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Environmental Toxicology and Chemistry Jul 2024Wastewater treatment plant (WWTP) effluent often releases pharmaceuticals like venlafaxine (a serotonin-norephinephrine reuptake inhibitor antidepressant) to freshwater...
Wastewater treatment plant (WWTP) effluent often releases pharmaceuticals like venlafaxine (a serotonin-norephinephrine reuptake inhibitor antidepressant) to freshwater ecosystems at levels causing adverse metabolic effects on fish. Changes to fish metabolism can be regulated by epigenetic mechanisms like microRNA (small RNA molecules that regulate mRNA translation), including regulating mitochondrial mRNAs. Nuclear-encoded microRNAs regulate mitochondrial gene expression in mammals, and have predicted effects in fish. We aimed to identify whether venlafaxine exposure changed mitochondrial respiration and resulted in differentially abundant mitochondrial microRNA (mitomiRs) in zebrafish brains. In vitro exposure of brain homogenate to below environmentally relevant concentrations of venlafaxine (<1 µg/L) caused a decrease in mitochondrial respiration, although this was not driven by changes to mitochondrial Complex I or II function. To identify whether these effects occur in vivo, zebrafish were exposed to 1 µg/L venlafaxine for 0, 1, 6, 12, 24, and 96 h. In vivo, venlafaxine exposure had no significant effects on brain mitochondrial respiration; however, select mitomiRs (dre-miR-301a-5p, dre-miR-301b-3p, and dre-miR-301c-3p) were also measured, because they were bioinformatically predicted to regulate mitochondrial cytochrome c oxidase subunit I (COI) abundance. These mitomiRs were differentially regulated based on venlafaxine exposure (with miR-301c-3p abundance differing during the day and miR-301b-3p being lower in exposed fish at night), and with respect to sex and time sampled. Overall, the results demonstrated that in vitro venlafaxine exposure to zebrafish brain caused a decrease in mitochondrial respiration, but these effects were not seen after acute in vivo exposure. Results may have differed because in vivo exposure allows for fish to mitigate effects through mechanisms that could include mitomiR regulation, and because fish were only acutely exposed. Environ Toxicol Chem 2024;43:1569-1582. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
Topics: Animals; Zebrafish; Venlafaxine Hydrochloride; Mitochondria; Brain; MicroRNAs; Water Pollutants, Chemical; Cell Respiration
PubMed: 38695684
DOI: 10.1002/etc.5884 -
Cureus Apr 2024Serotonin toxicity, an adverse consequence of elevated serotonin levels in the brain, poses a considerable threat to life. Antidepressants, frequently prescribed for...
Serotonin toxicity, an adverse consequence of elevated serotonin levels in the brain, poses a considerable threat to life. Antidepressants, frequently prescribed for various conditions in older adults, such as depression, anxiety, and sleep disturbances, significantly contribute to this risk. The elderly are particularly vulnerable due to multiple comorbidities, cognitive decline, medication interactions, polypharmacy, and chronic kidney disease. This case underscores the critical importance of considering serotonin syndrome as a potential diagnosis in patients using serotonin and norepinephrine reuptake inhibitors, especially within vulnerable populations. Here, we present the case of an 89-year-old female who presented with altered mental status and a hypertensive emergency. Following a thorough examination and exclusion of alternative causes of acute encephalopathy, serotonin syndrome induced by the use of venlafaxine and oxycodone was diagnosed.
PubMed: 38694682
DOI: 10.7759/cureus.57403 -
Water Research Jun 2024Separate collection and treatment of urine optimizes nutrient recovery and enhances micropollutant removal from municipal wastewater. One typical urine treatment train... (Comparative Study)
Comparative Study
Separate collection and treatment of urine optimizes nutrient recovery and enhances micropollutant removal from municipal wastewater. One typical urine treatment train includes nutrient recovery in three biological processes: anaerobic storage, followed by aerobic organics degradation concurrently with nitrification. These are usually followed by activated carbon adsorption to remove micropollutants. However, removing micropollutants prior to nitrification would protect nitrifiers from potential inhibition by pharmaceuticals. In addition, combining simplified biological treatment with activated carbon adsorption could offer a cheap and robust process for removing micropollutants where nutrient recovery is not the first priority, as a partial loss of ammonia occurs without nitrification. In this study, we investigated whether activated carbon adsorption could also take place between the three biological treatment steps. We tested the effectiveness of micropollutant removal with activated carbon after each biological treatment step by conducting experiments with anaerobically stored urine, organics-depleted urine, and nitrified urine. The urine solutions were spiked with 19 pharmaceuticals: amisulpride, atenolol, atenolol acid, candesartan, carbamazepine, citalopram, clarithromycin, darunavir, diclofenac, emtricitabine, fexofenadine, hydrochlorothiazide, irbesartan, lidocaine, metoprolol, N-acetylsulfamethoxazole, sulfamethoxazole, trimethoprim, venlafaxine, and two artificial sweeteners, acesulfame and sucralose. Batch experiments were conducted with powdered activated carbon (PAC) to determine how much activated carbon achieve which degree of micropollutant removal and how organics, pH, and speciation change from ammonium to nitrate influence adsorption. Micropollutant removal was also tested in granular activated carbon (GAC) columns, which is the preferred technology for micropollutant removal from urine. The carbon usage rates (CUR) per person were lower for all urine solutions than for municipal wastewater. The results showed that organics depletion would be needed when micropollutant removal was the sole aim of urine treatment, as the degradation of easily biodegradable organics prevented clogging of GAC columns. However, CUR did hardly improve with organics-depleted urine compared to stored urine. The lowest CUR was achieved with nitrified urine. This resulted from the additional organics removal during nitrification and not the lower pH or the partial conversion of ammonium to nitrate. In addition, we showed that the relative pharmaceutical removal in all solutions was independent of the initial pharmaceutical concentration unless the background organics matrix changed considerably. We conclude that removal of micropollutants in GAC columns from organics-depleted urine can be performed without clogging, but with the drawback of a higher carbon usage compared to removal from nitrified urine.
Topics: Adsorption; Water Pollutants, Chemical; Nitrification; Charcoal; Anaerobiosis; Waste Disposal, Fluid; Wastewater; Urine; Pharmaceutical Preparations; Water Purification
PubMed: 38692253
DOI: 10.1016/j.watres.2024.121615 -
The Science of the Total Environment Jun 2024Untangling the consumption rates of psychiatric drugs and their metabolites/ transformation products-(TPs) through wastewater gains attention lately. However, the...
Unravelling psychoactive substances and their metabolites and transformation products: High-Resolution Mass Spectrometry approaches for comprehensive target and suspect screening in wastewater.
Untangling the consumption rates of psychiatric drugs and their metabolites/ transformation products-(TPs) through wastewater gains attention lately. However, the potential environmental impact caused by their release remains ambiguous. As it follows, the monitoring of this class of pharmaceuticals as well as the evaluation of their potential toxicity is a matter of high concern. In the light of the above, here, wastewater samples, were collected in a 1-year and a half sampling campaign (2020-2021) and were further subjected to solid phase extraction. A Q Exactive Focus Orbitrap mass analyzer was employed for the analysis of the samples. For the data curation, except of the monitoring of targets, a comprehensive suspect screening workflow was developed and slightly optimized based on a lab made HRMS database for the investigation of legally or illegally prescribed psychiatric drugs and their relevant metabolites/TPs in influents and effluents. Carbamazepine and amisulpride were quantified at the highest mean concentrations 243 and 225 ng/L respectively, in influents. In effluents, the highest mean concentrations were calculated for carbamazepine (180 ng/L) and venlafaxine (117 ng/L). The implementation of suspect screening approach enhanced the comprehensiveness of analysis by detecting 29 compounds not included in the target list. O-Desmethylvenlafaxine was the predominant metabolite in influents presenting a mean concentration equal to 87 ng/L while the same pattern was also noticed in effluents where the mean concentration was up to 91 ng/L. From the group of suspect compounds for which no analytical standards were available, the predominant compounds with detection frequency 100 % were norephedrine and codeine in influents while in effluents, oxazepam was detected in 81 % of the analyzed samples. Finally, in silico and mathematical tools were employed for the assessment of the risk posed to environmental systems. Most of the detected compounds present high risk in all trophic levels.
Topics: Wastewater; Water Pollutants, Chemical; Psychotropic Drugs; Environmental Monitoring; Mass Spectrometry; Solid Phase Extraction
PubMed: 38688363
DOI: 10.1016/j.scitotenv.2024.172867 -
CNS Spectrums Jun 2024Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD).
METHODS
Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n = 585; placebo, n = 502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8 weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data.
RESULTS
At the end of 8 weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: -2.73 [-3.63, -1.82], < 0.0001) and amotivation scores (mean, 95% CI: -0.78 [-1.04, -0.52], < 0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time.
CONCLUSION
This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.
Topics: Humans; Venlafaxine Hydrochloride; Depressive Disorder, Major; Anhedonia; Adult; Male; Female; Middle Aged; Motivation; Antidepressive Agents, Second-Generation; Cyclohexanols; Treatment Outcome; Double-Blind Method
PubMed: 38685594
DOI: 10.1017/S1092852924000245 -
Journal of Pharmacological and... 2024We developed a novel, stress-free blood sampling method for minipigs, allowing continuous cortisol monitoring over 24 h. Baseline cortisol levels exhibited both...
We developed a novel, stress-free blood sampling method for minipigs, allowing continuous cortisol monitoring over 24 h. Baseline cortisol levels exhibited both ultradian and diurnal rhythms. During nighttime, smaller ultradian rhythms overlaid a lower baseline cortisol, which increased in sleeping pigs before lights were turned on. Additionally, we developed an analytical tool based on the R package "pracma" to quantify ultradian peak and circadian components of the cortisol profiles. To validate our model, we investigated the effects of Verucerfont, a CRH receptor antagonist, and Venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Verucerfont reduced cortisol levels during the first 9 h without affecting diurnal rhythm. Cortisol peak parameters decreased, with a 31% reduction in overall area under the curve (AUC) and a 38% reduction in ultradian average AUC. Ultradian peaks decreased from 7 to 4.5, with 34% lower amplitude. Venlafaxine maintained plasma concentrations within the targeted human effective range. This method enables us to enhance our understanding of cortisol regulation and provide valuable insights for the impact of investigation drugs on the diurnal and ultradian rhythms of cortisol.
Topics: Animals; Swine, Miniature; Swine; Hydrocortisone; Circadian Rhythm; Venlafaxine Hydrochloride; Ultradian Rhythm; Blood Specimen Collection; Area Under Curve; Male; Female
PubMed: 38678804
DOI: 10.1016/j.vascn.2024.107504 -
Central Nervous System Agents in... Apr 2024Seizures are a common presenting symptom of the central nervous system (CNS) and could occur from infections (such as toxins) or drugs.
BACKGROUND
Seizures are a common presenting symptom of the central nervous system (CNS) and could occur from infections (such as toxins) or drugs.
OBJECTIVE
The aim of this study was to present a systematic review of the association between infections, seizures, and drugs.
METHODS
Through February 18, 2024, according to the PRISMA guidelines and based on the PICO standard format, relevant, in-depth consequent guide approach and evidence-based options were selected associated with a knowledgeable collection of current, high-quality manuscripts.
RESULTS
Imbalance between inhibitory and excitatory neurotransmitters due to infections, drugs such as ticarcillin, amoxicillin, oxacillin, penicillin G, ampicillin, tramadol, venlafaxine, cyclosporine, tacrolimus, acyclovir, cellcept, the old generation of antiepileptic drugs, such as carbamazepine, phenytoin, and many other drugs could cause different stages of CNS disturbances ranging from seizure to encephalopathy. Infections could cause life-threatening status epilepticus by continuous unremitting seizures lasting longer than 5 minutes or recurrent seizures. Meningitis, tuberculosis, herpes simplex, cerebral toxoplasmosis, and many others could lead to status epilepticus. In fact, confusion, encephalopathy, and myoclonus were reported with drugs, such as ticarcillin, amoxicillin, oxacillin, penicillin G, ampicillin, and others. Penicillin G was reported as having the greatest epileptogenic potential. A high dose, in addition to prolonged use of metronidazole, was reported with seizure infection. Meropenem could decrease the concentration of valproic acid. Due to the inhibition of cytochrome P450 3A4, the combination of clarithromycin and erythromycin with carbamazepine needs vigilant monitoring.
CONCLUSION
Due to changes in drug metabolism, co-administration of antiseizure drugs and antibiotics may lead to an enhanced risk of seizures. In patients with neurocysticercosis, cerebral malaria, viral encephalitis, bacterial meningitis, tuberculosis, and human immunodeficiency virus, the evidence-based study recommended different mechanisms mediating epileptogenic properties of toxins and drugs.
PubMed: 38676494
DOI: 10.2174/0118715249288932240416071636 -
Environmental Pollution (Barking, Essex... Jun 2024Risk assessment of environmental hazards originating from xenobiotics extensively used worldwide (e.g., pharmaceuticals, bisphenols, or preservatives) requires a...
Identifying organic micropollutants' transformation products from the soil dissipation experiment by non-targeted high-resolution mass spectrometry approach: Can we gain more than transformation product identity?
Risk assessment of environmental hazards originating from xenobiotics extensively used worldwide (e.g., pharmaceuticals, bisphenols, or preservatives) requires a combined study of their effects, mobility, dissipation mechanisms, and subsequent transformation product identification and evaluation. We have developed an efficient accelerated solvent extraction method for a broad range of micropollutants of variable physical-chemical properties in soils to enable more accurate hazard characterisation. Micropollutant recoveries from freeze-dried soils were 60-120%, with the exception of atorvastatin, fexofenadine, and telmisartan, which had reduced recoveries (40-66%). The observed matrix effect ranged from -26% to 17% and was corrected by the matrix matching standard for quantitative analysis. The method allows sensitive and reliable determination of a wide range of analytes in soil samples and, consequently, qualitative analysis of transformation products (TP) with variable physicochemical properties. We identified TPs of five compounds (venlafaxine, telmisartan, valsartan, atorvastatin, and sertraline) by applying suspect and non-targeted data analyses. To our knowledge, the transformation product of atorvastatin was reported for the first time. All others were found in soil or other matrices. Valsartan (formed valsartan acid) and atorvastatin (transformed probably by oxidative decarboxylation of beta, delta dihydroxy heptanoic acid chain to propionic acid) were modified to a relatively large extent. All other compounds identified were only hydroxylated (sertraline and telmisartan) or demethylated (venlafaxine). We estimated the stability and presence of the identified TPs based on the constructed time trends and the ratio between TP formation and degradation rates. We demonstrated how valuable a non-targeted approach can be for complex evaluation of the fate and effect of soil pollutants.
Topics: Soil Pollutants; Soil; Environmental Monitoring; Mass Spectrometry
PubMed: 38670422
DOI: 10.1016/j.envpol.2024.124038 -
Toxics Mar 2024Molecular autopsy is a very important tool in forensic toxicology. However, many determinants, such as co-medication and physiological parameters, should be considered...
Molecular autopsy is a very important tool in forensic toxicology. However, many determinants, such as co-medication and physiological parameters, should be considered for optimal results. These determinants could cause phenoconversion (PC), a discrepancy between the real metabolic profile after phenoconversion and the phenotype determined by the genotype. This study's objective was to assess the PC of drug-metabolizing enzymes, namely CYP2D6, 2C19, and 3A4, in 45 cases where medications that are substrates, inducers, or inhibitors of these enzymes were detected. It also intended to evaluate how PC affected the drug's metabolic ratio (MR) in four cases. Blood samples from 45 cases of drug-related deaths were analyzed to detect and determine drug and metabolite concentrations. Moreover, all the samples underwent genotyping utilizing the HaloPlex Target Enrichment System for , , and . The results of the present study revealed a statistically significant rate of PC for the three investigated enzymes, with a higher frequency of poor metabolizers after PC. A compatibility was seen between the results of the genomic evaluation after PC and the observed MRs of venlafaxine, citalopram, and fentanyl. This leads us to focus on the determinants causing PC that may be mainly induced by drug interactions. This complex phenomenon can have a significant impact on the analysis, interpretation of genotypes, and accurate conclusions in forensic toxicology. Nevertheless, more research with more cases in the future is needed to confirm these results.
PubMed: 38668482
DOI: 10.3390/toxics12040260 -
Archives of Pharmacal Research May 2024Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder, social anxiety disorder, generalized...
PBPK modeling to predict the pharmacokinetics of venlafaxine and its active metabolite in different CYP2D6 genotypes and drug-drug interactions with clarithromycin and paroxetine.
Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder, social anxiety disorder, generalized anxiety disorder, and panic disorder. Venlafaxine is metabolized to the active metabolite desvenlafaxine mainly by CYP2D6. Genetic polymorphism of CYP2D6 and coadministration with other medications can significantly affect the pharmacokinetics and/or pharmacodynamics of venlafaxine and its active metabolite. This study aimed to establish the PBPK models of venlafaxine and its active metabolite related to CYP2D6 genetic polymorphism and to predict drug-drug interactions (DDIs) with clarithromycin and paroxetine in different CYP2D6 genotypes. Clinical pharmacogenomic data for venlafaxine and desvenlafaxine were collected to build the PBPK model. Physicochemical and absorption, distribution, metabolism, and excretion (ADME) characteristics of respective compounds were obtained from previously reported data, predicted by the PK-Sim software, or optimized to capture the plasma concentration-time profiles. Model evaluation was performed by comparing the predicted pharmacokinetic parameters and plasma concentration-time profiles to the observed data. Predicted plasma concentration-time profiles of venlafaxine and its active metabolite were visually similar to the observed profiles and all predicted AUC and C values for respective compounds were included in the twofold error range of observed values in non-genotyped populations and different CYP2D6 genotypes. When clarithromycin or clarithromycin plus paroxetine was concomitantly administered, predicted plasma concentration-time profiles of venlafaxine properly captured the observed profiles in two different CYP2D6 genotypes and all predicted DDI ratios for AUC and C were included within the acceptance range. Consequently, the present model successfully captured the pharmacokinetic alterations of venlafaxine and its active metabolite according to CYP2D6 genetic polymorphism as well as the DDIs between venlafaxine and two CYP inhibitors. The present model can be used to predict the pharmacokinetics of venlafaxine and its active metabolite considering different races, ages, coadministered drugs, and CYP2D6 activity of individuals and it can contribute to individualized pharmacotherapy of venlafaxine.
Topics: Venlafaxine Hydrochloride; Clarithromycin; Humans; Cytochrome P-450 CYP2D6; Drug Interactions; Paroxetine; Genotype; Models, Biological; Adult; Male; Serotonin and Noradrenaline Reuptake Inhibitors; Female; Polymorphism, Genetic; Young Adult
PubMed: 38664354
DOI: 10.1007/s12272-024-01495-0