-
International Journal of Molecular... Sep 2021Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019).... (Review)
Review
Anti-epileptic drugs (AEDs) are an important group of drugs of several generations, ranging from the oldest phenobarbital (1912) to the most recent cenobamate (2019). Cannabidiol (CBD) is increasingly used to treat epilepsy. The outbreak of the SARS-CoV-2 pandemic in 2019 created new challenges in the effective treatment of epilepsy in COVID-19 patients. The purpose of this review is to present data from the last few years on drug-drug interactions among of AEDs, as well as AEDs with other drugs, nutrients and food. Literature data was collected mainly in PubMed, as well as google base. The most important pharmacokinetic parameters of the chosen 29 AEDs, mechanism of action and clinical application, as well as their biotransformation, are presented. We pay a special attention to the new potential interactions of the applied first-generation AEDs (carbamazepine, oxcarbazepine, phenytoin, phenobarbital and primidone), on decreased concentration of some medications (atazanavir and remdesivir), or their compositions (darunavir/cobicistat and lopinavir/ritonavir) used in the treatment of COVID-19 patients. CBD interactions with AEDs are clearly defined. In addition, nutrients, as well as diet, cause changes in pharmacokinetics of some AEDs. The understanding of the pharmacokinetic interactions of the AEDs seems to be important in effective management of epilepsy.
Topics: Anticonvulsants; COVID-19; Cannabidiol; Carbamazepine; Clobazam; Drug Interactions; Epilepsy; Humans; Nutrients; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34502487
DOI: 10.3390/ijms22179582 -
JAMA Neurology Aug 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: American Medical Association; Periodicals as Topic; United States
PubMed: 34081094
DOI: 10.1001/jamaneurol.2021.2135 -
Clinical Epidemiology 2021To determine the risk of hip fracture in persons with Alzheimer´s disease (AD) who initiated antiepileptic drugs (AEDs).
OBJECTIVE
To determine the risk of hip fracture in persons with Alzheimer´s disease (AD) who initiated antiepileptic drugs (AEDs).
METHODS
In the Medication use and AD (MEDALZ) cohort of 70,719 Finnish community dwellers with clinically verified incident AD diagnosis in 2005-2011, we identified all incident users of AEDs using national Prescription register. AEDs were classified as older (valproate, carbamazepine, clonazepam, phenytoin, levetiracetam, primidone) or newer (pregabalin, gabapentin, oxcarbazepine, lamotrigine, topiramate). We matched each user to 2 non-users. Incident hip fractures until 2015 were identified from the Care register for health care. We calculated inverse probability of treatment weighted hazard ratios (HR), with 95% confidence intervals, using Cox regression.
RESULTS
Altogether 5522 incident users were identified and matched to 11,044 non-users (in both groups, women: 65%; median age: 81 years). Altogether 53.3% of users initiated with newer AEDs (pregabalin 79.8%, gabapentin 10.2%) while 46.7% initiated with older AEDs (valproate 67.6%, carbamazepine 13.0%). Age- and sex-adjusted IR of hip fracture per 100 person-years was 1.8 (95% CI 1.6-1.9) in non-users and 2.0 (95% CI 1.8-2.2) in users. Increased risk of hip fracture was observed in users (HR 1.17, 95% CI 1.05-1.30) compared with non-users. The risk was higher for short duration of use (<14 weeks, HR 3.64, 95% CI 2.90-4.58) than for medium duration (14 to <64 weeks, HR 1.74, 95% CI 1.48-2.05) or ≥64 weeks' use (HR 1.23, 95% CI 1.08-1.40), compared to non-users with same follow-up time. Older AEDs had HR of 1.46 (1.03-2.08) compared with newer AEDs.
CONCLUSION
Our results imply that AED use is associated with an increased risk of hip fracture in people with AD. These findings prompt careful consideration before prescribing AEDs to persons with AD. Persons with AD treated with antiepileptics should be carefully monitored due to their increased risk of falling and fractures.
PubMed: 33911901
DOI: 10.2147/CLEP.S278306 -
Environmental Science and Pollution... Aug 2021From 2001 to 2014, 13 surveys were conducted in the Baltic Sea, to determine its pollution of 50 micropollutants. The investigations focused mostly on the German western...
From 2001 to 2014, 13 surveys were conducted in the Baltic Sea, to determine its pollution of 50 micropollutants. The investigations focused mostly on the German western Baltic Sea; in 2008, one survey covered the entire Baltic Sea. Various groups of herbicides (such as triazines, phenoxyacetic acid, phenylurea), perfluoroalkyl substances, pharmaceuticals, and industrial products were analyzed during these surveys. The highest concentrations (median 1 to 4 ng/L) were observed for atrazine, simazine, chloridazone, 2,4-dichlorophenoxyacetic acid, benzotriazole, primidone, and carbamazepine. Most micropollutants exhibited a relatively homogenous spatial distribution, though some herbicides show elevated concentrations in certain regions (e.g., Odra estuary), indicating a riverine input. The data set was analyzed, both for seasonal influences and long-time trends. Some herbicides exhibited higher concentrations during summertime. Both upward- and downward-directed time trends could be identified for some herbicides and perfluorinated compounds. For most of the detected compounds, a low-risk quotient was calculated. Only the occurrence of carbendazim could potentially pose a higher risk to the Baltic Sea.
Topics: Baltic States; Environmental Monitoring; Estuaries; Risk Assessment; Seasons; Water Pollutants, Chemical
PubMed: 33755886
DOI: 10.1007/s11356-021-13254-5 -
Scientific Reports Feb 2021Trace organic compounds (TrOCs) enter rivers with discharge of treated wastewater. These effluents can contain high loads of dissolved organic matter (DOM). In a 48 h...
Trace organic compounds (TrOCs) enter rivers with discharge of treated wastewater. These effluents can contain high loads of dissolved organic matter (DOM). In a 48 h field study, we investigated changes in molecular composition of seven DOM compound classes (FTICR-MS) and attenuation of 17 polar TrOCs in a small urban stream receiving treated wastewater. Correlations between TrOCs and DOM were used to identify simultaneous changes in surface water and the hyporheic zone. Changes in TrOC concentrations in surface water ranged between a decrease of 29.2% for methylbenzotriazole and an increase of 152.2% for the transformation product gabapentin-lactam. In the hyporheic zone, only decreasing TrOC concentrations were observed, ranging from 4.9% for primidone to 93.8% for venlafaxine . TrOC attenuation coincided with a decline of molecular diversity of easily biodegradable DOM compound classes while molecular diversity of poorly biodegradable DOM compound classes increased. This concurrence indicates similar or linked attenuation pathways for biodegradable DOM and TrOCs. Strong correlations between TrOCs and DOM compound classes as well as high attenuation of TrOCs primarily occurred in the hyporheic zone. This suggests high potential for DOM turnover and TrOC mitigation in rivers if hyporheic exchange is sufficient.
PubMed: 33603043
DOI: 10.1038/s41598-021-83750-8 -
The Journal of Neuroscience : the... Mar 2021Transient receptor potential melastatin 3 (TRPM3) is a heat-activated ion channel in primary sensory neurons of the dorsal root ganglia (DRGs). Pharmacological and...
Transient receptor potential melastatin 3 (TRPM3) is a heat-activated ion channel in primary sensory neurons of the dorsal root ganglia (DRGs). Pharmacological and genetic studies implicated TRPM3 in various pain modalities, but TRPM3 inhibitors were not validated in TRPM3 mice. Here we tested two inhibitors of TRPM3 in male and female wild-type and TRPM3 mice in nerve injury-induced neuropathic pain. We found that intraperitoneal injection of either isosakuranetin or primidone reduced heat hypersensitivity induced by chronic constriction injury (CCI) of the sciatic nerve in wild-type, but not in TRPM3 mice. Primidone was also effective when injected locally in the hindpaw or intrathecally. Consistently, intrathecal injection of the TRPM3 agonist CIM0216 reduced paw withdrawal latency to radiant heat in wild-type, but not in TRPM3 mice. Intraperitoneal injection of 2 mg/kg, but not 0.5 mg/kg isosakuranetin, inhibited cold and mechanical hypersensitivity in CCI, both in wild-type and TRPM3 mice, indicating a dose-dependent off-target effect. Primidone had no effect on cold sensitivity, and only a marginal effect on mechanical hypersensitivity. Genetic deletion or inhibitors of TRPM3 reduced the increase in the levels of the early genes c-Fos and pERK in the spinal cord and DRGs in CCI mice, suggesting spontaneous activity of the channel. Intraperitoneal isosakuranetin also inhibited spontaneous pain related behavior in CCI in the conditioned place preference assay, and this effect was eliminated in TRPM3 mice. Overall, our data indicate a role of TRPM3 in heat hypersensitivity and in spontaneous pain after nerve injury. Neuropathic pain is a major unsolved medical problem. The heat-activated TRPM3 ion channel is a potential target for novel pain medications, but the pain modalities in which it plays a role are not clear. Here we used a combination of genetic and pharmacological tools to assess the role of this channel in spontaneous pain, heat, cold, and mechanical hypersensitivity in a nerve injury model of neuropathic pain in mice. Our findings indicate a role for TRPM3 in heat hyperalgesia, and spontaneous pain, but not in cold and mechanical hypersensitivity. We also find that not only TRPM3 located in the peripheral nerve termini, but also TRPM3 in the spinal cord or proximal segments of DRG neurons are important for heat hypersensitivity.
Topics: Animals; Female; Hot Temperature; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuralgia; Peripheral Nerve Injuries; TRPM Cation Channels
PubMed: 33478988
DOI: 10.1523/JNEUROSCI.1551-20.2020 -
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 -
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 -
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