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European Journal of Pharmacology Apr 2021Niemann-Pick disease type C (NPC) is caused by a loss of function of either NPC1 or NPC2 protein, resulting in the accumulation of unesterified, free-cholesterol... (Comparative Study)
Comparative Study
Beneficial effects of primidone in Niemann-Pick disease type C (NPC)-model cells and mice: Reduction of unesterified cholesterol levels in cells and extension of lifespan in mice.
Niemann-Pick disease type C (NPC) is caused by a loss of function of either NPC1 or NPC2 protein, resulting in the accumulation of unesterified, free-cholesterol (free-C) in cells/tissues and thus leading to cell/tissue damage. In the brain of patients/animals with NPC, as a consequence of the accumulation of free-C in late endosomes/lysosomes (LE/LY) in cells, multiple lipids including complex sphingolipids are accumulated, and almost all patients/animals ultimately develop progressive/fatal neurodegeneration. Several reagents that are considered to act in the brain show beneficial effects on NPC-model animals. In the present study, we investigated the effects of antiepileptic drugs, such as primidone and valproic acid, on the accumulation of free-C in NPC1-null CHO cells and NPC1* fibroblasts, human fibroblasts established from a patient with NPC1 mutation. Like valproic acid, treatment with primidone reduced free-C levels in LE/LY in NPC1-null/mutant cells. Down-regulation of cholesterol ester levels in NPC1-null cells and up-regulation of HMG-CoA reductase and low-density lipoprotein receptor mRNA levels in NPC1* cells were partially recovered by primidone treatment. Thus, primidone was suggested to enhance free-C trafficking from LE/LY to endoplasmic reticulum in NPC1-null/mutant cells. In NPC1-null mice, oral application of primidone (100 mg/kg/day) extended lifespan by approximately 5 days, although the first days showing ataxia, a typical symptom of neuromotor dysfunction, were not affected. Our findings suggest the potential of primidone for the treatment of NPC.
Topics: Animals; Biological Transport; CHO Cells; Cholesterol; Cricetulus; Disease Models, Animal; Endoplasmic Reticulum; Endosomes; Fibroblasts; Humans; Intracellular Signaling Peptides and Proteins; Longevity; Lysosomes; Mice, Inbred BALB C; Mice, Knockout; Motor Activity; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Primidone; Time Factors; Valproic Acid; Mice
PubMed: 33503462
DOI: 10.1016/j.ejphar.2021.173907 -
Water Research Jun 2023Micropollutant (MP) abatement efficiencies are critical information for optimizing water treatment process for cost-effective operations. Nevertheless, due to the vast...
Micropollutant (MP) abatement efficiencies are critical information for optimizing water treatment process for cost-effective operations. Nevertheless, due to the vast number of MPs in real water matrices, it is infeasible to measure their abatement efficiencies individually in practical applications. In this study, a probe compound-based kinetic model was developed for generalized prediction of MP abatement in various water matrices by the ultraviolet (UV)/chlorine process. The results show that by measuring the depletion of three probe compounds (ibuprofen, primidone, and dimetridazole) spiked in the water matrix, the exposures of main reactive chlorine species (RCS including chlorine radicals (Cl•), dichloride radicals (Cl•) and chlorine oxide radicals (ClO•)) and hydroxyl radicals (•OH) during the UV/chlorine process could be calculated using the model. Based on the determined exposures, the abatement efficiencies of various MPs in different water matrices (e.g., surface water, groundwater, and wastewater) could generally be predicted with acceptable accuracy by the model without prior water-specific calibration. In addition, the relative contribution of UV photolysis and oxidation with active chlorine, RCS, and •OH to MP abatement could be quantitatively simulated using the model to clarify the abatement mechanism of MPs during the UV/chlorine process. The probe-based kinetic model can thus offer a useful tool to guide practical water and wastewater treatment for MP abatement and to explore the mechanism of UV/chlorine process.
Topics: Chlorine; Water Pollutants, Chemical; Ultraviolet Rays; Wastewater; Hydrogen Peroxide; Chlorides; Oxidation-Reduction; Kinetics; Water Purification
PubMed: 37098285
DOI: 10.1016/j.watres.2023.119985 -
Water Research May 2023Pharmaceutical and personal care products (PPCPs) are frequently detected in water bodies and have potential risks to human health and the ecosystem. The degradation of...
Pharmaceutical and personal care products (PPCPs) are frequently detected in water bodies and have potential risks to human health and the ecosystem. The degradation of eight structurally diverse PPCPs by ammonia/chlorine was systematically investigated in this study. Compared with chlorination, ammonia/chlorine markedly enhanced PPCP degradation, and the degradation efficiencies of most PPCPs were greater than 70%. Tert-butanol strongly suppressed PPCP degradation, while bicarbonate suppressed it moderately, suggesting the importance of ClO⋅and ⋅CO in PPCP degradation. In neutral conditions, PPCP degradation was mainly attributed to ⋅OH, with its contribution ranging from 74% to 100% at a Cl/N molar ratio of 1.6. Regarding the effect of natural organic matter, atrazine and primidone were inhibited the most, while carbamazepine (CBZ), metoprolol (MTP), and atenolol (ATN) were affected the least. PPCP degradation was suppressed in reclaimed water; the degradation of CBZ, MTP, and ATN was suppressed the least, with degradation efficiencies of 77.1%-85.4%, 75.1%-77.1%, and 64.6%-68.8%, respectively. Furthermore, compared with chlorination, fewer volatile halogenated byproducts were formed in reclaimed water when using the ammonia/chlorine process, and the concentration of each byproduct formed by ammonia/chlorine was less than 10 µg/L. This study suggests the feasibility of using ammonia/chlorine oxidation to degrade PPCPs in reclaimed water.
Topics: Humans; Chlorine; Ammonia; Water Purification; Ecosystem; Water Pollutants, Chemical; Ultraviolet Rays; Water; Carbamazepine; Chlorides
PubMed: 36924555
DOI: 10.1016/j.watres.2023.119862 -
The Science of the Total Environment Jun 2023Electrochemical process coupling with ultraviolet light-emitting diode for micropollutant abatement was evaluated in the treatment of wastewater containing Cl. Four...
Insight into micropollutant abatement during ultraviolet light-emitting diode combined electrochemical process: Reaction mechanism, contributions of reactive species and degradation routes.
Electrochemical process coupling with ultraviolet light-emitting diode for micropollutant abatement was evaluated in the treatment of wastewater containing Cl. Four representative micropollutants, atrazine, primidone, ibuprofen and carbamazepine, were selected as target compounds. The impacts of operating conditions and water matrix on micropollutant degradation were investigated. Fluorescence excitation-emission matrix spectroscopy spectra and high performance size exclusion chromatography were employed to characterize the transformation of effluent organic matter in treatment. The degradation efficiencies of atrazine, primidone, ibuprofen and carbamazepine are 83.6 %, 80.6 %, 68.7 % and 99.8 % after 15 min treatment, respectively. The increment of current, Cl concentration and ultraviolet irradiance promote the micropollutant degradation. However, the presence of bicarbonate and humic acid inhibit micropollutant degradation. The mechanism of micropollutant abatement was elaborated based on reactive species contributions, density functional theory calculation and degradation routes. Free radicals (HO, Cl, ClO and Cl) could be generated by chlorine photolysis and subsequent propagation reactions. The concentrations of HO and Cl are 1.14 × 10 M and 2.0 × 10 M in optimal condition, respectively, and the total contributions of HO and Cl for the degradation of atrazine, primidone, ibuprofen and carbamazepine are 24 %, 48 %, 70 % and 43 %, respectively. The degradation routes of four micropollutants are elucidated based on intermediate identification, Fukui function and frontier orbital theory. Micropollutants can be effectively degraded in actual wastewater effluent, and the small molecule compound proportion increases during effluent organic matter evolution. Compared with photolysis and electrolysis, the coupling of the two processes has potential for energy saving in micropollutant degradation, which shed light on the prospects of ultraviolet light-emitting diode coupling with electrochemical process for effluent treatment.
PubMed: 36914136
DOI: 10.1016/j.scitotenv.2023.162798 -
The International Journal of... Jan 2024To examine the link between tremor and sex chromosome abnormalities, emphasizing the necessity of comprehensive physical examination.
PURPOSE
To examine the link between tremor and sex chromosome abnormalities, emphasizing the necessity of comprehensive physical examination.
CASE DESCRIPTION
An 18-year-old man exhibited an isolated action tremor in both hands. Despite having no familial history of tremors and no identifiable secondary causes, his tall stature and learning difficulties suggested a genetic origin. His karyotype confirmed the diagnosis of Jacob's syndrome (XYY syndrome). Therapies with primidone and propranolol were ineffective for his tremor.
CONCLUSIONS
Tremor can be caused by various conditions, and aneuploidies might often be overlooked as a cause. They should be considered in young patients with concrete phenotypes and negative familiar history of tremors. Karyotyping is a cost-effective diagnostic tool crucial for genetic counselling. Common treatments for tremors often yield unsatisfactory results in these cases.
PubMed: 38294709
DOI: 10.1080/00207454.2024.2313009 -
Epilepsy Currents 2022: Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease. : To quantify and model the...
: Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease. : To quantify and model the putative hazard of cardiovascular disease secondary to eiASM use. : This cohort study covered January 1990 to March 2019 (median [IQR] follow-up, 9 [4-15], years). The study linked primary care and hospital electronic health records at National Health Service hospitals in England. People aged 18 years or older diagnosed as having epilepsy after January 1, 1990, were included. All eligible patients were included with a waiver of consent. No patients were approached who withdrew consent. Analysis began January 2021 and ended August 2021. : Receipt of 4 consecutive EI ASMs (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate) following an adult-onset (age >/=18 years) epilepsy diagnosis or repeated exposure in a weighted cumulative exposure model. : Three cohorts were isolated, 1 of which comprised all adults meeting a case definition for epilepsy diagnosed after 1990, 1 comprised incident cases diagnosed after 1998 (hospital linkage date), and 1 was limited to adults diagnosed with epilepsy at 65 years or older. Outcome was incident cardiovascular disease (ischemic heart disease or ischemic or hemorrhagic stroke). Hazard of incident cardiovascular disease was evaluated using adjusted propensity-matched survival analyses and weighted cumulative exposure models. : Of 10,916,166 adults, 50,888 (.6%) were identified as having period-prevalent cases (median [IQR] age, 32 [19-50] years; 16 584 [53%] female), of whom 31,479 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline. In a propensity-matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status, and cardiovascular risk factors, the hazard ratio for incident cardiovascular disease was 1.21 (95% CI, 1.06-1.39) for those receiving eiASMs. The absolute difference in cumulative hazard diverges by more than 1% and greater after 10 years. For those with persistent exposure beyond 4 prescriptions, the median hazard ratio increased from a median (IQR) of 1.54 (1.28-1.79) when taking a relative defined daily dose of an eiASM of 1 to 2.38 (1.52-3.56) with a relative defined daily dose of 2 throughout a maximum of 25 years' follow-up compared with those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed when older than 65 years. : The hazard of incident cardiovascular disease is higher in those receiving eiASMs. The association is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.
PubMed: 35444497
DOI: 10.1177/15357597211070392 -
Hospital Pharmacy Aug 2023The management of the drug-drug interaction (DDI) between primidone, a moderate to strong cytochrome P-450 (CYP) 3A4 inducer, and apixaban, a direct oral anticoagulant...
The management of the drug-drug interaction (DDI) between primidone, a moderate to strong cytochrome P-450 (CYP) 3A4 inducer, and apixaban, a direct oral anticoagulant (DOAC) and CYP3A4 substrate is complex and limited evidence exists to guide management. This case report describes a 65-year-old male, receiving primidone for essential tremor who developed an acute venous thromboembolism (VTE) requiring oral anticoagulation. DOACs are preferred over vitamin K antagonists for acute VTE treatment. Based on patient-specific variables, provider preference, and the avoidance of other DDIs, apixaban was selected. Apixaban's package insert recommends avoiding use with concomitant strong P-gp and CYP3A4 inducers due to the decreased exposure to apixaban; however, no recommendations are available for drugs that are moderate to strong CYP3A4 inducers and lack P-gp effects. Given that phenobarbital is an active metabolite of primidone, extrapolation of evidence from such literature is theoretical but provides insight into the management of this multi-faceted DDI. In the absence of the ability to monitor plasma apixaban levels, a management strategy of avoidance with a washout period of primidone based on pharmacokinetic parameters was used in this case. Additional evidence is needed to clearly understand the degree of impact and clinical significance of the DDI between apixaban and primidone.
PubMed: 37360203
DOI: 10.1177/00185787221150928 -
Impact of EfOM in the elimination of PPCPs by UV/chlorine: Radical chemistry and toxicity bioassays.Water Research Oct 2021The UV/chlorine process as a potential tertiary municipal wastewater treatment alternative for removing refractory PPCPs has been widely investigated. However, the role...
The UV/chlorine process as a potential tertiary municipal wastewater treatment alternative for removing refractory PPCPs has been widely investigated. However, the role of effluent organic matter (EfOM) on the radical chemistry and toxicity alteration is unclear. The elimination of two model PPCPs, primidone (PRM) and caffeine (CAF), by the co-exposure of UV and free chlorine was investigated to elucidate the impact of EfOM. Experimental results indicated that both OH and reactive chlorine species (RCS) were importantly involved in the decay of PRM at acidic condition, while ClO played dominant role at alkaline pH. The decay of CAF was dominated by ClO under all conditions. Chlorine dose, initial contaminant concentration, solution pH, and water matrix affect the process efficiency at varying degree resulting from their specific effect on the radical speciation in the system. Presence of EfOM isolate remarkably inhibited the decay of PRM and CAF by preferentially scavenging RCS and particularly ClO. Good correlations (linear for PRM and exponential for CAF) between UV absorbance at 254 nm and the observed pseudo first-order rate constants (k') for all EfOM solutions were obtained, demonstrating the importance of aromatic moieties in inhibiting the degradation of targeted contaminants by UV/chlorine process. Degradation of PRM/CAF in reconstituted effluent spiked with the major effluent constituents (i.e., EfOM isolates, Cl, HCO, and NO) was comparable to the results obtained with the real WWTP effluent and fit well to the correlation between k' and UV absorbance at 254 nm, suggesting that EfOM isolates can be used to determine the efficiency of UV/chlorine process in real effluent. EfOM serves as the main precursor of adsorbable organic chlorine in the UV/chlorine treatment. Bioassays indicated that chlorine-containing compounds could induce oxidative stress, mitochondrial dysfunction, and increase the cell DNA damage. Among evaluated treatment conditions, the nature of EfOM, hydrophobic versus transphilic fraction, is likely the predominant factor affecting the cytotoxicity. Meanwhile the UV/chlorine treatment can significantly reduce the cytotoxicity of EfOM isolates. However, adding high level of selected contaminants (e.g., PRM and CAF) can inhibit this phenomenon due to the competition with reactive radicals.
Topics: Biological Assay; Caffeine; Chlorine; DNA Damage; Oxidative Stress
PubMed: 34543976
DOI: 10.1016/j.watres.2021.117634 -
Chemosphere Dec 2021Endorheic lakes (or terminal lakes, TLs) have no natural outlet other than evaporation and slow infiltration. Some TLs receive reclaimed wastewater which contains poorly...
Endorheic lakes (or terminal lakes, TLs) have no natural outlet other than evaporation and slow infiltration. Some TLs receive reclaimed wastewater which contains poorly removed trace organic contaminants (TrOCs). To determine if TLs accumulate TrOCs we conducted a preliminary assessment of the occurrence of ten TrOCs in three TLs receiving reclaimed wastewater and one TL which does not directly receive reclaimed wastewater. Five of ten TrOCs (carbamazepine, DEET, fluoxetine, primidone, and trimethoprim) were present in all four TLs' surface waters (~0.3-1109 ng/L), six (caffeine, carbamazepine, DEET, diphenhydramine, primidone, and trimethoprim) were present in sediment samples (0.1-77 ng/gDW) and in soil samples (0.1-137 ng/gDW). Concentrations of caffeine, carbamazepine, diphenhydramine, fluoxetine and meprobamate were significantly higher in TLs receiving wastewater from a secondary treatment plant compared to those TLs which received tertiary treated wastewater. Carbamazepine, fluoxetine, sulfamethoxazole, and trimethoprim were present at concentrations greater than is typical of other U.S. freshwater lakes, but other TrOC concentrations were present at lower concentrations than in other freshwater lakes. We conclude that some TrOCs may accumulate in TLs, but to a lesser extent than would be expected based on the accumulation of dissolved constituents alone, which indicates that there are other unidentified processes in TLs that contribute to TrOC losses. Other TLs across the globe may have similar levels of TrOCs due to anthropogenic influence and treated wastewater inputs.
Topics: Carbamazepine; Lakes; Sulfamethoxazole; Wastewater; Water Pollutants, Chemical
PubMed: 34242983
DOI: 10.1016/j.chemosphere.2021.131408 -
Epilepsy Research Mar 2020Certain antiepileptic drugs (AEDs) may be more suitable for elderly patients with epilepsy (EWE) relative to others. However, little is known regarding which...
OBJECTIVE
Certain antiepileptic drugs (AEDs) may be more suitable for elderly patients with epilepsy (EWE) relative to others. However, little is known regarding which antiepileptic drugs (AEDs) are being used to treat EWE in the United States and how it has changed over time.
METHODS
We performed a serial cross-sectional study evaluating noninstitutionalized US adults aged 65 years or older with a diagnosis of epilepsy using data from the Medical Expenditure Panel Survey (MEPS) from 2004 through 2015. Trends in AEDs used among EWE were examined. Using each AED as a dependent variable, we determined the p-value for the trend by performing a linear regression with the time interval as the explanatory variable.
RESULTS
There was a weighted total of 399,801 EWE. Between the years 2004-2006 and 2013-2015 use of phenytoin, carbamazepine and phenobarbital decreased from 60.7% to 31.1% (p ≤ 0.001), 13.7 % to 5.22 % (p = 0.03) and 12.5 % to 5.91 % (p = 0.04), respectively. Use of levetiracetam concomitantly increased from 6.70 % to 43.1 % (p ≤ 0.001). Patients with more medical comorbidities as measured by the Charlson Comorbidity Index had higher odds of levetiracetam use (OR = 2.52, 95 % CI = 1.19-5.34) and lower odds of phenytoin use (OR = 0.46, 95 % CI = 0.24-0.88).
CONCLUSIONS
There have been significant changes in AED prescriptions to EWE between 2004-2015. However, potentially harmful AEDs (e.g. phenytoin, carbamazepine, phenobarbital, primidone and valproate) were still being prescribed to 42.9 % of all patients between 2013-2015. Increased work to educate providers regarding the use of more appropriate AEDs in this population is needed.
Topics: Aged; Aged, 80 and over; Aging; Anticonvulsants; Carbamazepine; Cross-Sectional Studies; Epilepsy; Female; Humans; Levetiracetam; Male; Middle Aged; Phenytoin; Seizures; Zonisamide
PubMed: 32088517
DOI: 10.1016/j.eplepsyres.2020.106297