-
Environmental Toxicology and... Jun 2024Understanding interactions between legacy and emerging environmental contaminants has important implications for risk assessment, especially when mutagens and...
Understanding interactions between legacy and emerging environmental contaminants has important implications for risk assessment, especially when mutagens and carcinogens are involved, whose critical effects are chronic and therefore difficult to predict. The current work aimed to investigate potential interactions between benzo[a]pyrene (B[a]P), a carcinogenic polycyclic aromatic hydrocarbon and legacy pollutant, and diclofenac (DFC), a non-steroidal anti-inflammatory drug and pollutant of emerging concern, and how DFC affects B[a]P toxicity. Exposure to binary mixtures of these chemicals resulted in substantially reduced cytotoxicity in human HepG2 cells compared to single-chemical exposures. Significant antagonistic effects were observed in response to high concentrations of B[a]P in combination with DFC at IC and ⅕ IC. While additive effects were found for levels of intracellular reactive oxygen species, antagonistic mixture effects were observed for genotoxicity. B[a]P induced DNA strand breaks, γH2AX activation, and micronuclei formation at ½ IC concentrations or lower, whereas DFC induced only low levels of DNA strand breaks. Their mixture caused significantly lower levels of genotoxicity by all three endpoints compared to those expected based on concentration additivity. In addition, antagonistic mixture effects on CYP1 enzyme activity suggested that the observed reduced genotoxicity of B[a]P was due to its reduced metabolic activation as a result of enzymatic inhibition by DFC. Overall, the findings further support the growing concern that co-exposure to environmental toxicants and their non-additive interactions may be a confounding factor that should not be neglected in environmental and human health risk assessment.
Topics: Humans; Diclofenac; Benzo(a)pyrene; Hep G2 Cells; Carcinogens, Environmental; Reactive Oxygen Species; Cyclooxygenase 1; Cell Survival; Cyclooxygenase Inhibitors; Cyclooxygenase 2; DNA Damage; Cyclooxygenase 2 Inhibitors; Histones
PubMed: 38642625
DOI: 10.1016/j.etap.2024.104453 -
PloS One 2024Due to the lack of specific antagonists for general anaesthetics, the pharmacological stimulation of the arousal pathways might contribute to reduce recovery time. We...
INTRODUCTION
Due to the lack of specific antagonists for general anaesthetics, the pharmacological stimulation of the arousal pathways might contribute to reduce recovery time. We aimed at assessing the effect of methylphenidate on physiological parameters, nociceptive withdrawal reflex thresholds, electroencephalographic variables and time of reappearance of reflexes in pigs undergoing propofol anaesthesia.
MATERIALS AND METHODS
Two experiments have been performed. Five (experiment 1) and sixteen (experiment 2) healthy juvenile pigs were anaesthetised with propofol. In experiment 1, saline, methylphenidate 10 mg/kg or methylphenidate 20 mg/kg was administered intravenously at the end of propofol administration, using a cross-over design. In experiment 2, saline (n = 8) or methylphenidate 20 mg/kg (n = 8) was administered immediately after extubation. In both experiments, physiological parameters, nociceptive withdrawal reflex thresholds, electroencephalographic variables and time of reappearance of reflexes were assessed. Comparison among groups was performed using either the two-way repeated measures ANOVA followed by Bonferroni-Test or the t-test in case of parametric data, and either the Kruskal-Wallis test or the Mann-Whitney Rank Sum test in case of non-parametric data. A p value < 0.05 was considered statistically significant.
RESULTS
No clinically relevant changes were observed in both experiments for physiological parameters, nociceptive withdrawal reflex thresholds and electroencephalographic variables.
CONCLUSIONS
Methylphenidate does not shorten or modify anaesthesia recovery in pigs, when the sole propofol is administered.
Topics: Animals; Humans; Anesthesia; Anesthesia Recovery Period; Methylphenidate; Propofol; Swine; Cross-Over Studies
PubMed: 38626074
DOI: 10.1371/journal.pone.0302166 -
CNS Neuroscience & Therapeutics Apr 2024Classification of spinal muscular atrophy (SMA) is associated with the clinical prognosis; however, objective classification markers are scarce. This study aimed to...
AIMS
Classification of spinal muscular atrophy (SMA) is associated with the clinical prognosis; however, objective classification markers are scarce. This study aimed to identify metabolic markers in the cerebrospinal fluid (CSF) of children with SMA types II and III.
METHODS
CSF samples were collected from 40 patients with SMA (27 with type II and 13 with type III) and analyzed for metabolites.
RESULTS
We identified 135 metabolites associated with SMA types II and III. These were associated with lysine degradation and arginine, proline, and tyrosine metabolism. We identified seven metabolites associated with the Hammersmith Functional Motor Scale: 4-chlorophenylacetic acid, adb-chminaca,(+/-)-, dodecyl benzenesulfonic acid, norethindrone acetate, 4-(undecan-5-yl) benzene-1-sulfonic acid, dihydromaleimide beta-d-glucoside, and cinobufagin. Potential typing biomarkers, N-cyclohexylformamide, cinobufagin, cotinine glucuronide, N-myristoyl arginine, 4-chlorophenylacetic acid, geranic acid, 4-(undecan-5-yl) benzene, and 7,8-diamino pelargonate, showed good predictive performance. Among these, N-myristoyl arginine was unaffected by the gene phenotype.
CONCLUSION
This study identified metabolic markers are promising candidate prognostic factors for SMA. We also identified the metabolic pathways associated with the severity of SMA. These assessments can help predict the outcomes of screening SMA classification biomarkers.
Topics: Child; Humans; Spinal Muscular Atrophies of Childhood; Benzene; Metabolomics; Arginine; Phenylacetates
PubMed: 38615366
DOI: 10.1111/cns.14718 -
International Journal of Biological... May 2024This study involved creating oligomeric conjugates of 3-hydroxy fatty acids and diclofenac, named Dic-oligo(3HAs). Advanced NMR techniques confirmed no free diclofenac...
Physicochemical, structural and biological characterisation of poly(3-hydroxyoctanoate) supplemented with diclofenac acid conjugates - Harnessing the potential in the construction of materials for skin regeneration processes.
This study involved creating oligomeric conjugates of 3-hydroxy fatty acids and diclofenac, named Dic-oligo(3HAs). Advanced NMR techniques confirmed no free diclofenac in the mix. We tested diclofenac release under conditions resembling healthy and chronic wound skin. These oligomers were used to make P(3HO) blends, forming patches for drug delivery. Their preparation used the solvent casting/porogen leaching (SCPL) method. The patches' properties like porosity, roughness, and wettability were thoroughly analysed. Antimicrobial assays showed that Dic-oligo(3HAs) exhibited antimicrobial activity against reference (S. aureus, S. epidermis, S. faecalis) and clinical (Staphylococcus spp.) strains. Human keratinocytes (HaCaT) cell line tests, as per ISO 10993-5, showed no toxicity. A clear link between material roughness and HaCaT cell adhesion was found. Deep cell infiltration was verified using DAPI and phalloidin staining, observed under confocal microscopy. SEM also confirmed HaCaT cell growth on these scaffolds. The strong adhesion and proliferation of HaCaT cells on these materials indicate their potential as wound dressing layers. Additionally, the successful diclofenac release tests point to their applicability in treating both normal and chronic wounds.
Topics: Diclofenac; Humans; Skin; Regeneration; Keratinocytes; HaCaT Cells; Wound Healing; Cell Proliferation; Chemical Phenomena; Cell Line; Polymers; Porosity; Biocompatible Materials
PubMed: 38614181
DOI: 10.1016/j.ijbiomac.2024.131476 -
BMJ Mental Health Apr 2024Use of psychostimulants and relative drugs has increased worldwide in treatment of attention-deficit hyperactivity disorder (ADHD) in adolescents and adults. Recent...
BACKGROUND
Use of psychostimulants and relative drugs has increased worldwide in treatment of attention-deficit hyperactivity disorder (ADHD) in adolescents and adults. Recent studies suggest a potential association between use of psychostimulants and psychotic symptoms. The risk may not be the same between different psychostimulants.
OBJECTIVE
To assess whether amphetamine or atomoxetine use is associated with a higher risk of reporting symptoms of psychosis than methylphenidate use in adolescents and adults, particularly in patients with ADHD.
METHODS
Using VigiBase, the WHO's pharmacovigilance database, disproportionality of psychotic symptoms reporting was assessed among adverse drug reactions related to methylphenidate, atomoxetine and amphetamines, from January 2004 to December 2018, in patients aged 13-25 years. The association between psychotic symptoms and psychostimulants was estimated through the calculation of reporting OR (ROR).
FINDINGS
Among 13 863 reports with at least one drug of interest, we found 221 cases of psychosis with methylphenidate use, 115 with atomoxetine use and 169 with a prescription of an amphetamine drug. Compared with methylphenidate use, amphetamine use was associated with an increased risk of reporting psychotic symptoms (ROR 1.61 (95% CI 1.26 to 2.06)]. When we restricted the analysis to ADHD indication, we found a close estimate (ROR 1.94 (95% CI 1.43 to 2.64)). No association was found for atomoxetine.
CONCLUSION
Our study suggests that amphetamine use is associated with a higher reporting of psychotic symptoms, compared with methylphenidate use.
CLINICAL IMPLICATIONS
The prescription of psychostimulants should consider this potential adverse effect when assessing the benefit-risk balance.
Topics: Adult; Humans; Adolescent; Amphetamine; Methylphenidate; Atomoxetine Hydrochloride; Central Nervous System Stimulants; Psychotic Disorders; Drug-Related Side Effects and Adverse Reactions
PubMed: 38609318
DOI: 10.1136/bmjment-2023-300876 -
Journal of Child and Adolescent... Apr 2024This study aimed to examine switch from first-line methylphenidate (MPH) to lisdexamfetamine (LDX) in school-aged children with attention-deficit/hyperactivity disorder... (Observational Study)
Observational Study
This study aimed to examine switch from first-line methylphenidate (MPH) to lisdexamfetamine (LDX) in school-aged children with attention-deficit/hyperactivity disorder (ADHD). This is a retrospective observational study based on systematic review of patient records of all children (7-13 years) diagnosed with ADHD and referred to a Danish specialized outpatient clinic. The study included 394 children switching from MPH to LDX as either second-line or third-line treatment (atomoxetine [ATX] as second-line treatment) during the study period from April 1, 2013, to November 5, 2019. One in five children switched from MPH to LDX at some point during the study period. The most frequent reasons for switching to LDX were adverse effects (AEs; 70.0% for MPH, 68.3% for ATX) and lack of efficiency (52.0% for MPH, 72.7% for ATX). Top five AEs of LDX were decreased appetite (62.4%), insomnia (28.7%), irritability/aggression (26.1%), weight decrease (21.1%), and mood swings (13.9%). MPH and LDX had similar AE profiles, yet most AEs were less frequent after switching to LDX. At the end of the study period, the majority were prescribed LDX as second-line rather than third-line treatment (86.1% in 2019). However, the likelihood of LDX as second-line treatment decreased with the number of psychiatric comorbidities, ADHD symptom severity as assessed by parents, and if AEs were a reason for MPH discontinuation. Among children observed for at least 1 year after initiation of LDX, 41.3% continued LDX treatment for a year or longer. LDX continuation was less likely if AEs were a reason for MPH discontinuation. Similarly to MPH and ATX, the most frequent reasons for LDX discontinuation were AEs (74.4%) and lack of efficiency (34.7%). The findings support LDX as an important option in the personalized treatment of children with ADHD and may support prescribers in the clinical decision-making on switching medication.
Topics: Child; Humans; Attention Deficit Disorder with Hyperactivity; Lisdexamfetamine Dimesylate; Cohort Studies; Methylphenidate; Atomoxetine Hydrochloride; Ambulatory Care Facilities; Denmark
PubMed: 38608011
DOI: 10.1089/cap.2023.0077 -
Journal of Attention Disorders Jun 2024DR/ER-MPH (formerly HLD200) is an evening-dosed delayed-release and extended-release methylphenidate approved for the treatment of ADHD in patients ≥6 years.... (Randomized Controlled Trial)
Randomized Controlled Trial
A Post-Hoc Analysis of Emotional Lability With Delayed-Release/Extended-Release Methylphenidate in Children Aged 6 to 12 Years of Age Participating in Two Phase 3 Clinical Trials.
OBJECTIVE
DR/ER-MPH (formerly HLD200) is an evening-dosed delayed-release and extended-release methylphenidate approved for the treatment of ADHD in patients ≥6 years. analyses of two pivotal Phase 3 trials: HLD200-107 (NCT02493777) and HLD200-108 (NCT02520388) evaluated emotional lability (EL) with DR/ER-MPH treatment.
METHODS
Differences in Conners Global Index-Parent (CGI-P) EL subscale scores and age- and gender-adjusted -scores over an open-label titration phase (HLD200-107) and between treatment and placebo groups at endpoint (HLD200-108) were evaluated.
RESULTS
In HLD200-107 ( = 117) mean CGI-P EL subscale scores improved from 5.3 to 1.3 ( < .0001) after 6 weeks; in HLD200-108 significant improvements were observed in the treatment group ( = 81) versus placebo ( = 80; 3.11 vs. 4.08; = .0053). -scores showed an improvement with DR/ER-MPH treatment in both trials. Few emotional adverse events (AEs) were reported.
CONCLUSION
DR/ER-MPH treatment resulted in statistically significant improvements in EL to the level of non-ADHD peers as contextualized by -scores.
Topics: Humans; Methylphenidate; Delayed-Action Preparations; Child; Male; Female; Central Nervous System Stimulants; Attention Deficit Disorder with Hyperactivity; Double-Blind Method; Treatment Outcome; Affective Symptoms
PubMed: 38600754
DOI: 10.1177/10870547241243155 -
Cell Metabolism May 2024The gut-brain axis is implicated in depression development, yet its underlying mechanism remains unclear. We observed depleted gut bacterial species, including...
The gut-brain axis is implicated in depression development, yet its underlying mechanism remains unclear. We observed depleted gut bacterial species, including Bifidobacterium longum and Roseburia intestinalis, and the neurotransmitter homovanillic acid (HVA) in individuals with depression and mouse depression models. Although R. intestinalis does not directly produce HVA, it enhances B. longum abundance, leading to HVA generation. This highlights a synergistic interaction among gut microbiota in regulating intestinal neurotransmitter production. Administering HVA, B. longum, or R. intestinalis to mouse models with chronic unpredictable mild stress (CUMS) and corticosterone (CORT)-induced depression significantly improved depressive symptoms. Mechanistically, HVA inhibited synaptic autophagic death by preventing excessive degradation of microtubule-associated protein 1 light chain 3 (LC3) and SQSTM1/p62 proteins, protecting hippocampal neurons' presynaptic membrane. These findings underscore the role of the gut microbial metabolism in modulating synaptic integrity and provide insights into potential novel treatment strategies for depression.
Topics: Animals; Gastrointestinal Microbiome; Mice; Depression; Male; Mice, Inbred C57BL; Humans; Homovanillic Acid; Synapses; Hippocampus; Neurons; Female
PubMed: 38582087
DOI: 10.1016/j.cmet.2024.03.010 -
Rheumatology International Jun 2024Gout attacks are treated with uric-lowering and anti-inflammatory drugs. In patients with gout, non-steroidal anti-inflammatory drugs (NSAIDs) could be both...
Gout attacks are treated with uric-lowering and anti-inflammatory drugs. In patients with gout, non-steroidal anti-inflammatory drugs (NSAIDs) could be both cardiovascular beneficial, due to their anti-inflammatory actions, and cardiovascular hazardous, due to their prothrombotic, hypertensive, and proarrhythmic side effects. We, therefore, examined the risk of cardiovascular events associated with NSAID use in patients with gout. We conducted a nationwide, population-based case-crossover study of all Danes ≥ 18 years of age with first-time gout during 1997-2020, who experienced a cardiovascular event (myocardial infarction, ischemic stroke, congestive heart failure, atrial fibrillation/flutter, or cardiovascular death) (n = 59,150). The exposure was use of NSAIDs, overall and according to type (ibuprofen, naproxen, or diclofenac). We used the dates 300, 240, 180, and 120 before the outcome date as reference dates. We used the Mantel-Haenszel method to calculate odds ratios (ORs) with 95% confidence intervals (CIs) of the association between NSAID use and cardiovascular events. NSAID use was overall associated with 12% decreased odds of a cardiovascular event (OR = 0.88, 95% CI: 0.85-0.91). This decreased odds ratio was observed for the use of ibuprofen (OR = 0.92, 95% CI: 0.88-0.97) and naproxen (OR = 0.85, 95% CI: 0.74-0.97), but not for the use of diclofenac (OR = 0.97, 95% CI: 0.90-1.05). Overall, use of NSAIDs was associated with decreased odds of all the individual components of the composite outcome. NSAIDs were not associated with an increased cardiovascular event rate when used in gout patients. Ibuprofen and naproxen appeared to have better cardiovascular risk profiles than diclofenac.
Topics: Humans; Anti-Inflammatory Agents, Non-Steroidal; Gout; Male; Female; Middle Aged; Cross-Over Studies; Aged; Denmark; Cardiovascular Diseases; Naproxen; Ibuprofen; Adult; Diclofenac
PubMed: 38581450
DOI: 10.1007/s00296-024-05584-7 -
Molecular Pharmacology May 2024Liver fatty acid binding protein 1 (FABP1) binds diverse endogenous lipids and is highly expressed in the human liver. Binding to FABP1 alters the metabolism and...
Liver fatty acid binding protein 1 (FABP1) binds diverse endogenous lipids and is highly expressed in the human liver. Binding to FABP1 alters the metabolism and homeostasis of endogenous lipids in the liver. Drugs have also been shown to bind to rat FABP1, but limited data are available for human FABP1 (hFABP1). FABP1 has a large binding pocket, and up to two fatty acids can bind to FABP1 simultaneously. We hypothesized that drug binding to hFABP1 results in formation of ternary complexes and that FABP1 binding alters drug metabolism. To test these hypotheses, native protein mass spectrometry (MS) and fluorescent 11-(dansylamino)undecanoic acid (DAUDA) displacement assays were used to characterize drug binding to hFABP1, and diclofenac oxidation by cytochrome P450 2C9 (CYP2C9) was studied in the presence and absence of hFABP1. DAUDA binding to hFABP1 involved high (K = 0.2 M) and low (K > 10 M) affinity binding sites. Nine drugs bound to hFABP1 with equilibrium dissociation constant (K) values ranging from 1 to 20 M. None of the tested drugs completely displaced DAUDA from hFABP1, and fluorescence spectra showed evidence of ternary complex formation. Formation of DAUDA-hFABP1-diclofenac ternary complex was verified with native MS. Docking predicted diclofenac binding in the portal region of FABP1 with DAUDA in the binding cavity. The catalytic rate constant of diclofenac hydroxylation by CYP2C9 was decreased by ∼50% ( < 0.01) in the presence of FABP1. Together, these results suggest that drugs form ternary complexes with hFABP1 and that hFABP1 binding in the liver will alter drug metabolism and clearance. SIGNIFICANCE STATEMENT: Many commonly prescribed drugs bind fatty acid binding protein 1 (FABP1), forming ternary complexes with FABP1 and the fluorescent fatty acid 11-(dansylamino)undecanoic acid. These findings suggest that drugs will bind to apo-FABP1 and fatty acid-bound FABP1 in the human liver. The high expression of FABP1 in the liver, together with drug binding to FABP1, may alter drug disposition processes in vivo.
Topics: Fatty Acid-Binding Proteins; Humans; Diclofenac; Protein Binding; Cytochrome P-450 CYP2C9; Binding Sites; Liver; Oxidation-Reduction; Pharmaceutical Preparations
PubMed: 38580446
DOI: 10.1124/molpharm.124.000878