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NPJ Genomic Medicine Aug 2022Essential tremor (ET) is one of the most common movement disorders, affecting nearly 5% of individuals over 65 years old. Despite this, few genetic risk loci for ET have...
Essential tremor (ET) is one of the most common movement disorders, affecting nearly 5% of individuals over 65 years old. Despite this, few genetic risk loci for ET have been identified. Recent advances in pharmacogenomics have previously been useful to identify disease related molecular targets. Notably, gene expression has proven to be quite successful for the inference of drug response in cell models. We sought to leverage this approach in the context of ET where many patients are responsive to two drugs: propranolol and primidone. In this study, cerebellar DAOY and neural progenitor cells were treated for 5 days with clinical concentrations of propranolol and primidone, after which RNA-sequencing was used to identify convergent differentially expressed genes across treatments. Propranolol was found to affect the expression of genes previously associated with ET and other movement disorders such as TRAPPC11. Pathway enrichment analysis of these convergent drug-targeted genes identified multiple terms related to calcium signaling, endosomal sorting, axon guidance, and neuronal morphology. Furthermore, genes targeted by ET drugs were enriched within cell types having high expression of ET-related genes in both cortical and cerebellar tissues. Altogether, our results highlight potential cellular and molecular mechanisms associated with tremor reduction and identify relevant genetic biomarkers for drug-responsiveness in ET.
PubMed: 35927430
DOI: 10.1038/s41525-022-00318-9 -
Clinical Pharmacokinetics Sep 2022Ritonavir-boosted nirmatrelvir (RBN) has been authorized recently in several countries as an orally active anti-SARS-CoV-2 treatment for patients at high risk of... (Review)
Review
Clinically Relevant Interactions Between Ritonavir-Boosted Nirmatrelvir and Concomitant Antiseizure Medications: Implications for the Management of COVID-19 in Patients with Epilepsy.
Ritonavir-boosted nirmatrelvir (RBN) has been authorized recently in several countries as an orally active anti-SARS-CoV-2 treatment for patients at high risk of progressing to severe COVID-19 disease. Nirmatrelvir is the active component against the SARS-CoV-2 virus, whereas ritonavir, a potent CYP3A inhibitor, is intended to boost the activity of nirmatrelvir by increasing its concentration in plasma to ensure persistence of antiviral concentrations during the 12-hour dosing interval. RBN is involved in many clinically important drug-drug interactions both as perpetrator and as victim, which can complicate its use in patients treated with antiseizure medications (ASMs). Interactions between RBN and ASMs are bidirectional. As perpetrator, RBN may increase the plasma concentration of a number of ASMs that are CYP3A4 substrates, possibly leading to toxicity. As victims, both nirmatrelvir and ritonavir are subject to metabolic induction by concomitant treatment with potent enzyme-inducing ASMs (carbamazepine, phenytoin, phenobarbital and primidone). According to US and European prescribing information, treatment with these ASMs is a contraindication to the use of RBN. Although remdesivir is a valuable alternative to RBN, it may not be readily accessible in some settings due to cost and/or need for intravenous administration. If remdesivir is not an appropriate option, either bebtelovimab or molnupiravir may be considered. However, evidence about the clinical efficacy of bebtelovimab is still limited, and molnupiravir, the only orally active alternative, is deemed to have appreciably lower efficacy than RBN and remdesivir.
Topics: Antibodies, Neutralizing; Antiviral Agents; Epilepsy; Humans; Ritonavir; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35895276
DOI: 10.1007/s40262-022-01152-z -
Journal of Clinical Medicine May 2022(1) Background: The benefit of using inhibitors of carbonic anhydrase (CA), such as acetazolamide, in the treatment of epilepsy has previously been described. (2)...
(1) Background: The benefit of using inhibitors of carbonic anhydrase (CA), such as acetazolamide, in the treatment of epilepsy has previously been described. (2) Methods: In this paper, the effect on CA of the most well-known antiepileptic drugs was studied in vitro and in vivo. The effects, after chronic treatment, of carbamazepine, phenytoin, valproate, primidone, clonazepam, and ethosuximide were studied in vitro on purified CA, isozyme I (CA I) and CA, and isozyme II (CA II) activity and in vivo on epileptic erythrocyte CA I and CA II activity. (3) Results: In vitro results showed that all antiepileptic drugs reduced purified CA II activity according to dose-response relationships and slightly inhibited CA I activity. In vivo results showed that the chronic administration of antiseizure drugs induced a progressive reduction in erythrocyte CA II activity in all the groups studied. This study shows that CA II inhibition can be induced both in vitro and in vivo by major antiepileptic agents as it might be one of the effective mechanisms of these anticonvulsant drugs. (4) Conclusions: The decrease in CA II activity in epileptic patients after antiseizure treatment suggests the involvement of CA II in the pathogenesis of epilepsy.
PubMed: 35566738
DOI: 10.3390/jcm11092614 -
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 -
Seizure May 2022Recent position papers and guidelines encourage women with epilepsy (WWE) to exclusively breastfeed their infants because the benefits to their infants outweigh the... (Review)
Review
BACKGROUND
Recent position papers and guidelines encourage women with epilepsy (WWE) to exclusively breastfeed their infants because the benefits to their infants outweigh the potential adverse effects caused by exposure to antiseizure medications (ASMs).
OBJECTIVE
The objectives of this review were: to evaluate concentrations of ASMs in breastmilk of lactating WWE, qualitatively synthesize evidence that can be used to estimate theoretical doses as estimated daily intake (EDI) and relative infant dose (RID) of ASMs, and to evaluate potential risks to infants as a result of exposure to ASMs from breastmilk.
METHODS
This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as CRD42020223645. The databases: MEDLINE/PubMed, EMBASE, CINAHL/EBSCO, COCHRANE, SpringerLink, ScienceDirect, Summon, WHO International Clinical Trials Registry Platform, and SCOPUS were systematically searched. A qualitative synthesis was adopted in this study.
RESULTS
A total of 15 records were included in this systematic review. The included studies reported levels of 8 ASMs in the breastmilk of WWE. The highest RIDs of carbamazepine, lamotrigine, primidone, phenobarbital, gabapentin, valproic acid, ethosuximide, levetiracetam, and topiramate were 3.70%, 36.33%, 4.96%, 3.15%, 4.37%, 1.90%, 31.49%, 12.50%, and 12.18%, respectively. Breastfeeding might be limited or even discontinued when signs of excessive sedation/drowsiness and/or poor weight gain are evident on infants exposed to primidone and phenobarbital, ethosuximide/primidone, or ethosuximide/phenobarbital.
CONCLUSIONS
Concentrations of ASMs can be detected in breastmilk of WWE and plasma/serum of infants exposed via breastmilk. Healthcare providers and WWE might use the findings of this study to make informed decisions on the safety of breastfeeding while taking ASMs.
Topics: Anticonvulsants; Breast Feeding; Epilepsy; Ethosuximide; Female; Humans; Infant; Lactation; Milk, Human; Phenobarbital; Primidone
PubMed: 35427849
DOI: 10.1016/j.seizure.2022.03.017 -
Tremor and Other Hyperkinetic Movements... 2022Although first line therapies for essential tremor have been identified from small clinical trials, responses are variable. We conducted a survey of tremor management in...
BACKGROUND
Although first line therapies for essential tremor have been identified from small clinical trials, responses are variable. We conducted a survey of tremor management in a large sample of ET cases.
METHODS
The Movement Disorders Clinical Case Registry within a US Veterans Health Administration medical center was used to identify 1468 patients with ET.
RESULTS
Of 1468 charts reviewed, 1074 (73.19%) met criteria for ET with characterization of temporal course and treatment; 291/1074 subjects (27.1%) did not receive any treatment. Almost half (500/1074; 46.6%) of the patients received monotherapy, 196/1074 (18.2%) two, 66/1074 (6.1%) three, and 21/1074 (2.0%) four or more medications. Of all prescriptions, primidone was the most used (546/1172; 46.6%), followed by propranolol (419; 35.8%), topiramate (122; 10.4%) and gabapentin (35; 3.0%). Medication response was available for a total of 1030 prescriptions, of which 138 (13.4%) were discontinued due to side effects; 180 (17.5%) prescriptions were ineffective. Furthermore, 52/1074 patients (4.8%) were treated with botulinum toxin injections and 41/1074 (3.8%) underwent deep brain stimulation surgery.
DISCUSSION
Our data suggest that more widespread recognition of limitations underlying conventional approaches, as well as increased referrals for nonpharmacological therapies, may be necessary to achieve improved outcomes in ET populations.
Topics: Essential Tremor; Humans; Primidone; Propranolol; Retrospective Studies; Topiramate
PubMed: 35415009
DOI: 10.5334/tohm.682 -
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 -
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