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Life Sciences Mar 2021Sensory nerve activation modulates ureteral contractility by releasing neuropeptides including CGRP and neurokinin A (NKA). TRPM3 is a recently discovered...
AIMS
Sensory nerve activation modulates ureteral contractility by releasing neuropeptides including CGRP and neurokinin A (NKA). TRPM3 is a recently discovered thermosensitive channel expressed in nociceptive sensory neurons, and plays a key role in heat nociception and chronic pain. The aim of this study is to examine the role of TRPM3 activation in human ureter motility.
MAIN METHOD
Human proximal ureters were obtained from fourteen patients undergoing nephrectomy. Spontaneous or NKA-evoked contractions of longitudinal ureter strips were recorded in an organ bath. Ureteral TRPM3 expression was examined by immunofluorescence.
KEY FINDINGS
Spontaneous contractions were observed in 60% of examined strips. TRPM3 activation using pregnenolone sulphate (PS) or CIM0216 (specific TRPM3 agonists) dose-dependently reduced the frequency of spontaneous and NKA-evoked contractions, with IC50s of 241.7 μM and 4.4 μM, respectively. The inhibitory actions of TRPM3 agonists were mimicked by CGRP (10 to 100 nM) or a cAMP analogue (8-Br-cAMP; 1 mM). The inhibitory actions of TRPM3 agonists (300 μM PS or 30 μM CIM0216) were blocked by pretreatment with primidone (TRPM3 antagonist; 30 μM), tetrodotoxin (sodium channel blocker; 1 μM), olcegepant (CGRP receptor antagonist; 10 μM), or H89 (non-specific PKA inhibitor; 30 μM). TRPM3 was co-expressed with CGRP in nerves in the sub-urothelial and intermuscular regions of the ureter.
SIGNIFICANCE
TRPM3 channels expressed on sensory terminals of the human ureter involve in inhibitory sensory neurotransmission and modulate ureter motility via the CGRP-cAMP-PKA signal pathway. Targeting TRPM3 may be a pharmacological strategy for promoting the ureter stone passage.
Topics: Adult; Aged; Calcitonin Gene-Related Peptide; Capsaicin; Dose-Response Relationship, Drug; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Male; Middle Aged; Muscle Contraction; Nephrectomy; Neurokinin A; Organ Culture Techniques; Pregnenolone; Primidone; Sensory Receptor Cells; TRPM Cation Channels; Ureter
PubMed: 33417951
DOI: 10.1016/j.lfs.2020.118967 -
Neurological Research and Practice 2020Management of primary orthostatic tremor (POT) remains challenging, and medication is often ineffective. We report the case of a 53-year-old female with orthostatic...
Management of primary orthostatic tremor (POT) remains challenging, and medication is often ineffective. We report the case of a 53-year-old female with orthostatic tremor for 6 years who was refractory to gabapentin, clonazepam, primidone and propranolol. After treatment with 4 mg/day perampanel, she reported almost complete resolution of tremor. The diagnosis of POT was confirmed by tremor analysis using surface electromyography. Our report shows the potential use of the novel AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist perampanel for the treatment of POT. To date, only two similar patients, one refractory to treatment and the other previously treated with clonazepam only, have been reported. We would like to note that our patient was refractory to all previous therapy and responded to a low dose of perampanel without side effects. The striking clinical improvement suggests a putative role of glutamate in the pathophysiology of orthostatic tremor.
PubMed: 33324909
DOI: 10.1186/s42466-020-0050-0 -
Epilepsy & Behavior : E&B Feb 2021The aim of this study was to analyze the association between antiseizure medication (ASM) and the risk of urinary tract infections (UTI) in patients with epilepsy...
AIM
The aim of this study was to analyze the association between antiseizure medication (ASM) and the risk of urinary tract infections (UTI) in patients with epilepsy treated in general practices in Germany.
METHODS
This study includes a total of 2201 patients (mean age: 61.4) whose first documented UTI diagnosis occurred between January 2015 and December 2019 (index date) and who were prescribed at least one ASM in 1198 general practices in Germany within one year prior to the index date. Based on a case-control design, the association between predefined criteria and UTI was investigated by matching (1:1) controls without UTI to cases with UTI by sex, age, and codiagnoses. Logistic regression models were used to analyze the association between ASM use and UTI risk.
RESULTS
In the first regression model, phenytoin (PHT), primidone, carbamazepine (CBZ), and valproate (VPA) were associated with an increased risk of UTI. In the second model, these associations were confirmed with effects per prescription for PHT, primidone, CBZ, and VPA use. Additionally, the effect per prescription was significant for oxcarbazepine (OXC), topiramate, and gabapentin.
CONCLUSION
The study found that PHT, primidone, CBZ, and VPA in particular are associated with an increased risk of infections of the urinary tract. Oxcarbazepine, topiramate, and gabapentin are also associated with increased risk of UTI, albeit to a less significant extent. In general, the immunological and hematological side effects of these molecules may play an important role in the development of UTI under anticonvulsant therapy.
Topics: Anticonvulsants; Carbamazepine; Case-Control Studies; Germany; Humans; Middle Aged; Urinary Tract Infections; Valproic Acid
PubMed: 33323337
DOI: 10.1016/j.yebeh.2020.107502 -
Cell Death and Differentiation May 2021The receptor-interacting serine/threonine protein kinase 1 (RIPK1) is a key mediator of regulated cell death and inflammation. Recent studies suggest that RIPK1...
The receptor-interacting serine/threonine protein kinase 1 (RIPK1) is a key mediator of regulated cell death and inflammation. Recent studies suggest that RIPK1 inhibition would fundamentally improve the therapy of RIPK1-dependent organ damage in stroke, myocardial infarction, kidney failure, and systemic inflammatory response syndrome. Additionally, it could ameliorate or prevent multi-organ failure induced by cytokine release in the context of hyperinflammation, as seen in COVID-19 patients. Therefore, we searched for a RIPK1 inhibitor and present the aromatic antiepileptic and FDA-approved drug primidone (Liskantin®) as a potent inhibitor of RIPK1 activation in vitro and in a murine model of TNFα-induced shock, which mimics the hyperinflammatory state of cytokine release syndrome. Furthermore, we detected for the first time RIPK1 activation in the respiratory tract epithelium of hospitalized patients who tested positive for SARS-CoV-2 infection. Our data provide a strong rationale for evaluating the drug primidone in conditions of hyperinflammation in humans.
Topics: Animals; COVID-19; Cell Death; HEK293 Cells; HT29 Cells; Humans; Inflammation; Jurkat Cells; Mice; NIH 3T3 Cells; Primidone; Receptor-Interacting Protein Serine-Threonine Kinases; SARS-CoV-2; U937 Cells; COVID-19 Drug Treatment
PubMed: 33273695
DOI: 10.1038/s41418-020-00690-y -
Chemosphere Jun 2021This work evaluated different advanced oxidation processes (AOPs) operated at pilot-scale as tertiary treatment of municipal wastewater in terms of energy efficiency,...
This work evaluated different advanced oxidation processes (AOPs) operated at pilot-scale as tertiary treatment of municipal wastewater in terms of energy efficiency, disinfection by-products formation and pathogens inactivation. Investigated AOPs included UV/HO, UV/Cl, O, O/UV, HO/O/UV, Cl/O/UV. AOPs were operated using various ozone doses (1.5-9 mg L), and UV fluences (191-981 mJ cm). Electrical energy costs necessary for the oxidation of contaminants of emerging concern (CEC) (i.e., carbamazepine, fluoxetine, gemfibrozil, primidone, sulfamethoxazole, trimethoprim) were calculated using the electrical energy per order (E) parameter. Ozonation resulted by far the most energy efficient process, whereas UV/HO and UV/Cl showed the highest energy costs. Energy costs for AOPs based on the combination of UV and ozone were in the order O/UV ≈ Cl/O/UV > HO/O/UV, and they were significantly lower than energy costs of UV/HO and UV/Cl processes. Cl/O/UV increased bromate formation, O/UV and O had same levels of bromate formation, whereas HO/O/UV did not form bromate. In addition, UV photolysis resulted an effective treatment for NDMA mitigation even in combination with ozone and chlorine in AOP technologies. Ozonation (doses of 1.5-6 mg L) was the least effective process to inactivate somatic coliphages, total coliform, escherichia coli, and enterococci. UV irradiation was able to completely inactivate somatic coliphages, total coliform, escherichia coli at low fluence (191 mJ cm), whereas enterococci were UV resistant. AOPs that utilized UV irradiation were the most effective processes for wastewater disinfection resulting in a complete inactivation of selected indicator organisms by low ozone dose (1.5 mg L) and UV fluence (191-465 mJ cm).
Topics: Disinfection; Environmental Pollutants; Hydrogen Peroxide; Oxidation-Reduction; Ozone; Ultraviolet Rays; Water Pollutants, Chemical; Water Purification
PubMed: 33268086
DOI: 10.1016/j.chemosphere.2020.128527 -
Chemosphere Jan 2021Tertiary-treated effluent from a municipal wastewater treatment plant in Tucson, AZ, was added to recirculating hydroponic bed bioreactors filled with light expanded...
Tertiary-treated effluent from a municipal wastewater treatment plant in Tucson, AZ, was added to recirculating hydroponic bed bioreactors filled with light expanded clay aggregate (LECA) and recirculated for 10 days. Bioreactors were planted with high and low densities of sorghum (Sorghum bicolor), switchgrass (Panicum virgatum) and Bacillus thuringiensis cotton (Gossypium sp.). The experiment also included a non-planted bioreactor treatment and a control bioreactor with neither plants nor substrate medium. Of 46 contaminants of emerging conern assayed with liquid chromatography tandem mass spectrometry (LC-MS/MS), 16 were initially identified at detectable levels in the effluent. After one day, concentrations of Ibuprofen and Diphenhydramine fell below detection limits in all treatments as well as the control. After five days, initial concentrations of atenolol, benzotriazole, carbamazepine, hydrochlorothiazide, iohexol, iopamidol iopromide, primidone, sulfamethoxazole and tris TCPP were reduced by greater than 80% in all treatments, while the control exhibited little to no removal. Diclofenac, simazine and sucralose exhibited variable removal rates among treatments ranging from 44 to 84% after five days. After 10 days, concentrations of DEET, diclofenac, iopromide, primidone and simazine were all below detection levels, while there was near zero removal in the control. Bioreactors planted with cotton had significantly more removal of sulfamethoxazole than unplanted bioreactors by 16-19% after five days and by an additional 18-20% removal after 10 days. The percentage uptake of benzotriazole by every planted treatment was significantly higher than the non-planted treatment after five and 10 days. Significant contaminant removal occurred in the media substrate, likely through adsorption to LECA or microbial degradation. More research is needed to examine specific pathways of degradation and removal by various microbials and plants.
Topics: Adsorption; Biodegradation, Environmental; Bioreactors; Hydroponics; Plant Development; Plants; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical
PubMed: 33182119
DOI: 10.1016/j.chemosphere.2020.128121 -
Neurologia I Neurochirurgia Polska 2020Tremor is one of the most common movement disorders. It does not usually respond to first-line drug treatments (e.g. propranolol, primidone, anticholinergics, gabapentin... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Tremor is one of the most common movement disorders. It does not usually respond to first-line drug treatments (e.g. propranolol, primidone, anticholinergics, gabapentin and clonazepam) due to side effects and frequent dose limitations. Botulinum toxin type A (BoNT-A) has been widely used to treat tremor, but its efficacy and safety are uncertain.
AIMS
To evaluate the efficacy and safety of BoNT-A in the treatment of hand tremor.
METHODS
We searched the MEDLINE, EMBASE, PsycINFO and Cochrane Library databases for relevant randomised controlled trials of the effects of BoNT-A injections on tremors, up to 20 February 2020. A meta-analysis of comparative effects was performed using R studio software, and publication bias was examined using Egger's test.
RESULTS
Six studies examining a total of 245 participants with tremor were included in the meta-analysis. The primary outcome of meta-analysis showed no difference in clinical tremor scale scores between the BoNT-A group versus the placebo group (standardised mean difference (SMD): -0.42, 95% confidence interval (CI): -1.94 to 1.10; I2 = 96%). For clinical tremor scale scores, subgroup analyses suggested that the BoNT-A group may differ in terms of multiple sclerosis (MS) related tremor (SMD: -1.10; 95% CI: -2.17 to -0.04; I2 = 79%) compared to a placebo, but the difference did not exist in the outcome of essential tremor (ET) or hand tremor (MD: -1.31; 95% CI: -3.39; 1.31; I2 = 97%). Grip strength (MD: -1.25, 95% CI: -5.99 to 3.50, I2 = 97%) was slightly lower in the BoNT-A group, but the difference was not significant. The incidence of adverse events (AEs), including hand weakness (RR: 2.96, 95% CI: 1.40 to 6.24, I2 = 37%), was significantly greater in the BoNT-A group than in the placebo group. Two studies were assessed as having an overall low risk of bias.
CONCLUSIONS
Our study confirms that BoNT-A injections are unlikely to have an impact on patients with hand tremors. However, subgroup analysis suggested that BoNT-A injections could have possible benefits in MS-related tremor. While moderate to severe hand weakness AEs often limits their use in clinical practice, additional well-designed double-blind, placebo-controlled trials are needed to provide more robust conclusions.
Topics: Botulinum Toxins, Type A; Hand; Humans; Muscle Weakness; Tremor
PubMed: 33047784
DOI: 10.5603/PJNNS.a2020.0079 -
Journal of Clinical Neurology (Seoul,... Oct 2020Epilepsy is a common neurological disorder that is mainly treated using antiepileptic drugs. Several antiepileptic drugs such as phenobarbital, phenytoin, primidone, and... (Review)
Review
Epilepsy is a common neurological disorder that is mainly treated using antiepileptic drugs. Several antiepileptic drugs such as phenobarbital, phenytoin, primidone, and ethosuximide were developed in the early 20th century. More than 10 types of antiepileptic drugs have been developed since the 1990s, and there are now more than 20 antiepileptic drugs in active clinical use. The choice of antiepileptic drugs is based on the clinical features of the seizure types, electroencephalogram findings, epileptic syndrome, and drug stability. Currently there are 19 antiepileptic drugs approved by the Korean Food and Drug Administration, 18 of which (with the exclusion of brivaracetam) are covered by the National Health Insurance Service in Korea. We reviewed the selection of antiepileptic drugs according to the classification of epileptic seizures.
PubMed: 33029959
DOI: 10.3988/jcn.2020.16.4.547 -
Epilepsy & Behavior : E&B Nov 2020Several lines of evidence have suggested that exposure to enzyme-inducing antiseizure medications (EIASMs) may result in the subsequent development of hyperlipidemia, a...
OBJECTIVES
Several lines of evidence have suggested that exposure to enzyme-inducing antiseizure medications (EIASMs) may result in the subsequent development of hyperlipidemia, a well-known risk factor for vascular disease. This may be an issue of concern particularly in the context of additional comorbid vascular risk factors. We therefore aimed to investigate trends of and associations with the use of these medications among adult patients with epilepsy.
METHODS
The cross-sectional Medical Expenditure Panel Survey (MEPS) was interrogated to ascertain the prevalence of use of EIASMs by noninstitutionalized adult patients with epilepsy in the United States between the years 2004 and 2015. Any patient prescribed carbamazepine, phenytoin, phenobarbital, or primidone within a given year was defined as having been prescribed an EIASM. Trends over three-year epochs were evaluated with univariate logistic regression, while associations with demographic factors, vascular risk factors, and vascular disease were evaluated using a chi-square test corrected for survey design as well as multivariate logistic regression.
RESULTS
A total of 2281 (unweighted) patients were identified, representing 1,781,237 individuals. Between 2004 and 2015, 45.9% (95% confidence interval [CI]: 42.4%-49.4%) were prescribed EIASMs. Approximately one-quarter of patients aged 65 years and above used EIASMs compared with 18.5% of younger patients (odds ratio [OR]: 1.83, 95% CI = 1.27-2.65). Female patients (OR = 0.61, 95% CI = 0.47-0.79) and those with heart disease (OR: 0.63, 95% CI = 0.45-0.89) were significantly less likely to be prescribed EIASMs. Among those prescribed EIASMs, 38.9% had hypertension, 12.2% had diabetes, 61.6% were overweight or obese, 17.3% heart disease, 17.2% had a history of a cerebrovascular event, and 28.5% had diagnosed hyperlipidemia. Nonetheless, between 2004-2006 and 2013-2015, the odds of EIASM prescription decreased significantly (OR: 0.39, 95% CI: 0.28-0.55).
CONCLUSIONS
A substantial proportion of patients with comorbid vascular disease or vascular risk factors (e.g., hypertension and older age) is prescribed EIASMs. This could potentially increase patients' risk for subsequent negative outcomes such as cardiovascular or cerebrovascular disease. Though utilization of these medications has decreased, further efforts toward increasing use of newer antiseizure medications (ASMs) that are not associated with similar risks may be warranted.
Topics: Adult; Aged; Cross-Sectional Studies; Epilepsy; Female; Health Expenditures; Humans; Odds Ratio; Risk Factors; United States
PubMed: 32950766
DOI: 10.1016/j.yebeh.2020.107465 -
Neurotherapeutics : the Journal of the... Oct 2020Essential tremor is one of the most common tremor syndromes. According to the recent tremor classification, tremor as a symptom is defined as an involuntary, rhythmic,... (Review)
Review
Essential tremor is one of the most common tremor syndromes. According to the recent tremor classification, tremor as a symptom is defined as an involuntary, rhythmic, oscillatory movement of a body part and is classified along two axes: axis 1-defining syndromes based on the clinical features such as historical features, tremor characteristics, associated signs, and laboratory tests; and axis 2-classifying the etiology (Bhatia et al., Mov Disord 33:75-87, 2018). The management of this condition has two major approaches. The first is to exclude treatable etiologies, as particularly during the onset of this condition the presentation of a variety of etiologies can be with monosymptomatic tremor. Once the few etiologies with causal treatments are excluded, all further treatment is symptomatic. Shared decision-making with enabling the patient to knowledgeably choose treatment options is needed to customize the management. Mild to moderate tremor severity can sometimes be controlled with occupational treatment, speech therapy of psychotherapy, or adaptation of coping strategy. First-line pharmacological treatments include symptomatic treatment with propranolol, primidone, and topiramate. Botulinum toxin is for selected cases. Invasive treatments for essential tremor should be considered for severe tremors. They are generally accepted as the most powerful interventions and provide not only improvement of tremor but also a significant improvement of life quality. The current standard is deep brain stimulation (DBS) of the thalamic and subthalamic region. Focused ultrasound thalamotomy is a new therapy attracting increasing interest. Radiofrequency lesioning is only rarely done if DBS or focused ultrasound is not possible. Radiosurgery is not well established. We present our treatment algorithm.
Topics: Behavior Therapy; Botulinum Toxins; Deep Brain Stimulation; Diagnosis, Differential; Disease Management; Essential Tremor; Humans; Occupational Therapy; Radiosurgery; Treatment Outcome
PubMed: 32915385
DOI: 10.1007/s13311-020-00899-2