female (71%), and mean disease duration was 28 years (1-56). Disease onset was before age 15 years in 9 cases (64%), after age 35 years in 4 cases (28%), and 1 patient aged 26 years was asymptomatic (7%). All symptomatic patients had pes cavus and distal lower limbs weakness (100%). Distal lower limbs sensory symptoms were observed in 86% of cases, hand atrophy in 71%, and scoliosis in 21%. Nerve conduction studies showed a predominantly demyelinating sensorimotor neuropathy in all cases (100%), and 5 patients needed walking assistance after a mean disease duration of 50 years (47-56) (36%). Three patients were misdiagnosed as inflammatory neuropathy and treated with immunosuppressive drugs for years before diagnosis was corrected. Two patients presented with an additional neurologic disorder, including Steinert's myotonic dystrophy and spinocerebellar ataxia (14%). Eight EGR2 gene mutations were found, including 4 previously undescribed.

INTERPRETATION: Our findings demonstrate EGR2 gene-related hereditary neuropathies are rare and slowly progressive demyelinating neuropathies with 2 major clinical presentations, including a childhood-onset variant and an adult-onset variant which may mimic inflammatory neuropathy. Our study also expands the genotypic spectrum of EGR2 gene mutations.

PMID:37306961 | DOI:10.1111/jns.12572

Cancer Treat Res. 2023;185:141-175. doi: 10.1007/978-3-031-27156-4_9.

ABSTRACT

Cancer is the most challenging disease for medical professionals to treat. The factors underlying the complicated situation include anticancer drug-associated toxicity, non-specific response, low therapeutic window, variable treatment outcomes, development of drug resistance, treatment complications, and cancer recurrence. The remarkable advancement in biomedical sciences and genetics, over the past few decades, however, is changing the dire situation. The discovery of gene polymorphism, gene expression, biomarkers, particular molecular targets and pathways, and drug-metabolizing enzymes have paved the way for the development and provision of targeted and individualized anticancer treatment. Pharmacogenetics is the study of genetic factors having the potential to affect clinical responses and pharmacokinetic and pharmacodynamic behaviors of drugs. This chapter emphasizes pharmacogenetics of anticancer drugs and its applications in improving treatment outcomes, selectivity, toxicity of the drugs, and discovering and developing personalized anticancer drugs and genetic methods for prediction of drug response and toxicity.

PMID:37306909 | DOI:10.1007/978-3-031-27156-4_9

Handb Exp Pharmacol. 2023 Jun 13. doi: 10.1007/164_2023_658. Online ahead of print.

ABSTRACT

There is considerable inter-individual variability in the effectiveness and safety of pharmaceutical interventions. This phenomenon can be attributed to a multitude of factors; however, it is widely acknowledged that common genetic variation affecting drug absorption or metabolism play a substantial contributory role. This is a concept known as pharmacogenetics. Understanding how common genetic variants influence responses to medications, and using this knowledge to inform prescribing practice, could yield significant advantages for both patients and healthcare systems. Some health services around the world have introduced pharmacogenetics into routine practice, whereas others are less advanced along the implementation pathway. This chapter introduces the field of pharmacogenetics, the existing body of evidence, and discusses barriers to implementation. The chapter will specifically focus on efforts to introduce pharmacogenetics in the NHS, highlighting key challenges related to scale, informatics, and education.

PMID:37306816 | DOI:10.1007/164_2023_658

Pharmacogenet Genomics. 2023 Jun 12. doi: 10.1097/FPC.0000000000000501. Online ahead of print.

ABSTRACT

OBJECTIVE: In AIDS Clinical Trials Group study A5375, a pharmacokinetic trial of levonorgestrel emergency contraception, double-dose levonorgestrel (3 mg, versus standard dose 1.5 mg) offset the induction effects of efavirenz or rifampin on plasma levonorgestrel exposure over 8 h post-dose (AUC0-8h). We characterized the pharmacogenetics of these interactions.

METHODS: Cisgender women receiving efavirenz- or dolutegravir-based HIV therapy, or on isoniazid-rifampin for tuberculosis, were followed after a single oral dose of levonorgestrel. Linear regression models, adjusted for BMI and age, characterized associations of CYP2B6 and NAT2 genotypes (which affect plasma efavirenz and isoniazid exposure, respectively) with levonorgestrel pharmacokinetic parameters.

RESULTS: Of 118 evaluable participants, 17 received efavirenz/levonorgestrel 1.5 mg, 35 efavirenz/levonorgestrel 3 mg, 34 isoniazid-rifampin/levonorgestrel 3 mg, and 32 (control group) dolutegravir/levonorgestrel 1.5 mg. There were 73 Black and 33 Asian participants. Regardless of genotype, women on efavirenz and isoniazid-rifampin had higher levonorgestrel clearance. In the efavirenz/levonorgestrel 3 mg group, CYP2B6 normal/intermediate metabolizers had levonorgestrel AUC0-8h values similar to controls, while CYP2B6 poor metabolizers had AUC0-8h values of 40% lower than controls. In the isoniazid-rifampin group, NAT2 rapid/intermediate acetylators had levonorgestrel AUC0-8h values similar to controls, while NAT2 slow acetylators had AUC0-8h values 36% higher than controls.

CONCLUSION: CYP2B6 poor metabolizer genotypes exacerbate the efavirenz-levonorgestrel interaction, likely by increased CYP3A induction with higher efavirenz exposure, making the interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the rifampin-levonorgestrel interaction, likely by increased CYP3A inhibition with higher isoniazid exposure.

PMID:37306344 | DOI:10.1097/FPC.0000000000000501

Elife. 2023 Jun 12;12:e82401. doi: 10.7554/eLife.82401. Online ahead of print.

ABSTRACT

Bacteria within the gut microbiota possess the ability to metabolize a wide array of human drugs, foods, and toxins, but the responsible enzymes for these chemical events remain largely uncharacterized due to the time-consuming nature of current experimental approaches. Attempts have been made in the past to computationally predict which bacterial species and enzymes are responsible for chemical transformations in the gut environment, but with low accuracy due to minimal chemical representation and sequence similarity search schemes. Here, we present an in silico approach that employs chemical and protein Similarity algorithms that Identify MicrobioMe Enzymatic Reactions (SIMMER). We show that SIMMER accurately predicts the responsible species and enzymes for a queried reaction, unlike previous methods. We demonstrate SIMMER use cases in the context of drug metabolism by predicting previously uncharacterized enzymes for 88 drug transformations known to occur in the human gut. We validate these predictions on external datasets and provide an in vitro validation of SIMMER's predictions for metabolism of methotrexate, an anti-arthritic drug. After demonstrating its utility and accuracy, we made SIMMER available as both a command-line and web tool, with flexible input and output options for determining chemical transformations within the human gut. We present SIMMER as a computational addition to the microbiome researcher's toolbox, enabling them to make informed hypotheses before embarking on the lengthy laboratory experiments required to characterize novel bacterial enzymes that can alter human ingested compounds.

PMID:37306300 | DOI:10.7554/eLife.82401

Front Neurol. 2023 May 25;14:1148327. doi: 10.3389/fneur.2023.1148327. eCollection 2023.

ABSTRACT

Research interest in understanding tinnitus has increased severalfold in the last decade to find a cure for this auditory disorder. Hyperacusis can also accompany tinnitus, although the mechanisms involved in hyperacusis and tinnitus are different. Millions of people suffer from some degree of tinnitus with hearing loss. Tinnitus is believed to be a form of sensory epilepsy, spawning neuronal hyperactivity from the cochlear nucleus and inferior colliculus of the auditory brainstem region. Cannabis has been used for recreation, medicinal purposes, and served as an entheogen from time immemorial. With the current and increasing global medical and recreational cannabis legalization, there is renewed enthusiasm for the use of cannabinoid drugs, and the role of the endocannabinoid system (ECS) in several health disorders including tinnitus which is associated with COVID-19. The ECS signaling pathways have been proposed to affect the underlying pathophysiology of tinnitus. Cannabinoid receptors (CBRs) have been found in the auditory system, raising interest in ECS signaling in hearing and tinnitus. However, previous studies mostly in animal models of tinnitus did not investigate the involvement of CB2Rs but focused on CB1R-based responses, which suggested that CB1R ligands had no effect and may even be harmful and worsen tinnitus. With new molecular techniques and transgenic approaches used to dissect the complexity of the ECS, the role of ECS/CB2R neuroimmunological function in the auditory system and tinnitus is emerging. This perspective proposes the role of emerging neuroimmune crosstalk of the ECS in sound-sensing structures of the auditory system as a potential pharmacogenomic therapeutic target using cannabinoid CB2R ligands in tinnitus in the era of the COVID-19 pandemic.

PMID:37305742 | PMC:PMC10248455 | DOI:10.3389/fneur.2023.1148327

Innov Pharm. 2022 Dec 26;13(4). doi: 10.24926/iip.v13i4.5035. eCollection 2022.

ABSTRACT

Background: Sertraline is commonly prescribed to children for the treatment of anxiety and major depressive disorder and is metabolized in part by CYP2C19. While dosing recommendations based on CYP2C19 genotype exist, there is sparse data in children on the relationship between sertraline concentrations and CYP2C19 genotype. Additionally, although rarely utilized in the United States, therapeutic drug monitoring can also help to guide dosing. The primary objective of this pilot study was to compare sertraline concentrations with CYP2C19 genotype. Secondary objectives included exploring the feasibility of using pharmacogenetic testing and therapeutic drug monitoring in a residential treatment center for children and adolescents. Methods: This study was a prospective, open-label study of children prescribed sertraline being treated at a residential treatment center for children and adolescents. Individuals were included if they were < 18 years of age, taking sertraline for at least 2 weeks allowing them to reach steady-state concentrations, being treated through the residential treatment program, and able to understand and speak English. Results: A total of 20 participants (80% female) completed all study procedures, including pharmacogenetic testing and therapeutic drug monitoring, with an average age of 15.4 years (range: 9-17 years). Forty percent (n=8) of participants had a diagnosis of Generalized Anxiety Disorder, while 30% (n=6) had a diagnosis of Major Depressive Disorder. Overall, average sertraline and desmethylsertraline concentrations were 21.1 ng/ml (range: 1-78 ng/ml) and 52.4 ng/ml (range: 1-258 n/ml). Based on CYP2C19 genotypes, 60% (n=12) were normal metabolizers, 10% (n=2) were intermediate metabolizers, and 30% (n=6) were rapid metabolizers. Daily sertraline dose (mg/day) accounted for a significant amount of the observed variability in sertraline (p<0.0001; r2=0.62) and desmethylsertraline concentrations (p<0.001; r2=0.45). When comparing weight-based dosing by sertraline and desmethylsertraline concentrations, sertraline daily dose by weight (mg/kg/day) also accounted for a significant amount of the observed variability in sertraline (p<0.0001; r2=0.60) and desmethylsertraline (p<0.0001; r2=0.59) concentrations. Average daily and weight-based doses for CYP2C19 intermediate, normal, and rapid metabolizers were 75 mg/day, 87.5 mg/day, and 79.2 mg/day and 1.5 mg/kg/day, 1.3 mg/kg/day, and 1.1 mg/kg/day, though these were not significantly different. Conclusion: This small, pilot study showed sertraline dose to be significantly associated with sertraline and desmethylsertraline concentrations. No differences were noted between CYP2C19 metabolizer groups, likely due to the limited sample size. These results also suggest that ordering pharmacogenetic testing and therapeutic drug monitoring in the setting of a child and adolescent residential treatment center is feasible.

PMID:37305603 | PMC:PMC10256290 | DOI:10.24926/iip.v13i4.5035

Front Pharmacol. 2023 May 26;14:1116226. doi: 10.3389/fphar.2023.1116226. eCollection 2023.

ABSTRACT

Objectives: This study was performed to develop a population pharmacokinetic model of pyrazinamide for Korean tuberculosis (TB) patients and to explore and identify the influence of demographic and clinical factors, especially geriatric diabetes mellitus (DM), on the pharmacokinetics (PK) of pyrazinamide (PZA). Methods: PZA concentrations at random post-dose points, demographic characteristics, and clinical information were collected in a multicenter prospective TB cohort study from 18 hospitals in Korea. Data obtained from 610 TB patients were divided into training and test datasets at a 4:1 ratio. A population PK model was developed using a nonlinear mixed-effects method. Results: A one-compartment model with allometric scaling for body size effect adequately described the PK of PZA. Geriatric patients with DM (age >70 years) were identified as a significant covariate, increasing the apparent clearance of PZA by 30% (geriatric patients with DM: 5.73 L/h; others: 4.50 L/h), thereby decreasing the area under the concentration-time curve from 0 to 24 h by a similar degree compared with other patients (geriatric patients with DM: 99.87 μg h/mL; others: 132.3 μg h/mL). Our model was externally evaluated using the test set and provided better predictive performance compared with the previously published model. Conclusion: The established population PK model sufficiently described the PK of PZA in Korean TB patients. Our model will be useful in therapeutic drug monitoring to provide dose optimization of PZA, particularly for geriatric patients with DM and TB.

PMID:37305528 | PMC:PMC10250603 | DOI:10.3389/fphar.2023.1116226

Chronic Dis Transl Med. 2023 Feb 8;9(2):154-163. doi: 10.1002/cdt3.59. eCollection 2023 Jun.

ABSTRACT

BACKGROUND: This study aimed to assess the prescribing patterns of evidence-based pharmacotherapy and their association with clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF) in Thailand.

METHODS: A retrospective cohort study of patients with HFrEF was conducted. Treatment with a β-blocker and renin-angiotensin system inhibitors (RASIs) with or without mineralocorticoid receptor antagonists (MRAs) at discharge was regarded as guideline-directed medical therapy (GDMT). All others were considered non-GDMT. The primary endpoint was the composite of all-cause mortality or heart failure (HF) rehospitalization. Inverse-probability-treatment-weighted adjusted Cox proportional hazard models were used to examine the treatment effects.

RESULTS: In total, 653 patients with HFrEF (mean age 64.1 ± 14.3 years; 55.9% male) were included. GDMT with β-blockers and RASIs with or without MRAs was prescribed at a rate of 35.4%. During a median of 1-year follow-up, 167 patients (27.5%) had a composite event, 81 patients (13.3%) had all-cause mortality, and 109 patients (18.0%) had HF rehospitalization. Patients treated with GDMT at discharge showed significantly lower rates of the primary endpoint (adjusted hazard ratio [HR] 0.63; 95% CI 0.44-0.89; p = 0.009) compared with patients who did not receive GDMT. The use of GDMT was also associated with a significantly lower risk of all-cause mortality (adjusted HR 0.59; 95% CI 0.36-0.98; p = 0.045) and HF rehospitalization (adjusted HR 0.65; 95% CI 0.43-0.96; p = 0.031).

CONCLUSIONS: For HFrEF treatment, GDMT initiation at hospital discharge was associated with a significantly reduced risk of all-cause mortality and HF rehospitalization. Nevertheless, prescribing GDMT remains underused, and it could be encouraged to improve HF outcomes in real-world settings.

PMID:37305111 | PMC:PMC10249177 | DOI:10.1002/cdt3.59

Clin Pharmacol Ther. 2023 May 24. doi: 10.1002/cpt.2957. Online ahead of print.

ABSTRACT

Pharmacogenetics can improve clinical outcomes by reducing adverse drug effects and enhancing therapeutic efficacy for commonly used drugs that treat a wide range of cardiovascular diseases. One of the major barriers to the clinical implementation of cardiovascular pharmacogenetics is limited education on this field for current healthcare providers and students. The abundance of pharmacogenetic literature underscores its promise, but it can also be challenging to learn such a wealth of information. Moreover, current clinical recommendations for cardiovascular pharmacogenetics can be confusing because they are outdated, incomplete, or inconsistent. A myriad of misconceptions about the promise and feasibility of cardiovascular pharmacogenetics among healthcare providers also has halted clinical implementation. Therefore, the main goal of this tutorial is to provide introductory education on the use of cardiovascular pharmacogenetics in clinical practice. The target audience is any healthcare provider (or student) with patients that use or have indications for cardiovascular drugs. This tutorial is organized into the following 6 steps: (1) understand basic concepts in pharmacogenetics; (2) gain foundational knowledge of cardiovascular pharmacogenetics; (3) learn the different organizations that release cardiovascular pharmacogenetic guidelines and recommendations; (4) know the current cardiovascular drugs/drug classes to focus on clinically and the supporting evidence; (5) discuss an example patient case of cardiovascular pharmacogenetics; and (6) develop an appreciation for emerging areas in cardiovascular pharmacogenetics. Ultimately, improved education among healthcare providers on cardiovascular pharmacogenetics will lead to a greater understanding for its potential in improving outcomes for a leading cause of morbidity and mortality.

PMID:37303270 | DOI:10.1002/cpt.2957

Med Sci Monit. 2023 Jun 12;29:e940119. doi: 10.12659/MSM.940119.

ABSTRACT

BACKGROUND Pharmacogenomics (PGx) has a direct influence on personalized drug therapy for various types of disorders and has been proven to have an important role in the future of medicine. The present study evaluated the awareness of PGx testing of clinicians and healthcare workers in the Republic of Poland. To the best of our knowledge, this is the first direct assessment of Polish healthcare professionals' attitudes toward introducing PGx tests into daily clinical practice. MATERIAL AND METHODS We used a comprehensive anonymous questionnaire with queries on level of education, background knowledge of PGx tests, advantages and barriers for implementation of such tests, and clinicians' desire to order the test that was distributed online to doctors, healthcare workers, related students/Ph.D. students, and administrative staff managing healthcare units. RESULTS We gathered 315 responses. According to the answers, two-thirds of participants had heard about PGx before (64.4%). An overwhelming majority of respondents appreciated the benefits of PGx (93.3%). Indeed, prior knowledge and level of education showed significant associations with positive attitudes toward PGx clinical testing (P≤0.05). However, all participants agreed there are major challenges for including such tests as part of routine clinical practice. CONCLUSIONS While the awareness and interest in PGx clinical testing in Polish healthcare providers are rising, some main barriers for implementation of these tests still need to be addressed in Poland.

PMID:37303136 | DOI:10.12659/MSM.940119

Int J Risk Saf Med. 2023 Jun 7. doi: 10.3233/JRS-220028. Online ahead of print.

ABSTRACT

BACKGROUND: There is currently no widespread implementation of pharmacogenetic testing (PGx) methods in the practice of phthisiology service.

OBJECTIVE: The aim of this study is to determine how informed and prepared phthisiologists, residents, and postgraduate students of the Russian Medical Academy of Continuing Professional Education (RMACPE, Moscow) use PGx techniques in their work to improve treatment safety, predict the occurrence of adverse reactions (ADRs), and personalize therapy.

METHODS: A survey was conducted among phthisiologists (n = 314) living in different regions of the Russian Federation and studying at RMACPE, such as residents and post-graduate students (n = 185). The survey was developed on the Testograf.ru web platform and had 25 questions for physicians and 22 for residents and post-graduate students.

RESULTS: More than 50% of respondents are ready to use PGx in clinical practice and thus are aware of the method's possibilities. At the same time only a small part of participants were aware of the pharmgkb.org resource. The absence of PGx in clinical guidelines and treatment standards, according to 50.95% of phthisiologists and 55.13% of students of RMACPE, the absence of large-scale randomized clinical trials, according to 37.26% of phthisiologists and 43.33% of students, and the lack of physician knowledge on PGx, according to 41.08% of phthisiologists and 57.83% of students, are all factors that prevent the implementation of PGx in Russia.

CONCLUSION: According to the survey, the overwhelming majority of participants recognize the importance of PGx and are willing to use the method in practice. However, there is a low level of awareness among all respondents about the possibilities of PGx and the pharmgkb.org resource. The implementation of this service could significantly increase patient compliance, lower ADRs, and enhance anti-tuberculosis (TB) therapy quality.

PMID:37302041 | DOI:10.3233/JRS-220028

J Exp Clin Cancer Res. 2023 Jun 10;42(1):145. doi: 10.1186/s13046-023-02718-w.

ABSTRACT

BACKGROUND: Metabolic reprogramming is a well-known marker of cancer, and it represents an early event during hepatocellular carcinoma (HCC) development. The recent approval of several molecular targeted agents has revolutionized the management of advanced HCC patients. Nevertheless, the lack of circulating biomarkers still affects patient stratification to tailored treatments. In this context, there is an urgent need for biomarkers to aid treatment choice and for novel and more effective therapeutic combinations to avoid the development of drug-resistant phenotypes. This study aims to prove the involvement of miR-494 in metabolic reprogramming of HCC, to identify novel miRNA-based therapeutic combinations and to evaluate miR-494 potential as a circulating biomarker.

METHODS: Bioinformatics analysis identified miR-494 metabolic targets. QPCR analysis of glucose 6-phosphatase catalytic subunit (G6pc) was performed in HCC patients and preclinical models. Functional analysis and metabolic assays assessed G6pc targeting and miR-494 involvement in metabolic changes, mitochondrial dysfunction, and ROS production in HCC cells. Live-imaging analysis evaluated the effects of miR-494/G6pc axis in cell growth of HCC cells under stressful conditions. Circulating miR-494 levels were assayed in sorafenib-treated HCC patients and DEN-HCC rats.

RESULTS: MiR-494 induced the metabolic shift of HCC cells toward a glycolytic phenotype through G6pc targeting and HIF-1A pathway activation. MiR-494/G6pc axis played an active role in metabolic plasticity of cancer cells, leading to glycogen and lipid droplets accumulation that favored cell survival under harsh environmental conditions. High miR-494 serum levels associated with sorafenib resistance in preclinical models and in a preliminary cohort of HCC patients. An enhanced anticancer effect was observed for treatment combinations between antagomiR-494 and sorafenib or 2-deoxy-glucose in HCC cells.

CONCLUSIONS: MiR-494/G6pc axis is critical for the metabolic rewiring of cancer cells and associates with poor prognosis. MiR-494 deserves attention as a candidate biomarker of likelihood of response to sorafenib to be tested in future validation studies. MiR-494 represents a promising therapeutic target for combination strategies with sorafenib or metabolic interference molecules for the treatment of HCC patients who are ineligible for immunotherapy.

PMID:37301960 | DOI:10.1186/s13046-023-02718-w

J Am Heart Assoc. 2023 Jun 10:e029361. doi: 10.1161/JAHA.123.029361. Online ahead of print.

ABSTRACT

Background Cyclin-dependent kinase (CDK) 4 and 6 inhibitors have significantly improved survival in patients with hormone receptor-positive metastatic breast cancer. There are few data regarding the epidemiology of cardiovascular adverse events (CVAEs) with these therapies. Methods and Results Using the OneFlorida Data Trust, adult patients without prior cardiovascular disease who received at least 1 CDK4/6 inhibitor were included in the analysis. CVAEs identified from International Classification of Diseases, Ninth and Tenth Revisions (ICD-9/10) codes included hypertension, atrial fibrillation(AF)/atrial flutter (AFL), heart failure/cardiomyopathy, ischemic heart disease, and pericardial disease. Competing risk analysis (Fine-Gray model) was used to determine the association between CDK4/6 inhibitor therapy and incident CVAEs. The effect of CVAEs on all-cause death was studied using Cox proportional hazard models. Propensity-weight analyses were performed to compare these patients to a cohort of patients treated with anthracyclines. A total of 1376 patients treated with CDK4/6 inhibitors were included in the analysis. CVAEs occurred in 24% (35.9 per 100 person-years). CVAEs were slightly higher in patients who received CKD4/6 inhibitors compared with anthracyclines (P=0.063), with higher death rate associated with the development of AF/AFL or cardiomyopathy/heart failure in the CDK4/6 group. The development of cardiomyopathy/heart failure and AF/AFL was associated with increased all-cause death (adjusted hazard ratio [HR], 4.89 [95% CI, 2.98-8.05]; and 5.88 [95% CI, 3.56-9.73], respectively). Conclusions CVAEs may be more common with CDK4/6 inhibitors than previously recognized, with increased death rates in these patients who develop AF/AFL or heart failure. Further research is needed to definitively determine cardiovascular risk associated with these novel anticancer treatments.

PMID:37301767 | DOI:10.1161/JAHA.123.029361

Clin Ther. 2023 Jun 8:S0149-2918(23)00135-2. doi: 10.1016/j.clinthera.2023.04.006. Online ahead of print.

ABSTRACT

PURPOSE: The anticoagulation activity of warfarin in populations with CYP2C9, VKORC1, and CYP4F2 variants differs between individuals and is correlated with poor international normalized ratio (INR) control. Pharmacogenetics-guided warfarin dosing has been successfully developed for patients with genetic variations in recent years. However, few real-world data have been used to investigate the INR and warfarin dosage and the time to target INR. This study examined the largest collection of genetic and clinical real-world data related to warfarin to provide further evidence supporting the benefits of pharmacogenetics in clinical outcomes.

METHODS: We retrieved a total of 69,610 INR-warfarin records after the index date from 2,613 patients in the China Medical University Hospital database between January 2003 and December 2019. Each INR reading was obtained from the latest laboratory data after the hospital visit date. Patients with a history of malignant neoplasms or pregnancy before the index date were excluded, as were patients without data on INR measurements after the fifth day of prescription, genetic information, or gender variables. The primary outcomes were the INR and warfarin dosage during days 7, 14, 28, 56, and 84 after prescription. The secondary outcome was the time required to reach the INR ranges of 1.5 to 3.0 and >4.0.

FINDINGS: A total of 59,643 INR-warfarin records from 2188 patients were retrieved. The average INR was higher for homozygous carriers of the minor allele at CYP2C9 and VKORC1 during the first 7 days (1.83 [1.03] [CYP2C9*1] and 2.46 [1.44] [CYP2C9*3], P < 0.001; 1.39 [0.36] [rs9923231 G/G], 1.55 [0.79] [rs9923231 G/A], and 1.96 [1.13] [rs9923231 A/A], P < 0.001) than for the wild-type allele. These patients with variants required lower warfarin doses than those with the wild-type allele during the first 28 days. CYP4F2 variant patients seemed to require higher doses of warfarin than those in the wild-type group; however, no significant difference in the average INR was observed (1.95 [1.14] [homozygous V433 carriers], 1.78 [0.98] [heterozygous V433M carriers], and 1.66 [0.91] [homozygous M433 carriers], P = 0.016).

IMPLICATIONS: Our study indicates that genetic variants in the Han population may enhance warfarin responsiveness, which holds clinical relevance. An increased warfarin dosage was not linked to a shorter time to therapeutic INR between CYP4F2 variant patients and those with a wild-type allele. Assessing CYP2C9 and VKORC1 genetic polymorphisms before initiating warfarin treatment in real-world practice is essential for potentially vulnerable patients and is likely to optimize therapeutic dosing.

PMID:37301690 | DOI:10.1016/j.clinthera.2023.04.006