RESUMEN
OBJECTIVES: Primidone is an anticonvulsive drug used in the treatment of epilepsy and essential tremor. It offers beneficial effects in controlling seizures, but its usage is also associated with possible side effects. To ensure optimal therapy, it is crucial to measure its concentration through accurate quantification methods. Therefore, our main goal was to develop and validate a new reference measurement procedure (RMP) for accurately measuring primidone levels in human serum and plasma. METHODS: In our study, we focused on the separation of primidone from both known and unknown interferences using a C18 column. To achieve accurate sample preparation, we developed a protocol involving protein precipitation followed by a high dilution step. The validation of the assay and determination of measurement uncertainty were carried out following guidelines from organizations such as the Clinical and Laboratory Standards Institute, the International Conference on Harmonization, and the Guide to the Expression of Uncertainty in Measurement. These rigorous validation processes ensure the reliability and accuracy of our method for quantifying primidone levels in human serum and plasma samples. RESULTS: The RMP was shown to be highly selective and specific, with no evidence of matrix interference. It can be used to quantify primidone in the range of 0.150-30.0⯵g/mL. Intermediate precision was less than 4.0â¯%, and repeatability CV ranged from 1.0 to 3.3â¯% across all concentration levels. The relative mean bias ranged from 0.1 to 3.9â¯% for native serum levels, and from -2.6 to 2.8â¯% for lithium-heparin plasma levels. The measurement uncertainties for single measurements and target value assignment were 1.5-4.1â¯% and 0.9-1.0â¯%, respectively. CONCLUSIONS: In this study, we introduce an innovative LC-MS/MS-based candidate RMP specifically designed for primidone in human serum and plasma. Our RMP offers a traceable platform, facilitating the standardization of routine assays and enabling the evaluation of clinically relevant samples. With this novel approach, we aim to enhance the accuracy and reliability of primidone measurements, ultimately benefiting the field of clinical research and patient care.
Asunto(s)
Primidona , Espectrometría de Masas en Tándem , Humanos , Espectrometría de Masas en Tándem/métodos , Espectrometría de Masas en Tándem/normas , Primidona/sangre , Cromatografía Liquida/métodos , Cromatografía Liquida/normas , Estándares de Referencia , Reproducibilidad de los Resultados , Técnicas de Dilución del Indicador , Límite de Detección , Anticonvulsivantes/sangre , Cromatografía Líquida con Espectrometría de MasasRESUMEN
In the last decades there has been progress in the treatment of essential tremor (TE) especially in the surgical field and to a lesser extent in the pharmacological field. We carry out a review of the currently available treatments. The first intervention is the use of non-pharmacological and non-surgical strategies (general advice, occupational therapy, speech therapy, psychotherapy). With discrete advances, the pharmacological treatment is not very satisfactory. Only 30-60% of patients have a positive response, and in these the anti-tremor effectiveness is 40-60%. The first-line drugs are still propranolol and primidone. In cases with severe tremor we will consider a surgical option, the method of choice being thalamotomy using high-intensity focused ultrasound. In the future we must continue to study the pathophysiology of TE, develop drugs specifically designed for TE and improve the technology of available invasive techniques.
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Temblor Esencial , Temblor Esencial/terapia , Temblor Esencial/tratamiento farmacológico , Humanos , Propranolol/uso terapéutico , Primidona/uso terapéutico , Ultrasonido Enfocado de Alta Intensidad de Ablación , Anticonvulsivantes/uso terapéutico , Tálamo , Antagonistas Adrenérgicos beta/uso terapéuticoRESUMEN
Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to mediate pathogenesis of ALS. Primidone has been identified as an old drug that can also inhibit RIPK1 kinase. We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1G93A mice and ALS patients. SOD1G93A mice treated with primidone showed significant delay of symptomatic onset and improved motor performance. One-hundred-sixty-two ALS participants dosed daily with primidone (62.5 mg) completed 24-week follow-up. A significant reduction was showed in serum levels of RIPK1 and IL-8, which were significantly higher in ALS patients than that of healthy controls (P < 0.0001). Serum RIPK1 levels were correlated positively with the severity of bulbar symptoms (P < 0.05). Our study suggests that serum levels of RIPK1 and IL-8 in peripheral can be used as clinical biomarkers for the activation of RIPK1 in central nervous system in human ALS patients. Repurposing primidone may provide a promising therapeutic strategy for ALS. The effect of primidone for the treatment of other inflammatory diseases may also be considered, since the activation of RIPK1 has been implicated in mediating a variety of inflammatory diseases including COVID-19-associated cytokine release syndrome (CRS). (ChiCTR2200060149).
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Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Animales , Humanos , Ratones , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Biomarcadores , Interleucina-8/genética , Ratones Transgénicos , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Enfermedades Neurodegenerativas/metabolismo , Primidona/metabolismo , Primidona/farmacología , Primidona/uso terapéutico , Proteínas Quinasas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/farmacología , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/farmacología , Superóxido Dismutasa/uso terapéutico , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Superóxido Dismutasa-1/farmacologíaRESUMEN
Illegal mining has overshadowed pharmaceutical pollution even though exposure to pharmaceutical waste is high. Consumption of fish potentially polluted with pharmaceuticals from the rivers continues with little concern or potential threat it poses. In the present study, the residues of one antibiotic (Chloramphenicol), five hormones (progesterone, 17-beta Estradiol, Estrone, 17a-Ethynylestradiol, and one), three environmental contaminants (4-para-nonylphenol, 4-tert-octylphenol, and Bisphenol A), one barbiturate (Primidone) and one analgesic (Diclofenac sodium salt), were investigated from fish samples from the rivers Pra, Narkwa, and the Volta. The results show a high concentration of drugs in River Pra in comparison to those in Rivers Narkwa and Volta. The hazard quotients (HQs) for the environmental contaminants were all above 1, except Bisphenol A. Furthermore, the HQs from this study suggest that consumers of fish from any of the three rivers stand a hazard risk of Chloramphenicol (19), 17a-Ethynylestradiol (4), Estrone (1.366), Diclofenac sodium salt (3.29), Progesterone (4.598), 4-tert-octylphenol (87.2), and 4-para-nonylphenol (7.252), but negligible risk against E2 (0.687), Primidone (0.014), Testosterone (0.16), and Bisphenol A (0.642). Of the fish species studied, the highest concentration of all pharmaceuticals put together is found in Clarias gariepinus, Labeo senegalensis, and Chrysichthys nigrodigitatus in that order.
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Bagres , Contaminantes Químicos del Agua , Animales , Estrona , Progesterona/análisis , Ghana , Primidona/análisis , Diclofenaco , Preparaciones Farmacéuticas , Medición de Riesgo , Cloranfenicol/análisis , Agua , Contaminantes Químicos del Agua/análisis , Ríos/química , Monitoreo del Ambiente/métodosRESUMEN
Ticagrelor and aspirin is a common dual antiplatelet therapy regimen for patients who undergo percutaneous coronary intervention. Despite its ability to significantly reduce cardiovascular complications, ticagrelor response may be altered by other medications causing subtherapeutic effects. Traditionally, ticagrelor is thought to have fewer drug-drug interactions compared to other thienopyridine antiplatelet medications such as clopidogrel. Primidone, metabolized into phenobarbital, is a strong CYP-3A inducer that can reduce serum concentrations of ticagrelor resulting in ineffective antiplatelet therapy. We present a 67-year-old male who suffered in-stent thrombosis after percutaneous intervention possibly due to the interaction between primidone and ticagrelor.
Ticagrelor and aspirin is a common antiplatelet regimen for patients who undergo coronary intervention and stent implantation. Ticagrelor is typically less associated with drugdrug interactions; however, our case illustrates an interaction between ticagrelor and primidone causing acute in-stent thrombosis to recently implanted drug-eluting stents.
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Síndrome Coronario Agudo , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Masculino , Humanos , Anciano , Ticagrelor/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Primidona , Clopidogrel/uso terapéutico , Intervención Coronaria Percutánea/métodos , Síndrome Coronario Agudo/terapia , Resultado del TratamientoRESUMEN
Based on the evidence level, the first-line agents for managing essential tremors include sympathomimetic agents and primidone; however, from a tolerability standpoint, sympathomimetic agents are the first choice. Arotinolol is the first treatment of choice because it is the only drug developed in Japan approved for treating essential tremors. If sympathomimetic agents are unavailable or ineffective, a change to primidone, or a combination of both, should be considered. Benzodiazepines and other anti-epileptic drugs should also be administered.
Asunto(s)
Temblor Esencial , Primidona , Humanos , Primidona/uso terapéutico , Temblor Esencial/tratamiento farmacológico , Simpatomiméticos/uso terapéutico , Japón , Anticonvulsivantes/uso terapéuticoRESUMEN
Developmental and epileptic encephalopathy with continuous spike-and-wave activation in sleep (CSWS) or DEE-SWAS is an age-dependent disease, often accompanied by a decline in cognitive abilities. Early successful treatment of CSWS is associated with a better cognitive outcome. We retrospectively analyzed the clinical, electrophysiological, radiological, and genetic data of children with DEE-SWAS associated with melastatin-related transient receptor type 3 gene (TRPM3) missense variants. We report two unrelated children with pharmacoresistant DEE-SWAS and developmental delay/regression and different heterozygous de novo missense variants in the TRPM3 gene (NM_001366145.2; c.3397 T > C/p.Ser1133Pro, c.2004G > A/p.Val1002Met). The variant p.Val1002Met (previously known as p.Val990Met or p.Val837Met) and p.Ser1133Pro were recently shown to result in a gain-of-function effect. Based on this finding, previous drug resistance, and the experimentally demonstrated inhibitory effect of primidone on TRPM3, we initiated an individualized therapy with this drug. In both children, developmental regression was stopped, psychomotor development improved, and CSWS was no longer detectable. To our knowledge, this is the first report of a treatment with primidone in TRPM3-associated CSWS. Our results highlight the importance of early genetic diagnosis in patients with epilepsy and the possibility of precision medicine, which should be considered in the future in individuals with a TRPM3-linked DEE-SWAS.
Asunto(s)
Anticonvulsivantes , Epilepsia , Primidona , Humanos , Femenino , Primidona/administración & dosificación , Epilepsia/tratamiento farmacológico , Estudios Retrospectivos , Células HEK293 , Electroencefalografía , Anticonvulsivantes/administración & dosificación , Masculino , Preescolar , NiñoRESUMEN
BACKGROUND: There are no prospective, longitudinal studies investigating patterns of medication use among essential tremor (ET) patients. Our goal was to fill this knowledge gap. We also had a unique opportunity to examine medication use patterns primarily among elders with longstanding ET. We hypothesized that by the time ET patients reach advanced ages, medication changes would be uncommon - that is, they may have reached some kind of equipoise. METHODS: A prospective, longitudinal cohort of ET cases was evaluated across three time points. Cases were not ascertained from a treatment setting, thereby removing important selection biases. Each reported current medications and dosages of each. RESULTS: There were 144 cases (mean baseline age = 76.1 ± 9.4 years). The mean observation period = 2.9 ± 0.2 years. Primidone and propranolol were the most commonly used medications, although almost one-half of cases (44.4%) reported using neither during this period. A third of primidone users (33.3%) and a quarter of propranolol users (24.6%) reported changes in use vs. nonuse during the observation period. The majority of our cases made some change in their daily medication dosage during the course of the study - 73.3% of primidone users and 57.9% of propranolol users. CONCLUSION: In this prospective, longitudinal study, use vs. nonuse and daily dosage of both primidone and propranolol fluctuated across time for a sizable proportion of ET cases. Even among elders with chronic, longstanding ET, there is considerable ongoing medication adjustment, underscoring the need to improve the medication situation for ET patients.
Asunto(s)
Temblor Esencial , Primidona , Humanos , Anciano , Anciano de 80 o más Años , Primidona/uso terapéutico , Temblor Esencial/tratamiento farmacológico , Temblor Esencial/epidemiología , Propranolol/uso terapéutico , Estudios Longitudinales , Temblor/tratamiento farmacológicoRESUMEN
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.
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Temblor Esencial , Actividades Cotidianas , Temblor Esencial/tratamiento farmacológico , Temblor Esencial/cirugía , Humanos , Japón , Primidona/uso terapéuticoRESUMEN
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 (CaO2), 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 (CaO2) 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 CaO2 dosage increased efficiencies of PhACs attenuation and pathogens inactivation, and both exhibited pseudo-first-order degradation kinetics (R2 > 0.90). PhACs attenuation were mainly via oxidization (H2O2, â¢OH/Oâ¢-, and O2â¢-) and alkaline hydrolysis (OH-) from CaO2. 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 CaO2 was 0.1 g L-1. The oxidability (18-64%) and alkalinity (82-36%) generated from CaO2 played vital roles in pathogen inactivation. In addition, CaO2 at 0.01-0.1 g L-1 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-1 CaO2, and inactivate 100% of test bacteria under 0.1 g L-1 CaO2. In short, capability of CaO2 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.
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Tianfenicol , Contaminantes Químicos del Agua , Carbamazepina/análisis , Escherichia coli , Peróxido de Hidrógeno , Oxidantes , Preparaciones Farmacéuticas , Primidona , Contaminantes Químicos del Agua/análisisRESUMEN
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.
Asunto(s)
Temblor Esencial , Temblor Esencial/tratamiento farmacológico , Humanos , Primidona/uso terapéutico , Propranolol/uso terapéutico , Estudios Retrospectivos , Topiramato/uso terapéuticoRESUMEN
ABSTRACT: 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.
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Dolor Crónico , Cistitis Intersticial , Cistitis , Canales Catiónicos TRPM , Canales de Potencial de Receptor Transitorio , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Dolor Crónico/complicaciones , Ciclofosfamida/toxicidad , Cistitis/inducido químicamente , Cistitis/complicaciones , Cistitis/metabolismo , Cistitis Intersticial/complicaciones , Hiperalgesia/tratamiento farmacológico , Primidona/uso terapéutico , ARN , ARN Mensajero/metabolismo , Ratas , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Regulación hacia Arriba , Vejiga Urinaria/inervaciónRESUMEN
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.
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Epilepsia , Leche Humana , Anticonvulsivantes/efectos adversos , Lactancia Materna , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Etosuximida/uso terapéutico , Femenino , Humanos , Lactante , Lactancia , Fenobarbital/uso terapéutico , Primidona/uso terapéuticoRESUMEN
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.
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Fibrilación Atrial , Dabigatrán , Anciano , Anticoagulantes , Fibrilación Atrial/tratamiento farmacológico , Dabigatrán/efectos adversos , Humanos , Relación Normalizada Internacional , Pruebas de Función Hepática , Masculino , Primidona/uso terapéutico , WarfarinaRESUMEN
Niemann-Pick disease type C (NPC) is caused by a loss of function of either NPC1 or NPC2 protein, resulting in the accumulation of unesterified, free-cholesterol (free-C) in cells/tissues and thus leading to cell/tissue damage. In the brain of patients/animals with NPC, as a consequence of the accumulation of free-C in late endosomes/lysosomes (LE/LY) in cells, multiple lipids including complex sphingolipids are accumulated, and almost all patients/animals ultimately develop progressive/fatal neurodegeneration. Several reagents that are considered to act in the brain show beneficial effects on NPC-model animals. In the present study, we investigated the effects of antiepileptic drugs, such as primidone and valproic acid, on the accumulation of free-C in NPC1-null CHO cells and NPC1* fibroblasts, human fibroblasts established from a patient with NPC1 mutation. Like valproic acid, treatment with primidone reduced free-C levels in LE/LY in NPC1-null/mutant cells. Down-regulation of cholesterol ester levels in NPC1-null cells and up-regulation of HMG-CoA reductase and low-density lipoprotein receptor mRNA levels in NPC1* cells were partially recovered by primidone treatment. Thus, primidone was suggested to enhance free-C trafficking from LE/LY to endoplasmic reticulum in NPC1-null/mutant cells. In NPC1-null mice, oral application of primidone (100 mg/kg/day) extended lifespan by approximately 5 days, although the first days showing ataxia, a typical symptom of neuromotor dysfunction, were not affected. Our findings suggest the potential of primidone for the treatment of NPC.
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Colesterol/metabolismo , Fibroblastos/efectos de los fármacos , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Primidona/farmacología , Animales , Transporte Biológico , Células CHO , Cricetulus , Modelos Animales de Enfermedad , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Endosomas/efectos de los fármacos , Endosomas/metabolismo , Fibroblastos/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/genética , Longevidad/efectos de los fármacos , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Ratones Endogámicos BALB C , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C/genética , Enfermedad de Niemann-Pick Tipo C/metabolismo , Enfermedad de Niemann-Pick Tipo C/fisiopatología , Factores de Tiempo , Ácido Valproico/farmacologíaRESUMEN
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.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/metabolismo , Células Receptoras Sensoriales/metabolismo , Canales Catiónicos TRPM/metabolismo , Uréter/fisiología , Adulto , Anciano , Capsaicina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Nefrectomía , Neuroquinina A/metabolismo , Neuroquinina A/farmacología , Técnicas de Cultivo de Órganos , Pregnenolona/farmacología , Primidona/farmacología , Células Receptoras Sensoriales/efectos de los fármacos , Canales Catiónicos TRPM/agonistas , Canales Catiónicos TRPM/antagonistas & inhibidores , Uréter/efectos de los fármacosRESUMEN
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.
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Temblor Esencial , Primidona , Anciano , Temblor Esencial/tratamiento farmacológico , Humanos , Primidona/efectos adversos , TemblorAsunto(s)
Fibrilación Atrial , Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Administración Oral , Anticoagulantes/efectos adversos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Isquemia Encefálica/inducido químicamente , Inhibidores del Factor Xa/efectos adversos , Humanos , Primidona/uso terapéutico , Rivaroxabán/efectos adversos , Accidente Cerebrovascular/etiología , Resultado del TratamientoRESUMEN
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.
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COVID-19/enzimología , Primidona/farmacología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , SARS-CoV-2/metabolismo , Animales , COVID-19/patología , Muerte Celular/efectos de los fármacos , Células HEK293 , Células HT29 , Humanos , Inflamación/tratamiento farmacológico , Inflamación/enzimología , Inflamación/patología , Células Jurkat , Ratones , Células 3T3 NIH , Células U937 , Tratamiento Farmacológico de COVID-19RESUMEN
Objective: Gingival hyperplasia (GH) is one of the side effects of anticonvulsant drugs. The aim of this study was to verify the prevalence of GH associated with the use of anticonvulsant, through a systematic review. Material and Methods: Systematic search was done at databases Pubmed and Embase between January 1984 and March of 2020 for identification of articles addressing the prevalence of GH associated with the use of anticonvulsant drugs. The methodological index for non-randomized studies (MINORS) was independently assessed for quality in the selected papers. Results: The search identified 4.471 references. Nine articles were selected and evaluated 632 participants. All of the studies included in the systematic review showed a low risk of bias. The anticonvulsants used by patients were carbamazepine, ethosuximide, phenytoin, primidone, phenobarbital, sodium valproate. The studies showed a correlation between different types of anticonvulsants and GH prevalence, with a range from 0% to 73%. Among the anticonvulsants used, phenytoin showed the greatest incidence of GH, varying between 15.61% and 73% in patients. Conclusion: In the analysis of the results obtained in the literature, it is possible to notice that the great majority of studies presented incidence of GH associated with anticonvulsant use. However, further studies are necessary to understand the anticonvulsant action mechanism inducing GH, as well as the prevention forms, given that GH is a significant side effect. (AU)
Objetivo: Hiperplasia gengival (HG) é um dos efeitos colaterais das drogas anticonvulsivantes. O objetivo deste estudo foi verificar a prevalência de HG associada ao uso de anticonvulsivantes, por meio de uma revisão sistemática. Material e Métodos: A busca sistemática foi realizada nas bases de dados Pubmed e Embase entre janeiro de 1984 e março de 2020 para identificação de artigos que abordassem a prevalência de HG associada ao uso de drogas anticonvulsivantes. Foi avaliado independentemente, o risco de viés através do "Methodological index for non-randomized studies" (MINORS), para análise da qualidade dos trabalhos selecionados. Resultados: A pesquisa identificou 4.471 referências. Nove artigos foram selecionados e avaliaram 632 participantes. Todos os estudos incluídos na revisão sistemática mostraram baixo risco de viés. Os anticonvulsivantes utilizados pelos pacientes foram carbamazepina, etossuximida, fenitoína, primidona, fenobarbital e valproato de sódio. Os estudos mostraram correlação entre os diferentes tipos de anticonvulsivantes e a prevalência de HG, com variação entre 0% a 73%. Entre os anticonvulsivantes utilizados, a fenitoína apresentou a maior incidência de HG, variando entre 15,61% e 73% em pacientes. Conclusão: Na análise dos resultados obtidos na literatura, é possível notar que a grande maioria dos estudos apresentou incidência de HG associada ao uso de anticonvulsivantes. No entanto, estudos adicionais são necessários para compreender o mecanismo de ação do anticonvulsivante para a indução da HG, bem como as formas de prevenção, dado que a HG é um efeito colateral significativo (AU)