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International Review of Neurobiology 2022Essential tremor is one of the most prevalent movement disorders. Propranolol and primidone are the first-line pharmacological therapies. They provide symptomatic... (Review)
Review
Essential tremor is one of the most prevalent movement disorders. Propranolol and primidone are the first-line pharmacological therapies. They provide symptomatic control in less than 50% of patients. Topiramate, alprazolam, clonazepam, gabapentin, and botulinum toxin injections are the next line of treatments. These medications lead to modest improvements and are therefore commonly used as add-on agents. Surgical therapies, including deep brain stimulation (DBS) surgery and focused ultrasound beam targeted to the thalamus, are considered for treating tremor refractory to medications and lead to greater than 75% improvements in tremor symptoms. However, DBS is a costly and an invasive procedure; some patients report tolerance to benefits. Focused ultrasound therapy leading to brain lesions is associated with a possibility for permanent clinical deficits. Therefore, research efforts to develop the next generation of oral medications with greater benefits and lesser adverse effects are warranted. There is considerable evidence that the increased functions of calcium channels (P/Q-type and T-type channels) and reduced functions of calcium-activated potassium channels (SK channels) located in the neuronal membranes lead to tremor oscillations. Consequently, many new pharmacological studies have targeted these channels to leverage better clinical outcomes. The current review will discuss the pathophysiology, the specific importance of these channels, and the early clinical experience of using compounds targeting these channels to treat essential tremor.
Topics: Calcium Channels, T-Type; Essential Tremor; Humans; Thalamus; Tremor
PubMed: 35750369
DOI: 10.1016/bs.irn.2022.02.008 -
International Review of Neurobiology 2022γ-Aminobutyric acid (GABA) is the most prevalent inhibitory CNS neurotransmitter. Activating GABA-A receptors hyperpolarizes cells via Cl influx, which inhibits action...
γ-Aminobutyric acid (GABA) is the most prevalent inhibitory CNS neurotransmitter. Activating GABA-A receptors hyperpolarizes cells via Cl influx, which inhibits action potentials. Although the exact pathophysiologies of tremor are incompletely understood, proposed neuroanatomy extensively implicates GABA pathways. Pathological studies and imaging studies also show GABA abnormalities in patients with ET. Most importantly, medications that activate GABA-A receptors, such as primidone, often improve tremor. Ongoing clinical trials and physiology research should further refine potential future GABAergic targets and treatments, which are currently the most promising targets for pharmacological intervention.
Topics: Essential Tremor; Humans; Receptors, GABA; Receptors, GABA-A; Tremor; gamma-Aminobutyric Acid
PubMed: 35750368
DOI: 10.1016/bs.irn.2022.02.007 -
Environmental Research Sep 2022Water polluted by pharmaceutically active compounds (PhACs) and water-borne pathogens urgently need to develop eco-friendly and advanced water treatment techniques. This...
In-situ chemical attenuation of pharmaceutically active compounds using CaO: Influencing factors, mechanistic modeling, and cooperative inactivation of water-borne microbial pathogens.
Water polluted by pharmaceutically active compounds (PhACs) and water-borne pathogens urgently need to develop eco-friendly and advanced water treatment techniques. This paper evaluates the potential of using calcium peroxide (CaO), a safe and biocompatible oxidant both PhACs (thiamphenicol, florfenicol, carbamazepine, phenobarbital, and primidone) and pathogens (Escherichia coli, Staphylococcus aureus) in water. This paper evaluates the potential of using calcium peroxide (CaO) as a safe and biocompatible oxidant to remove both PhACs (thiamphenicol, florfenicol, carbamazepine, phenobarbital, and primidone) and pathogens (Escherichia coli, Staphylococcus aureus) in water. The increased CaO dosage increased efficiencies of PhACs attenuation and pathogens inactivation, and both exhibited pseudo-first-order degradation kinetics (R > 0.90). PhACs attenuation were mainly via oxidization (HO, •OH/O, and O) and alkaline hydrolysis (OH) from CaO. Moreover, concentrations of these reactive species and their contributions to PhACs attenuation were quantified, and mechanistic model was established and validated. Besides, possible transformation pathways of target PhACs except primidone were proposed. As for pathogen indicators, the suitable inactivation dosage of CaO was 0.1 g L. The oxidability (18-64%) and alkalinity (82-36%) generated from CaO played vital roles in pathogen inactivation. In addition, CaO at 0.01-0.1 g L can be applied in remediation of SW contaminated by PhACs and pathogenic bacteria, which can degrade target PhACs with efficiencies of 21-100% under 0.01 g L CaO, and inactivate 100% of test bacteria under 0.1 g L CaO. In short, capability of CaO to remove target PhACs and microbial pathogens reveals its potential to be used as a representative technology for the advanced treatment of waters contaminated by organic compounds and microbial pathogens.
Topics: Carbamazepine; Escherichia coli; Hydrogen Peroxide; Oxidants; Pharmaceutical Preparations; Primidone; Thiamphenicol; Water Pollutants, Chemical
PubMed: 35613632
DOI: 10.1016/j.envres.2022.113531 -
Brain and Nerve = Shinkei Kenkyu No... May 2022For essential tremors that are refractory to standard medical treatment, surgical treatment is considered when there is obstruction in activities of daily living....
For essential tremors that are refractory to standard medical treatment, surgical treatment is considered when there is obstruction in activities of daily living. However, there are patients who do not wish to undergo or are contraindicated for surgical treatment. In this paper, we explored what is considered to be the standard medical treatment and when surgery cannot be performed. In Japan, medical treatment is based on the use of arotinolol and primidone, and combination therapy and second-line drugs are extensively discussed. Furthermore, an algorithm of the treatment for essential tremors in Japan has been provided.
Topics: Activities of Daily Living; Essential Tremor; Humans; Japan; Primidone
PubMed: 35589658
DOI: 10.11477/mf.1416202091 -
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 -
The Science of the Total Environment Sep 2022As human population growth has expanded in Southwest Florida, water quality has become degraded with an increased occurrence of harmful algal blooms (HABs). Red tide...
As human population growth has expanded in Southwest Florida, water quality has become degraded with an increased occurrence of harmful algal blooms (HABs). Red tide (Karenia brevis) originating offshore, intensifies in nearshore waters along Florida's Gulf Coast, and blue-green algae (Microcystis spp.) originating in Lake Okeechobee is discharged into the Caloosahatchee River. These HABs could be enhanced by anthropogenic nitrogen (N) and phosphorus (P) from adjacent watersheds. North Fort Myers is a heavily developed, low-lying city on the Caloosahatchee River Estuary serviced by septic systems with documented nutrient and bacterial pollution. To identify sources of pollution within North Fort Myers and determine connections with downstream HABs, this multiyear (2017-2020) study examined septic system- groundwater- surface water couplings through the analysis of water table depth, nutrients (N, P), fecal indicator bacteria (FIB), molecular markers (HF183, GFD, Gull2), chemical tracers (sucralose, pharmaceuticals, herbicides, pesticides), stable isotopes of groundwater (δN-NH, δN-NO) and particulate organic matter (POM; δN, δC), and POM elemental composition (C:N:P). POM samples were also collected during K. brevis and Microcystis spp. HAB events. Most (>80%) water table depth measurements were too shallow to support septic system functioning (<1.07 m). High concentrations of NH and NO, up to 1094 μM and 482 μM respectively, were found in groundwater and surface water. δN values of groundwater (+4.7‰) were similar to septic effluent (+4.9‰), POM (+4.7‰), and downstream HABs (+4.8 to 6.9‰), indicating a human waste N source. In surface water, FIB were elevated and HF183 was detected, while in groundwater and surface water sucralose, carbamazepine, primidone, and acetaminophen were detected. These data suggest that groundwater and surface water in North Fort Myers are coupled and contaminated by septic system effluent, which is negatively affecting water quality and contributing to the maintenance and intensification of downstream HABs.
Topics: Environmental Monitoring; Florida; Groundwater; Harmful Algal Bloom; Humans; Microcystis; Particulate Matter; Water Pollutants, Chemical; Water Quality
PubMed: 35452738
DOI: 10.1016/j.scitotenv.2022.155319 -
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 -
Pain Nov 2022The transient receptor potential cation channel subfamily M member-3 (TRPM3) channel is a recently recognized noxious heat sensor that is involved in inflammatory...
The transient receptor potential cation channel subfamily M member-3 (TRPM3) channel is a recently recognized noxious heat sensor that is involved in inflammatory thermal hyperalgesia. To examine its involvement in the development of hyperalgesia in interstitial cystitis/painful bladder syndrome (IC/PBS), rats with cyclophosphamide (CYP)-induced chronic cystitis were used as a model of IC/PBS. Mechanical and thermal hyperalgesia in lower abdominal region overlying the bladder in CYP rats were measured using von Frey filaments and radiant heat, respectively. Transient receptor potential cation channel subfamily M member-3 expression at the mRNA, protein, and functional levels in dorsal root ganglion neurons innervating the bladder was detected using RNA in situ hybridization (RNAscope), Western blotting, immunohistochemistry, and Ca 2+ imaging, respectively. Transient receptor potential cation channel subfamily M member-3 channels were expressed on most of the bladder primary afferent nerve terminals containing calcitonin gene-related peptide and their cell bodies in L6-S1 dorsal root ganglion. Activation of TRPM3 in the bladder wall by its specific agonist pregnenolone sulphate or CIM0216 induced spontaneous bladder pain, calcitonin gene-related peptide release, and neurogenic inflammation that was evidenced by edema, plasma extravasation, inflammatory cell accumulation, and mast cell infiltration. In CYP rats, pretreatment with the TRPM3 antagonist primidone (2 mg/kg, i.p.) significantly alleviated the mechanical and thermal hyperalgesia, bladder submucosal edema, mast cell infiltration, and bladder hyperactivity. Cyclophosphamide-induced cystitis was associated with TRPM3 upregulation at the mRNA, protein, and functional levels in bladder afferent neurons. Our results suggest that upregulation of TRPM3 channels is involved in the development of chronic pain in CYP-induced cystitis, and targeting TRPM3 may be a pharmacological strategy for treating bladder pain in IC/PBS.
Topics: Animals; Calcitonin Gene-Related Peptide; Chronic Pain; Cyclophosphamide; Cystitis; Cystitis, Interstitial; Hyperalgesia; Primidone; RNA; RNA, Messenger; Rats; TRPM Cation Channels; Transient Receptor Potential Channels; Up-Regulation; Urinary Bladder
PubMed: 35413036
DOI: 10.1097/j.pain.0000000000002616