Circ Res. 2023 Apr 14. doi: 10.1161/CIRCRESAHA.122.321833. Online ahead of print.

ABSTRACT

BACKGROUND: Cardiac contractile function requires high energy from mitochondria, and Ca2+ from the sarcoplasmic reticulum (SR). Via local Ca2+ transfer at close mitochondria-SR contacts, cardiac excitation feedforward regulates mitochondrial ATP production to match surges in demand (excitation-bioenergetics coupling). However, pathological stresses may cause mitochondrial Ca2+ overload, excessive reactive oxygen species production and permeability transition, risking homeostatic collapse and myocyte loss. Excitation-bioenergetics coupling involves mitochondria-SR tethers but the role of tethering in cardiac physiology/pathology is debated. Endogenous tether proteins are multifunctional; therefore, nonselective targets to scrutinize interorganelle linkage. Here, we assessed the physiological/pathological relevance of selective chronic enhancement of cardiac mitochondria-SR tethering.

METHODS: We introduced to mice a cardiac muscle-specific engineered tether (linker) transgene with a fluorescent protein core and deployed 2D/3D electron microscopy, biochemical approaches, fluorescence imaging, in vivo and ex vivo cardiac performance monitoring and stress challenges to characterize the linker phenotype.

RESULTS: Expressed in the mature cardiomyocytes, the linker expanded and tightened individual mitochondria-junctional SR contacts; but also evoked a marked remodeling with large dense mitochondrial clusters that excluded dyads. Yet, excitation-bioenergetics coupling remained well-preserved, likely due to more longitudinal mitochondria-dyad contacts and nanotunnelling between mitochondria exposed to junctional SR and those sealed away from junctional SR. Remarkably, the linker decreased female vulnerability to acute massive β-adrenergic stress. It also reduced myocyte death and mitochondrial calcium-overload-associated myocardial impairment in ex vivo ischemia/reperfusion injury.

CONCLUSIONS: We propose that mitochondria-SR/endoplasmic reticulum contacts operate at a structural optimum. Although acute changes in tethering may cause dysfunction, upon chronic enhancement of contacts from early life, adaptive remodeling of the organelles shifts the system to a new, stable structural optimum. This remodeling balances the individually enhanced mitochondrion-junctional SR crosstalk and excitation-bioenergetics coupling, by increasing the connected mitochondrial pool and, presumably, Ca2+/reactive oxygen species capacity, which then improves the resilience to stresses associated with dysregulated hyperactive Ca2+ signaling.

PMID:37057625 | DOI:10.1161/CIRCRESAHA.122.321833

Frontline Gastroenterol. 2022 Nov 17;14(3):258-262. doi: 10.1136/flgastro-2022-102342. eCollection 2023.

NO ABSTRACT

PMID:37056322 | PMC:PMC10086732 | DOI:10.1136/flgastro-2022-102342

Eur J Surg Oncol. 2023 Apr 13:S0748-7983(23)00438-9. doi: 10.1016/j.ejso.2023.04.001. Online ahead of print.

ABSTRACT

Despite the wide reportage of prognostic factors for glioblastoma (GBM), it is difficult to determine how these factors interact to affect patients' survival. To determine the combination of prognostic factors, we retrospectively analyzed the clinic data of 248 IDH wild-type GBM patients and built a novel prediction model. The survival variables of patients were identified via univariate and multivariate analyses. In addition, the score prediction models were constructed by combining classification and regression tree (CART) analysis with Cox regression analysis. Finally, the prediction model was internally validated using the bootstrap method. Patients were followed for a median of 34.4 (interquartile range, 26.1-46.0) months. Multivariate analysis identified gross total resection (GTR) (HR 0.50, 95% CI: 0.38-0.67), unopened ventricles (HR 0.75 [0.57-0.99]), and MGMT methylation (HR 0.56 [0.41-0.76]) as favorable independent prognostic factors for PFS. GTR (HR 0.67 [0.49-0.92]), unopened ventricles (HR 0.60 [0.44-0.82]), and MGMT methylation (HR 0.54 [0.38-0.76]) were favorable independent prognostic factors for OS. In the process of building the model, we incorporated GTR, ventricular opening, MGMT methylation status, and age. The model had six and five terminal nodules in PFS and OS respectively. We grouped terminal nodes with similar hazard ratios together to form three sub-groups with different PFS and OS (P < 0.001). After the internal verification of bootstrap method, the model had a good fitting and calibration. GTR, unopened ventricles, and MGMT methylation were independently associated with more satisfactory survival. The novel score prediction model which we construct can provide a prognostic reference for GBM.

PMID:37076410 | DOI:10.1016/j.ejso.2023.04.001

Food Sci Nutr. 2023 Jan 13;11(4):1657-1670. doi: 10.1002/fsn3.3217. eCollection 2023 Apr.

ABSTRACT

Antioxidants are compounds that inhibit the oxidation of other molecules and protect the body from the effects of free radicals, produced either by normal cell metabolism or as an effect of pollution and exposure to other external factors and are responsible for premature aging and play a role in cardiovascular disease. degenerative diseases such as cataracts, Alzheimer's disease, and cancer. While many antioxidants are found in nature, others are obtained in synthetic form and reduce oxidative stress in organisms. This review highlights the pharmacological relevance of antioxidants in fruits, plants, and other natural sources and their beneficial effect on human health through the analysis and in-depth discussion of studies that included phytochemistry and their pharmacological effects. The information obtained for this review was collected from several scientific databases (ScienceDirect, TRIP database, PubMed/Medline, Scopus, Web of Science), professional websites, and traditional medicine books. Current pharmacological studies and evidence have shown that the various natural antioxidants present in some fruits, seeds, foods, and natural products have different health-promoting effects. Adopting functional foods with high antioxidant potential will improve the effective and affordable management of free radical diseases while avoiding the toxicities and unwanted side effects caused by conventional medication.

PMID:37051367 | PMC:PMC10084981 | DOI:10.1002/fsn3.3217

Molecules. 2023 Mar 31;28(7):3128. doi: 10.3390/molecules28073128.

ABSTRACT

Herein, the antitumor activity of a novel synthetic analog with 5,8-quinolinedione scaffold, diethyl (2-(2-chlorophenyl)-4,9-dioxo-4,9-dihydrofuro [3,2-g]quinolin-3-yl)phosphonate (AJ-418) was investigated on two breast cancer cell lines. This analog was selected from a small library of synthetic quinolinediones on the basis of its strong antiproliferative activity against MCF-7 and MDA-MB-231 cells and 4-5-fold lower cytotoxicity towards healthy MCF-10A cells. The morphology of MCF-7 and MDA-MB-231 cancer cells treated with AJ-418 changed drastically, while non-tumorigenic MCF-10A cells remained unaffected. In MCF-7 cells, after 24 h incubation, the increased number of apoptotic cells coincided with a decrease in proliferation and cell viability. The 24 h treatment of MDA-MB-231 cells with the tested compound reduced their cell viability and proliferation rate; however, a significant pro-apoptotic effect was visible only after longer incubation times (48 h and 72 h). Then, the maximum tolerated dose (MTD) of compound AJ-418 in C3H mice after subcutaneous administration was determined to be 160 mg/kg, showing that this analog was well tolerated and can be further evaluated to assess its potential therapeutic effect in tumor-bearing mice.

PMID:37049894 | DOI:10.3390/molecules28073128

JACC Cardiovasc Interv. 2023 Apr 10;16(7):826-828. doi: 10.1016/j.jcin.2023.02.008.

NO ABSTRACT

PMID:37045503 | DOI:10.1016/j.jcin.2023.02.008

Cell Rep Med. 2023 Apr 11:101021. doi: 10.1016/j.xcrm.2023.101021. Online ahead of print.

ABSTRACT

Swen et al.1 examine the utility of multi-gene pharmacogenetic testing in a large multi-national cohort. They show fewer adverse drug reactions among patients receiving testing and prescribing recommendations based on genotype results compared with those receiving usual care.

PMID:37084734 | DOI:10.1016/j.xcrm.2023.101021

Drug Metab Dispos. 2023 Apr 11:DMD-AR-2023-001310. doi: 10.1124/dmd.123.001310. Online ahead of print.

ABSTRACT

Single-nucleotide substitutions of human flavin-containing monooxygenase 3 (FMO3) identified in the whole-genome sequences of the updated Japanese population reference panel (now containing 38,000 subjects) were investigated. In this study, 2 stop codon mutations, 2 frameshifts, and 43 amino-acid-substituted FMO3 variants were identified. Among these 47 variants, 1 stop codon mutation, 1 frameshift, and 24 substituted variants were already recorded in the National Center for Biotechnology Information database. Functionally impaired FMO3 variants are known to be associated with the metabolic disorder trimethylaminuria; consequently, the enzymatic activities of the 43 substituted FMO3 variants were investigated. Twenty-seven recombinant FMO3 variants expressed in bacterial membranes had similar activities toward trimethylamine N-oxygenation (~75-125%) to that of wild-type FMO3 (98 min-1). However, 6 recombinant FMO3 variants (Arg51Gly, Val283Ala, Asp286His, Val382Ala, Arg387His, and Phe451Leu) had moderately decreased (≈50%) activities toward trimethylamine N-oxygenation, and 10 recombinant FMO3 variants (Gly11Asp, Gly39Val, Met66Lys, Asn80Lys, Val151Glu, Gly193Arg, Arg387Cys, Thr453Pro, Leu457Trp, and Met497Arg) showed severely decreased FMO3 catalytic activity (<10%). Because of the known deleterious effects of FMO3 C-terminal stop codons, the four truncated FMO3 variants (Val187SerfsTer25, Arg238Ter, Lys416SerfsTer72, and Gln427Ter) were suspected to be inactive with respect to trimethylamine N-oxygenation. The FMO3 p.Gly11Asp and p.Gly193Arg variants were located within the conserved sequences of flavin adenine dinucleotide (positions 9-14) and NADPH (positions 191-196) binding sites, which are important for FMO3 catalytic function. Whole-genome sequence data and kinetic analyses revealed that 20 of the 47 nonsense or missense FMO3 variants had moderately or severely impaired activity toward N-oxygenation of trimethylaminuria. Significance Statement The number of single-nucleotide substitutions in human FMO3 recorded in the expanded Japanese population reference panel database was updated. One novel stop mutation, FMO3 p.Gln427Ter; one novel frameshift (p.Lys416SerfsTer72); and 19 novel amino-acid-substituted FMO3 variants were identified, along with p.Arg238Ter, p.Val187SerfsTer25, and 24 amino-acid-substituted variants already recorded with individual rs numbers. Recombinant FMO3 Gly11Asp, Gly39Val, Met66Lys, Asn80Lys, Val151Glu, Gly193Arg, Arg387Cys, Thr453Pro, Leu457Trp, and Met497Arg variants showed severely decreased FMO3 catalytic activity, possibly associated with the metabolic disorder trimethylaminuria.

PMID:37041084 | DOI:10.1124/dmd.123.001310

Pediatr Pulmonol. 2023 Apr 10. doi: 10.1002/ppul.26412. Online ahead of print.

ABSTRACT

INTRODUCTION: Reports of neuropsychiatric symptoms proximal to cystic fibrosis transmembrane conductance regulator (CFTR) modulator initiation are emerging, but their prevalence and management remain poorly characterized.

METHODS: Retrospective chart review was used to categorize symptom trajectories of all adults at a single CF Center who initiated elexacaftor/tezacaftor/ivacaftor (ETI) before March 2022 and subsequently had ≥1 outpatient visit with the consulting CF psychiatrist. For those who developed neuropsychiatric symptoms probably related to ETI and modified treatment in response, the strategy resulting in greatest improvement with acceptable physical course and tolerability was identified. Ratings were made by a psychiatrist not involved in clinical care.

RESULTS: Of 148 adults initiating ETI, 31 were psychiatrically evaluated, 16 of whom developed new/worsening and unexpected neuropsychiatric symptoms probably related to ETI, including neurocognitive (word finding, brain fog, memory, attention/concentration), insomnia, depression, anxiety, fatigue/low energy, mania/hypomania, other distress. This group had higher maximum lifetime Generalized Anxiety Disorder-7 scores (14.42 ± 0.96; p = 0.05) than those with improved, unchanged, or worsening/possibly related symptoms (N = 15; 9.9 ± 1.82). Treatment strategies resulting in much/very much improvement included pharmacologic interventions, psychotherapy, and dose reduction/discontinuing ETI.

CONCLUSIONS: Although many people initiating ETI experience improved physical and mental health and quality of life, a subset report worsening neurocognition, mood, and anxiety. As novel therapies are developed, ascertaining and evaluating neuropsychiatric symptoms in clinical and research settings is advisable. Larger studies are needed to characterize prevalence, course, and risk factors (e.g., age, gender, clinical status, pharmacokinetics/pharmacogenomics, drug-drug interactions) for neuropsychiatric adverse events related to CFTR modulators and guide effective management.

PMID:37036050 | DOI:10.1002/ppul.26412

JHEP Rep. 2023 Feb 26;5(5):100716. doi: 10.1016/j.jhepr.2023.100716. eCollection 2023 May.

ABSTRACT

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH)-induced liver fibrosis is emerging as the most common cause of liver disease. For evaluation of therapies, there is a pressing need to identify non-invasive, mechanism-based biomarkers. A pro-fibrotic process relevant to human NASH involves a pathway in which a transcriptional regulator called TAZ (WWTR1) in hepatocytes induces the secretion of pro-fibrotic Indian hedgehog (IHH). We therefore reasoned that circulating IHH may be a useful mechanism-based marker to assess changes in NASH fibrosis.

METHODS: Circulating IHH was assessed in wild-type and hepatocyte-TAZ-silenced NASH mice and in three separate cohorts of patients with mild-moderate NASH.

RESULTS: Circulating IHH was elevated in mice with diet-induced NASH compared with chow-fed mice or with NASH mice in which hepatocyte TAZ was silenced, which is an effective means to decrease NASH fibrosis. In patients with fatty liver disease with or without NASH, NASH fibrosis was associated with increased concentrations of circulating IHH.

CONCLUSIONS: The results of these analyses support further investigation to determine whether circulating IHH may be useful as a mechanism-based indicator of target engagement in anticipated future clinical trials testing NASH fibrosis therapies that block the IHH pathway.

IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH)-induced liver fibrosis is a common cause of liver disease. Circulating biomarkers that reflect liver fibrosis in NASH would be very useful to evaluate therapies. One mechanism of NASH fibrosis with potential as a therapeutic target involves a liver-secreted protein called Indian hedgehog (IHH). We report that circulating levels of IHH in experimental and human NASH associates with NASH and NASH-associated liver fibrosis, providing the premise for further investigation into using circulating IHH to evaluate anticipated future NASH therapies that block the IHH pathway in liver.

PMID:37035456 | PMC:PMC10074197 | DOI:10.1016/j.jhepr.2023.100716

Clin Pharmacol Ther. 2023 Apr 9. doi: 10.1002/cpt.2903. Online ahead of print.

ABSTRACT

Serotonin reuptake inhibitor antidepressants, including selective serotonin reuptake inhibitors (SSRIs; i.e., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin and norepinephrine reuptake inhibitors (SNRIs; i.e., desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine), and serotonin modulators with SSRI-like properties (i.e., vilazodone and vortioxetine) are primary pharmacologic treatments for major depressive and anxiety disorders. Genetic variation in CYP2D6, CYP2C19, and CYP2B6 influences the metabolism of many of these antidepressants, which may potentially affect dosing, efficacy, and tolerability. In addition, the pharmacodynamic genes SLC6A4 (serotonin transporter) and HTR2A (serotonin-2A receptor) have been examined in relation to efficacy and side effect profiles of these drugs. This guideline updates and expands the 2015 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and SSRI dosing and summarizes the impact of CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes on antidepressant dosing, efficacy, and tolerability. We provide recommendations for using CYP2D6, CYP2C19 and CYP2B6 genotype results to help inform prescribing these antidepressants and describe the existing data for SLC6A4 and HTR2A which do not support their clinical use in antidepressant prescribing.

PMID:37032427 | DOI:10.1002/cpt.2903

Behav Brain Res. 2023 Apr 6:114423. doi: 10.1016/j.bbr.2023.114423. Online ahead of print.

ABSTRACT

Persicaria minor (P. minor) is a herbal plant with many uses in food, perfume, and the medical industry. P. minor extract contains flavonoids with antioxidant and anticholinesterase capacity, which could enhance cognitive functions. P. minor extract has been proven to enhance memory. However, its role in an animal model of chronic cerebral hypoperfusion (CCH), which resembles human vascular dementia, has yet to be explored. Therefore, the present study investigates the effects of chronic (14 days) administration of aqueous P. minor extract on different stages of learning and memory processes and the metabolic pathways involved in the chronic cerebral hypoperfused rats induced by the permanent bilateral occlusion of common carotid arteries (PBOCCA) surgery. Chronic treatment of P. minor extract at doses of 200 and 300mg/kg, enhanced recognition memory of the PBOCCA rats. P. minor extract (200mg/kg) was also found to restore the spatial memory impairment induced by CCH. A high dose (300mg/kg) of the P. minor extract significantly increased the expression of both ACh and GABA neurotransmitters in the hippocampus. Further, distinctive metabolite profiles were observed in rats with different treatments. Three major pathways involved in the cognitive enhancement mechanism of P. minor were identified. The present findings demonstrated an improving effect of P. minor extract on memory in the CCH rat model, suggesting that P. minor extract could be a potential treatment for vascular dementia and Alzheimer's patients. P. minor is believed to improve cognitive deficits by regulating pathways involved in retinol, histidine, pentose, glucuronate, and CoA metabolism.

PMID:37030545 | DOI:10.1016/j.bbr.2023.114423

Small. 2023 Apr 8:e2300395. doi: 10.1002/smll.202300395. Online ahead of print.

ABSTRACT

Phenytoin (PHT) is a first-line antiepileptic drug in clinics, which could decrease neuronal bioelectric activity by blocking the voltage-operated sodium channels. However, the intrinsically low blood-brain-barrier (BBB)-crossing capability of PHT and upregulated expression level of the efflux transporter p-glycoprotein (P-gp) coded by the gene Abcb1 in epileptic neurons limit its efficacy in vivo. Herein, a nanointegrated strategy to overcome PHT resistance mechanisms for enhanced antiepileptic efficacy is reported. Specifically, PHT is first incorporated into calcium phosphate (CaP) nanoparticles through biomineralization, followed by the surface modification of the PEGylated BBB-penetrating TAT peptide. The CaP@PHT-PEG-TAT nanoformulation could effectively cross the BBB to be taken in by epileptic neurons. Afterward, the acidic lysosomal environment would trigger their complete degradation to release Ca2+ and PHT into the cytosol. Ca2+ ions would inhibit mitochondrial oxidative phosphorylation to reverse cellular hypoxia to block hypoxia-inducible factor-1α (Hif1α)-Abcb1-axis, as well as disrupt adenosine triphosphate generation, leading to simultaneous suppression of the expression and drug efflux capacity of P-gp to enhance PHT retention. This study offers an approach for effective therapeutic intervention against drug-resistant epilepsy.

PMID:37029709 | DOI:10.1002/smll.202300395

Oncologist. 2023 Apr 7:oyad050. doi: 10.1093/oncolo/oyad050. Online ahead of print.

ABSTRACT

BACKGROUND: Severe chemotherapy-related toxicities are frequent among older patients. The Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) and the Cancer and Aging Research Group Study (CARG) score were both developed to predict these events.

PATIENTS AND METHODS: The objective of this study was to evaluate the scores' predictive performance in a prospective cohort, which included patients aged 70 years and older referred for a geriatric assessment prior to chemotherapy for a solid tumor. The main endpoints were grades 3/4/5 toxicities for the CARG score and grades 4/5 hematologic toxicities and grades 3/4/5 non-hematologic toxicities for the CRASH score.

RESULTS: A total of 248 patients were included, of which 150 (61%) and 126 (51%) experienced at least one severe adverse event as defined respectively in CARG and CRASH studies. The incidence of adverse events was not significantly greater in the intermediate and high-risk CARG groups than in the low-risk group (odds ratio (OR) [95% CI] = 0.3 [0.1-1.4] (P = .1) and 0.4 [0.1-1.7], respectively). The area under curve (AUC) was 0.55. Similarly, the incidence of severe toxicities was no greater in the intermediate-low, intermediate-high, and high-risk CRASH groups than in the low-risk CRASH group (OR [95%CI] = 1 [0.3-3.6], 1 [0.3-3.4], and 1.5 [0.3-8.1], respectively). The AUC was 0.52. The type of cancer, performance status, comorbidities, body mass index, and MAX2 index were independently associated with grades 3/4/5 toxicities.

CONCLUSION: In an external cohort of older patients referred for a pretherapeutic GA, the CARG and CRASH scores were poor predictors of the risk of chemotherapy severe toxicities.

PMID:37027521 | DOI:10.1093/oncolo/oyad050

Heliyon. 2023 Mar 28;9(4):e14968. doi: 10.1016/j.heliyon.2023.e14968. eCollection 2023 Apr.

ABSTRACT

OBJECTIVES: To describe hospital spending and length of stay for mental disorders in Hunan, China.

METHODS: We extracted hospital care data for Hunan province from the Chinese National Health Statistics Network Reporting System. Patients with mental disorders (ICD-10 codes: F00 to F99) as the principal diagnosis and hospitalized between January 1, 2017 and December 31, 2019 were included. We retrieved information on age, sex, number of comorbidities, diagnosis, level of hospital, hospital costs, date of admission and discharge, length of stay (LOS), and method of payment of eligible participants. Spending at the provincial level, and spending and LOS at the individual level were described. Quantile regression and linear regression were conducted to investigate factors for hospital cost and LOS for major mental disorders.

RESULTS: The 2019 annual spending on mental disorders in Hunan province was 160 million US dollars, and 71.7% was paid by insurance. The annual spending on schizophrenia was 84 million dollars, contributing to a primary burden of mental disorders. The median spending for mental disorders was $1,085 per patient, and the median hospital stay was 22 days. The study identified several significant factors associated with hospital cost and LOS, including age, sex, comorbidity, and level of the hospital. In particular, a higher level of the hospital was associated with a higher hospital spending but a shorter LOS. Women with schizophrenia had a comparable hospital spending but a significantly shorter LOS than men with schizophrenia.

CONCLUSION: Hospitalization spending for patients with mental disorders is substantial. Schizophrenia is the major burden of hospitalization for mental disorders. While patients treated at a higher level of hospital had higher spending, they stayed shorter in these hospitals.

PMID:37025795 | PMC:PMC10070638 | DOI:10.1016/j.heliyon.2023.e14968

Front Genet. 2023 Mar 21;14:1114742. doi: 10.3389/fgene.2023.1114742. eCollection 2023.

ABSTRACT

The CYP2C19 gene, located in the CYP2C cluster, encodes the major drug metabolism enzyme CYP2C19. This gene is highly polymorphic and no-function (CYP2C19*2 and CYP2C19*3), reduced function (CYP2C19*9) and increased function (CYP2C19*17) star alleles (haplotypes) are commonly used to predict CYP2C19 metabolic phenotypes. CYP2C19*17 and the genotype-predicted rapid (RM) and ultrarapid (UM) CYP2C19 metabolic phenotypes are absent or rare in several Native American populations. However, discordance between genotype-predicted and pharmacokinetically determined CYP2C19 phenotypes in Native American cohorts have been reported. Recently, a haplotype defined by rs2860840T and rs11188059G alleles in the CYP2C cluster has been shown to encode increased rate of metabolism of the CYP2C19 substrate escitalopram, to a similar extent as CYP2C19*17. We investigated the distribution of the CYP2C:TG haplotype and explored its potential impact on CYP2C19 metabolic activity in Native American populations. The study cohorts included individuals from the One Thousand Genomes Project AMR superpopulation (1 KG_AMR), the Human Genome Diversity Project (HGDP), and from indigenous populations living in Brazil (Kaingang and Guarani). The frequency range of the CYP2C:TG haplotype in the study cohorts, 0.469 to 0.598, is considerably higher than in all 1 KG superpopulations (range: 0.014-to 0.340). We suggest that the high frequency of the CYP2C:TG haplotype might contribute to the reported discordance between CYP2C19-predicted and pharmacokinetically verified CYP2C19 metabolic phenotypes in Native American cohorts. However, functional studies involving genotypic correlations with pharmacokinetic parameters are warranted to ascertain the importance of the CYP2C:TG haplotype.

PMID:37025454 | PMC:PMC10071019 | DOI:10.3389/fgene.2023.1114742

Indian J Clin Biochem. 2023 Apr;38(2):262-274. doi: 10.1007/s12291-022-01046-8. Epub 2022 May 2.

ABSTRACT

The presence of dyskinesia is the most common side effect of chronic administration of levodopa in Parkinson's disease (PD) subjects. Genetic polymorphisms in levodopa metabolizing gene, catechol-O-methyl transferase (COMT), is shown to influence the inter-individual variability in drug response and adverse events. In the present study, the association of COMT rs6269, rs4633, rs4818, and rs4680 polymorphisms and haplotypes on pharmacokinetics and adverse events with levodopa was investigated in 150 PD patients. The age of onset of PD was 58.00 ± 10 yrs. The most common side effect faced by 78% of the subjects was dyskinesia. The AUC of levodopa was found to be significantly higher in subjects with dyskinesia (1695 ± 113 ng/ml/hr, p < 0.0001) than those without dyskinesia (1550 ± 122 ng/ml/hr). We found that the frequency of subjects presenting dyskinesia was significantly higher in subjects carrying variant genotype of COMT rs6269, rs4633, and rs4680 than that with wild genotype and these subjects presented higher AUC of levodopa. In addition, in subjects with dyskinesia, the AUC of levodopa was found to be significantly higher with low COMT (ACCG) haplotype. The association of COMT rs6269, COMT rs4633, COMT rs4818, and COMT rs4680 variant genotypes with the risk of dyskinesia due to levodopa therapy showed an ROC AUC of 0.67 indicating the moderate prediction of dyskinesia (p = 0.0021) with these COMT variants. In conclusion, PD subjects carrying the variant genotypes of COMT strongly influence high levodopa-induced dyskinesia. Hence the genotyping of COMT before the levodopa therapy will be useful to reduce the adverse events associated with the chronic levodopa treatment.

PMID:37025429 | PMC:PMC10070583 | DOI:10.1007/s12291-022-01046-8

J Am Pharm Assoc (2003). 2023 Mar 2:S1544-3191(23)00062-6. doi: 10.1016/j.japh.2023.02.020. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) is used as a medication management strategy by a small but growing number of institutions. PGx allows prescribers to individually treat patients concordant with their genes. Recent litigation for preventable PGx-mediated adverse events highlights the need to accelerate PGx implementation for patient safety. Genetic variations cause drug metabolism, transport, and target changes, affecting medication response and tolerability. PGx testing often consists of targeted testing aimed at specific gene-drug pairs or disease states. Conversely, expanded panel testing can evaluate all known actionable gene-drug interactions, enhancing proactive clarity regarding patient response.

OBJECTIVES: Evaluate the divergence of targeted PGx testing with a single gene-drug pair test (cardiac), a two-gene panel, and a focused psychiatric panel compared to expanded PGx testing.

METHODS: An expanded PGx panel (≥25 genes) was compared to a single gene-drug pair test of CYP2C19/clopidogrel, a dual gene test of CYP2C19/CYP2D6, a seven-gene psychiatric list, and a fourteen-gene psychiatric panel to inform specific depression and pain management drugs. The expanded panel provided a baseline to evaluate total PGx variations compared to those possibly missed by targeted testing.

RESULTS: Targeted testing did not identify up to 95% of total PGx gene-drug interactions discovered. The expanded panel reported all gene-drug interactions for any medication with Clinical Pharmacogenomics Implementation Consortium (CPIC) guidance or food and Drug Administration (FDA) labeling for that gene. Single gene CYP2C19/clopidogrel testing missed or did not report on ∼95% of total interactions, CYP2C19/CYP2D6 testing missed or did not report ∼89%, and the fourteen-gene panel missed or did not report on ∼73%. The seven-gene list missed ∼20% of discovered potential PGx interactions but was not designed to identify gene-drug interactions.

CONCLUSIONS: Targeted PGx testing for limited genes or by specialty may miss or not report significant portions of PGx gene-drug interactions. This can lead to potential patient harm from the missed interactions and subsequent failed therapies and/or adverse reactions.

PMID:37024375 | DOI:10.1016/j.japh.2023.02.020

J Oncol Pharm Pract. 2023 Apr 6:10781552231167554. doi: 10.1177/10781552231167554. Online ahead of print.

ABSTRACT

BACKGROUND: Despite robust evidence and international guidelines, to support routine pharmacogenetic (PGx) testing, integration in practice has been limited. This study explored clinicians' views and experiences of pre-treatment DPYD and UGT1A1 gene testing and barriers to and enablers of routine clinical implementation.

METHODS: A study-specific 17-question survey was emailed (01 February-12 April 2022) to clinicians from the Medical Oncology Group of Australia (MOGA), the Clinical Oncology Society of Australia (COSA) and International Society of Oncology Pharmacy Practitioners (ISOPP). Data were analysed and reported using descriptive statistics.

RESULTS: Responses were collected from 156 clinicians (78% medical oncologists, 22% pharmacists). Median response rate of 8% (ranged from 6% to 24%) across all organisations. Only 21% routinely test for DPYD and 1% for UGT1A1. For patients undergoing curative/palliative intent treatments, clinicians reported intent to implement genotype-guided dosing by reducing FP dose for DPYD intermediate metabolisers (79%/94%), avoiding FP for DPYD poor metabolisers (68%/90%), and reducing irinotecan dose for UGT1A1 poor metabolisers (84%, palliative setting only). Barriers to implementation included: lack of financial reimbursements (82%) and perceived lengthy test turnaround time (76%). Most Clinicians identified a dedicated program coordinator, i.e., PGx pharmacist (74%) and availability of resources for education/training (74%) as enablers to implementation.

CONCLUSION: PGx testing is not routinely practised despite robust evidence for its impact on clinical decision making in curative and palliative settings. Research data, education and implementation studies may overcome clinicians' hesitancy to follow guidelines, especially for curative intent treatments, and may overcome other identified barriers to routine clinical implementation.

PMID:37021580 | DOI:10.1177/10781552231167554

Front Mol Biosci. 2023 Mar 20;10:1178115. doi: 10.3389/fmolb.2023.1178115. eCollection 2023.

NO ABSTRACT

PMID:37021112 | PMC:PMC10067906 | DOI:10.3389/fmolb.2023.1178115