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Therapeutic Drug Monitoring Apr 2022Therapeutic drug monitoring (TDM) of antiseizure medications (ASMs) is widely used to guide therapy, avoid toxicity, and assess patient compliance. Commercial...
Simultaneous Quantification of 11 Antiseizure Medications and Metabolites in Serum for Therapeutic Drug Monitoring Using High-Performance Liquid Chromatography with Ultraviolet Detection: A Short Communication.
BACKGROUND
Therapeutic drug monitoring (TDM) of antiseizure medications (ASMs) is widely used to guide therapy, avoid toxicity, and assess patient compliance. Commercial immunologic quantification methods are common practice; however, as they are only applicable to one specific drug and prone to cross-reacting metabolites, their practical applicability is limited. In this article, the authors proposed a high-performance liquid chromatography method using ultraviolet detection (HPLC-UV) for simultaneous quantification of 11 ASMs and active metabolites (carbamazepine, felbamate, lacosamide, lamotrigine, levetiracetam, phenobarbital, phenytoin, primidone, zonisamide, carbamazepine-10,11-epoxide, and licarbazepine) in serum.
METHODS
Chromatographic separation was performed on a Phenomenex Luna PFP(2) (3-µm particle size; 150 × 4.6 mm i.d.) analytical column. The mobile phase comprised phosphate buffer (20 mM; pH 3), acetonitrile (ACN), and methanol using gradient elution. Analyses were conducted at 35°C and a 1.3-mL/min flow rate. The detection wavelength for all analytes was 210 nm. The samples were prepared by protein precipitation using ACN.
RESULTS
The HPLC-UV method was validated according to the FDA guidelines and applied to measure patient samples in TDM. Calibration curves showed excellent linearity (r2 > 0.99) and covered the entire reference range for each analyte. Intraday and interday imprecisions and inaccuracies were <10% for all samples. Extensive stability testing showed no significant degradation (<15%), and interference measurements additionally ensured clinical applicability. Furthermore, the sensitivity was comparable with that of previously published HPLC methods using mass spectrometry.
CONCLUSIONS
The authors developed an HPLC-UV method for the simultaneous quantification of 11 ASMs in the human serum and demonstrated its practical applicability in TDM. The method requires only standard laboratory equipment and simple sample preparation, making TDM available in less specialized laboratories.
Topics: Anticonvulsants; Carbamazepine; Chromatography, High Pressure Liquid; Drug Monitoring; Humans; Phenytoin
PubMed: 35292610
DOI: 10.1097/FTD.0000000000000908 -
The Science of the Total Environment Jul 2022Effluents from ten full-scale municipal wastewater treatment plants (WWTPs) that discharge into the Hudson River, surface waters, and wild-caught fish samples were...
Effluents from ten full-scale municipal wastewater treatment plants (WWTPs) that discharge into the Hudson River, surface waters, and wild-caught fish samples were analyzed using liquid chromatography with tandem mass spectrometry (LC/MS/MS) to examine the influence of wastewater discharge on the concentrations of contaminants of emerging concern (CECs) and their ecological impacts on fish. Analysis was based on targeted detection of 41 pharmaceuticals, and non-targeted analysis (suspect screening) of CECs. Biological effects of treated WWTP effluents were assessed using a larval zebrafish (Danio rerio) swimming behavior assay. Concentrations of residues in surface waters were determined in grab samples and polar organic chemical integrative samplers (POCIS). In addition, vitellogenin peptides, used as biomarkers of endocrine disruption, were quantified using LC/MS/MS in the wild-caught fish plasma samples. Overall, 94 chemical residues were identified, including 63 pharmaceuticals, 10 industrial chemicals, and 21 pesticides. Eight targeted pharmaceuticals were detected in 100% of effluent samples with median detections of: bupropion (194 ng/L), carbamazepine (91 ng/L), ciprofloxacin (190 ng/L), citalopram (172 ng/L), desvenlafaxine (667 ng/L), iopamidol (3790 ng/L), primidone (86 ng/L), and venlafaxine (231 ng/L). Over 30 chemical residues were detected in wild-caught fish tissues. Notably, zebrafish larvae exposed to chemical extracts of effluents from 9 of 10 WWTPs, in at least one season, were significantly hyperactive. Vitellogenin expression in male or immature fish occurred 2.8 times more frequently in fish collected from the Hudson River as compared to a reference site receiving no direct effluent input. Due to the low concentrations of pharmaceuticals detected in effluents, it is likely that chemicals other than pharmaceuticals measured are responsible for the behavioral changes observed. The combined use of POCIS and non-target analysis demonstrated significant increase in the chemical coverage for CEC detection, providing a better insight on the impacts of WWTP effluents and agricultural practices on surface water quality.
Topics: Animals; Environmental Monitoring; Male; Organic Chemicals; Pharmaceutical Preparations; Rivers; Tandem Mass Spectrometry; Vitellogenins; Wastewater; Water Pollutants, Chemical; Zebrafish
PubMed: 35245556
DOI: 10.1016/j.scitotenv.2022.154176 -
American Journal of Health-system... Jul 2022We report a unique case of transiently elevated liver function test (LFT) values associated with concurrent use of dabigatran and primidone, which has not previously...
PURPOSE
We report a unique case of transiently elevated liver function test (LFT) values associated with concurrent use of dabigatran and primidone, which has not previously been described in the scientific literature.
SUMMARY
Management of drug-drug interactions requires a fundamental understanding of pharmacodynamic and pharmacokinetic parameters. Despite the use of available best predictive models, idiosyncratic drug reactions may still occur when a newly approved medication begins to be used in the general population. We report a case of a possible interaction (Naranjo adverse drug reaction probability score of 3, Roussel Uclaf causality assessment method score of 3) between dabigatran and primidone in a 70-year-old Caucasian male resulting in a transient elevation of LFT values. The patient was transitioned from warfarin to dabigatran in the setting of persistently subtherapeutic international normalized ratio values. During a routine outpatient follow-up appointment approximately 1 month after dabigatran initiation, the patient was discovered to have LFT values greater than 5 times the upper limit of normal. Dabigatran was thus discontinued; the patient was returned to warfarin therapy and their LFT values returned to baseline.
CONCLUSION
Studies have indicated a potential for reduced dabigatran efficacy with concurrent use of primidone due to P-glycoprotein induction, thereby potentiating the risk for thrombosis. To date, reports of this interaction resulting in hepatic injury are lacking. The present case suggests that this interaction may be clinically significant with regard to selection of antithrombotic medication therapy in patients on primidone therapy.
Topics: Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Humans; International Normalized Ratio; Liver Function Tests; Male; Primidone; Warfarin
PubMed: 35212353
DOI: 10.1093/ajhp/zxac054 -
The Science of the Total Environment May 2022Although combined ozonation with activated carbon (AC) adsorption is a promising technique for leachate treatment, little is known about how ozone-induced changes in...
Although combined ozonation with activated carbon (AC) adsorption is a promising technique for leachate treatment, little is known about how ozone-induced changes in leachate characteristics affect the organics adsorption, especially in view of emerging micropollutants (MPs) removal. Furthermore, the online monitoring of MPs is challenging but desirable for efficient treatment operation. This study investigates how preceding ozonation impacts the adsorption of bulk organics (expressed as chemical oxygen demand (COD)) and ozone-recalcitrant MPs, i.e., primidone, atrazine and alachlor, in leachate using batch and column adsorption tests. Additionally, a new surrogate-based model was evaluated for predicting MPs breakthrough. Batch tests revealed that ozonation results in a decreasing apparent affinity of COD towards AC, but the non-adsorbable part did not obviously change. The adsorption of MPs in ozonated leachate was (1-41%) higher than that in non-ozonated leachate, especially for the more hydrophobic alachlor and atrazine, due to a reduced sites competition from bulk organics. Column adsorption showed that ozonation delayed COD and MPs breakthrough due to the reduced COD loading and sites competition, respectively. An increased empty bed contact time (EBCT, 10-40 min) led to an increased COD uptake by a factor of 3.0-3.2 for ozonated and non-ozonated leachates, while MPs adsorption also increased, suggesting that pore blockage rather than site competition could be the dominant inhibitory effect. The data from column adsorption demonstrate the applicability of developed surrogate-based model for predicting MPs breakthrough. Particularly, the fitting parameters were not affected by change of leachate characteristics, while they were impacted by change of EBCT.
Topics: Adsorption; Charcoal; Follow-Up Studies; Ozone; Water Pollutants, Chemical
PubMed: 35077794
DOI: 10.1016/j.scitotenv.2022.153349 -
Tremor and Other Hyperkinetic Movements... 2021There are few medications for the treatment of essential tremor (ET). One of these, primidone, which is one of only two front-line agents, is associated with... (Review)
Review
BACKGROUND
There are few medications for the treatment of essential tremor (ET). One of these, primidone, which is one of only two front-line agents, is associated with considerable adverse drug reactions (ADRs). It is unclear why some primidone-treated ET patients develop ADRs whereas others do not, and why these ADRs seem to be more prevalent in ET patients than primidone-treated patients with epilepsy.
OBJECTIVE
To review several possible explanations underlying the above-referenced differences.
METHODS
A literature search was conducted in PubMed in October 2021. Studies reporting the ADRs of primidone in different neurological conditions were comprehensively reviewed.
DISCUSSION
Although there were no head-to-head data, a review of the previous studies on ET and epilepsy patients indicates that the former is relatively more intolerant to primidone. Moreover, not all ET patients develop ADR of similar nature or severity. We discuss several potential mechanisms for this variability in the intolerance to primidone. These include: (i) older age (ET vs. epilepsy patients), (ii) cross-tolerance to primidone in patients with epilepsy, (iii) neurobiological (GABA-related) abnormalities associated with ET.
CONCLUSION
We speculate that there are several possible explanations for primidone intolerance in ET. These possibilities should be tested in future studies, and we propose the roadmap for designing these studies. It is of value to obtain detailed insight into these complex issues because primidone remains one of the few frontline anti-tremor medications in ET. Answers to issues we have raised in this article could facilitate more customized formulation of primidone in ET patients.
Topics: Aged; Essential Tremor; Humans; Primidone; Tremor
PubMed: 35070493
DOI: 10.5334/tohm.672 -
Journal of Veterinary Internal Medicine Jan 2022Orthostatic tremor (OT) is a rare movement disorder characterized by high-frequency (>12 Hz) involuntary, rhythmic, sinusoidal movements affecting predominantly the...
BACKGROUND
Orthostatic tremor (OT) is a rare movement disorder characterized by high-frequency (>12 Hz) involuntary, rhythmic, sinusoidal movements affecting predominantly the limbs while standing.
OBJECTIVE
To describe the signalment, presenting complaints, phenotype, diagnostic findings, treatment, and outcome of a large sample of dogs with OT.
ANIMALS
Sixty dogs diagnosed with OT based on conscious electromyography.
METHODS
Multicenter retrospective case series study. Dogs were included if they had a conscious electromyography consistent with muscle discharge frequency >12 Hz while standing.
RESULTS
Fifty-three cases were diagnosed with primary OT (POT). Giant breed dogs represented most cases (83%; 44/53). Most dogs (79%; 42/53) were younger than 2 years of age at onset of signs, except for Retrievers which were all older than 3.5 years of age. The most common presenting complaints were pelvic limb tremors while standing (85%; 45/53) and difficulty when rising or sitting down (45%; 24/53). Improvement of clinical signs occurred in most dogs (85%; 45/53) treated medically with phenobarbital, primidone, gabapentin, pregabalin or clonazepam, but it was mostly partial rather than complete. Orthostatic tremor-plus was seen in 7 dogs that had concurrent neurological diseases.
CONCLUSIONS AND CLINICAL IMPORTANCE
Primary OT is a progressive disease of young, purebred, giant/large-breed dogs, which appears to begin later in life in Retrievers. Primary OT apparently responds partially to medications. Orthostatic tremor-plus exists in dogs and can be concomitant or associated with other neurological diseases.
Topics: Animals; Dizziness; Dog Diseases; Dogs; Electromyography; Retrospective Studies; Tremor
PubMed: 34897811
DOI: 10.1111/jvim.16328 -
Nature Reviews. Disease Primers Nov 2021Essential tremor (ET) is one of the most common movement disorders, with a reported >60 million affected individuals worldwide. The definition and underlying... (Review)
Review
Essential tremor (ET) is one of the most common movement disorders, with a reported >60 million affected individuals worldwide. The definition and underlying pathophysiology of ET are contentious. Patients present primarily with motor features such as postural and action tremors, but may also have other non-motor features, including cognitive impairment and neuropsychiatric symptoms. Genetics account for most of the ET risk but environmental factors may also be involved. However, the variable penetrance and challenges in validating data make gene-environment analysis difficult. Structural changes in cerebellar Purkinje cells and neighbouring neuronal populations have been observed in post-mortem studies, and other studies have found GABAergic dysfunction and dysregulation of the cerebellar-thalamic-cortical circuitry. Commonly prescribed medications include propranolol and primidone. Deep brain stimulation and ultrasound thalamotomy are surgical options in patients with medically intractable ET. Further research in post-mortem studies, and animal and cell-based models may help identify new pathophysiological clues and therapeutic targets and, together with advances in omics and machine learning, may facilitate the development of precision medicine for patients with ET.
Topics: Animals; Essential Tremor; Humans
PubMed: 34764294
DOI: 10.1038/s41572-021-00314-w -
Water Research Nov 2021Numerous studies report on the synergy between ozonation and photocatalytic oxidation (TiO/UVA), which could open the way to the application of photocatalytic ozonation...
Numerous studies report on the synergy between ozonation and photocatalytic oxidation (TiO/UVA), which could open the way to the application of photocatalytic ozonation (PCOz) in water treatment. With the aim of establishing the existence of this synergy and its origin, in this work, using TiO P25, 365 nm UVA LEDs and ozone transferred doses up to 5 mg (mg DOC) (DOC 7 - 10 mg L), a systematic study has been carried out featuring the effect of pH, alkalinity and water matrix in each of the systems involved in PCOz, with special attention to the role of organics adsorption onto TiO. In ultrapure water, an increase in pH and carbonates content exerted a slight negative effect on the photocatalytic degradation of primidone (low adsorption onto TiO and mainly abated by free HO), this effect being higher on its mineralization. The negative effect of pH and alkalinity was much stronger for oxalic acid (high tendency to adsorb and mainly oxidized by positive holes). Accordingly, the results obtained at pH < pH (point of zero charge of the catalyst) in ultrapure water cannot at all be extrapolated to secondary effluents, since their composition negatively affects the photocatalytic performance. At the experimental conditions applied, only for the secondary effluent a synergy between O/UVA and TiO/UVA systems was observed. This synergy would be related, on the one hand, to the generation, from the matrix itself, of reactive entities or intermediates that promote the decomposition of ozone into HO; and, on the other hand, to an increase in catalyst activity as the matrix UVA absorption decreases, rather than from direct interactions between both systems. Despite de above, ozone requirement to achieve a significant reduction of DOC is high and would only be an interesting strategy for the elimination of ozone-refractory micropollutants.
Topics: Catalysis; Oxidation-Reduction; Ozone; Titanium; Water Pollutants, Chemical; Water Purification
PubMed: 34624657
DOI: 10.1016/j.watres.2021.117727 -
JAMA Neurology Nov 2021Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease.
IMPORTANCE
Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease.
OBJECTIVE
To quantify and model the putative hazard of cardiovascular disease secondary to eiASM use.
DESIGN, SETTING, AND PARTICIPANTS
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.
EXPOSURES
Receipt of 4 consecutive eiASMs (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.
MAIN OUTCOMES AND MEASURES
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.
RESULTS
Of 10 916 166 adults, 50 888 (0.6%) 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 amedian (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.
CONCLUSIONS AND RELEVANCE
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.
Topics: Adult; Anticonvulsants; Cardiovascular Diseases; Cohort Studies; Epilepsy; Female; Humans; Incidence; Male; Middle Aged; Retrospective Studies
PubMed: 34605857
DOI: 10.1001/jamaneurol.2021.3424