RESUMEN
About 30% of patients with epilepsy are drug resistant. Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS) and tuberous sclerosis complex (TSC) are diseases for which high-purified-cannabidiol (CBD) known as Epidiolex® (GW pharma) can be prescribed in add-on of other medications in case of drug-resistance. Currently, there are only a few recent data in the literature about the efficacy and safety of CBD in other forms of refractory epilepsies especially focal epilepsies in adults. We report retrospectively the experience of high-purified-CBD use in two French reference medical centers for epilepsy in various forms of drug-resistant epilepsy. We distinguished two groups of patients: group A with epileptic encephalopathies and group B with focal or multifocal epilepsy. Safety and efficacy (% of responder patients) were evaluated. Finally, 73 patients (51 in group A and 22 in group B) used high-purified CBD as an add-on treatment for their drug-resistant epilepsy. Patients in group A were significantly younger (P=0.0155), with a longer exposition of treatment (P=0.0497) than group B and with higher doses (P=0.0300). Respectively, 15 patients (29.4%) and five patients (22.7%) were responders during the follow-up period (P=0.552). The association with clobazam was more frequent in responders than in non-responder patients (16 patients [80%] versus four [20%]). The most frequent side effect was somnolence. At the end of follow-up, 15 patients in group A (29.4%) and nine patients in group B (40.1%) had stopped the high-purified-CBD treatment due to aggravation of seizure, absence of positive effects, or adverse events. This study showed no significant difference regarding the type of drug-resistant epilepsy and suggests that this treatment may be of interest for all types of drug-resistant epilepsy.
Asunto(s)
Cannabidiol , Epilepsia Refractaria , Epilepsias Mioclónicas , Epilepsia , Adulto , Humanos , Cannabidiol/efectos adversos , Epilepsia Refractaria/tratamiento farmacológico , Anticonvulsivantes/efectos adversos , Estudios Retrospectivos , Epilepsia/tratamiento farmacológico , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/inducido químicamenteRESUMEN
BACKGROUND: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) currently present a therapeutic challenge. A pharmaceutical cannabidiol (CBD) specialty (Epidyolex®) has been approved by the FDA and EMA for the treatment of seizures in these syndromes. However, in Italy, the use of galenic formulations versus the pharmaceutical CBD has not been clearly regulated. AIM: To share and disseminate expert' opinions on how to use and administer pharmaceutical CBD in patients with DS and LGS as well as identifying a possible strategy for the switch from galenic to pharmaceutical specialty. METHODS: A nominal group technique (NGT) was used, involving eight Italian adult and pediatric neurologists. Two questionnaires were consecutively administered and the Clinician' responses were discussed in a final meeting in order to draw the own conclusions. RESULTS: The use of a pharmaceutical CBD is considered preferable to galenic formulations, in terms of reproducibility, safety, and control of the delivered dose. CONCLUSION: The use of a pharmaceutical CBD in DS and LGS patients is useful for both seizure treatment and quality of life (QoL) improvement. However, further studies are needed to confirm the improvement in QoL and the best strategy for switching from a galenic formulation to pharmaceutical CBD.
Asunto(s)
Cannabidiol , Epilepsias Mioclónicas , Síndrome de Lennox-Gastaut , Niño , Adulto , Humanos , Cannabidiol/uso terapéutico , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Calidad de Vida , Anticonvulsivantes/uso terapéutico , Reproducibilidad de los Resultados , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/inducido químicamente , Convulsiones/tratamiento farmacológico , Preparaciones FarmacéuticasRESUMEN
PURPOSE OF REVIEW: Epilepsy affects 70 million people worldwide and is a significant cause of morbidity and early mortality. The mainstay of therapy is oral medications. Epilepsy drug development is escalating, driven by continued drug resistance in up to a third of epilepsy patients. Treatment development now focuses on discovery of novel mechanisms of action and syndrome-specific therapies. RECENT FINDINGS: Difficult-to-treat epilepsy related to conditions including tuberous sclerosis complex (TSC), Lennox Gastaut syndrome (LGS) and Dravet syndrome (DS) have been the target of recent developments. Disease-modifying therapy for epilepsy related to TSC with vigabatrin at onset of first electroencephalographic epileptiform changes, rather than after first clinical seizure, has demonstrated strongly positive seizure and developmental outcomes. Fenfluramine, approved for DS and, more recently, LGS, has robust data supporting efficacy, safety/tolerability, as well as mortality, quality of life and cognitive function. Rescue therapy has expanded to include better tolerated benzodiazepines in the form of nasal midazolam and valium. Cenobamate, a first-in-class inactivator of the persistent voltage-gated sodium channel and approved for adult partial onset epilepsy, has exceptional efficacy and tolerability and will be expanded to children and to generalized onset epilepsy in adults. SUMMARY: The repertoire of available and developmental therapies for epilepsy is rapidly expanding, and now includes disease-modifying vigabatrin in TSC and agents with extraordinary efficacy, fenfluramine and cenobamate.
Asunto(s)
Epilepsias Mioclónicas , Epilepsias Parciales , Epilepsia , Síndrome de Lennox-Gastaut , Niño , Adulto , Humanos , Anticonvulsivantes/uso terapéutico , Vigabatrin/uso terapéutico , Calidad de Vida , Epilepsia/tratamiento farmacológico , Epilepsia/etiología , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Convulsiones/tratamiento farmacológico , Epilepsias Mioclónicas/inducido químicamente , Epilepsias Mioclónicas/tratamiento farmacológico , Fenfluramina/uso terapéuticoAsunto(s)
Epilepsias Mioclónicas , Estado Epiléptico , Humanos , Adulto , Convulsiones/tratamiento farmacológico , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológico , Carbamazepina/efectos adversos , Epilepsias Mioclónicas/inducido químicamente , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/genética , Anticonvulsivantes/efectos adversos , ElectroencefalografíaRESUMEN
OBJECTIVE: The objective of this systematic review with meta-analysis was to evaluate the efficacy, safety, and short- and long-term tolerability of cannabidiol (CBD), as an adjunct treatment, in children and adults with Dravet syndrome (SD), Lennox-Gataut syndrome (LGS), or tuberous sclerosis complex (TSC), with inadequate control of seizures. METHODS: This systematic review was conducted through a search for scientific evidence in the Mediline/PubMed, Central Cochrane, and ClinicalTrials.gov databases until April 2022. Selected randomized clinical trials (RCTs) that presented the outcomes: reduction in the frequency of seizures and total seizures (all types), number of patients with a response greater than or equal to 50%, change in caregiver global impression of change (CGIC) (improvement ≥1 category on the initial scale), adverse events (AEs), and tolerability to treatment. This review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses. RESULTS: Notably, six RCTs were included, with a total of 1,034 patients with SD, LGS, and TSC, of which 3 were open-label extension RCTs. The meta-analysis of the studies showed that the use of CBD as compared with placebo, in patients with convulsive seizures refractory to the use of medications, reduces the frequency of seizures by 33%; increases the number of patients with a reduction ≥50% in the frequency of seizures by 20%; increases the number of patients with absence of seizures by 3%; improves the clinical impression evaluated by the caregiver or patient (S/CGIC) in 21%; increases total AEs by 12%; increases serious AE by 16%; increases the risk of treatment abandonment by 12%; and increases the number of patients with transaminase elevation (≥3 times the referral) by 15%. CONCLUSIONS: This systematic review, with meta-analysis, supports the use of CBD in the treatment of patients with seizures, originated in DS, LGS, and TSC, who are resistant to the common medications, presenting satisfactory benefits in reducing seizures and tolerable toxicity.
Asunto(s)
Cannabidiol , Epilepsias Mioclónicas , Epilepsia , Síndrome de Lennox-Gastaut , Esclerosis Tuberosa , Adulto , Niño , Humanos , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/efectos adversos , Cannabidiol/uso terapéutico , Cannabidiol/efectos adversos , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/inducido químicamente , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Convulsiones/etiología , Convulsiones/inducido químicamente , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/tratamiento farmacológico , Esclerosis Tuberosa/inducido químicamenteRESUMEN
BACKGROUND: Cannabidiol (CBD) has become a promising therapeutic option in the treatment of epilepsy. Recent studies provide robust evidence that CBD is effective and safe. Limitations in current knowledge and regulatory issues still limit CBD use. CBD use regarding epilepsy types still lacks clear guidelines. OBJECTIVE: To critically review the main current pharmacological features and clinical issues regarding CBD use in epilepsy, to provide current regulatory background regarding CBD use in Brazil, and to suggest a practical CBD therapeutic guide in Brazil. METHODS: Non-systematic literature review (up to February 2022) of current concepts of CBD and epilepsy, including the authors' personal experience. RESULTS: Five pivotal trials have led to CBD approval as an adjunctive treatment for Dravet and Lennox-Gastaut syndromes, and for the tuberous sclerosis complex. Efficacy of CBD in other drug-resistant epilepsies remains not completely understood. CBD adverse event profile and drug interactions are better understood. CBD is well tolerated. In Brazil, CBD is not classified as a medication, but as a product subject to a distinct regulatory legislation. CBD is still not offered by the National Brazilian health system, but can be purchased in authorized pharmacies or imported under prescription and signed informed consent. CONCLUSION: CBD is a recognized novel treatment for epilepsy. Future well-designed studies and public health strategies are needed to offer widespread access to CBD, and to improve the quality of life of people living with epilepsy in Brazil.
Asunto(s)
Cannabidiol , Epilepsias Mioclónicas , Epilepsia , Anticonvulsivantes/efectos adversos , Brasil , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Epilepsias Mioclónicas/inducido químicamente , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Humanos , Calidad de VidaRESUMEN
OBJECTIVE: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare treatment-resistant childhood epilepsies classed as developmental and epileptic encephalopathies. ELEKTRA investigated the efficacy and safety of soticlestat (TAK-935) as adjunctive therapy in children with DS or LGS (NCT03650452). METHODS: ELEKTRA was a phase 2, randomized, double-blind, placebo-controlled study of soticlestat (≤300 mg twice daily, weight-adjusted) in children (aged 2-17 years) with DS, demonstrating three or more convulsive seizures/month, or with LGS, demonstrating four or more drop seizures/month at baseline. The 20-week treatment period comprised an 8-week dose-optimization period and a 12-week maintenance period. Efficacy endpoints included change from baseline in seizure frequency versus placebo. Safety assessments included incidence of treatment-emergent adverse events (TEAEs). RESULTS: ELEKTRA enrolled 141 participants; 126 (89%) completed the study. The modified intent-to-treat population included 139 participants who received one or more doses of study drug and had one or more efficacy assessments (DS, n = 51; LGS, n = 88). ELEKTRA achieved its primary endpoint: the combined soticlestat-treated population demonstrated a placebo-adjusted median reduction in seizure frequency of 30.21% during the maintenance period (p = .0008, n = 139). During this period, placebo-adjusted median reductions in convulsive and drop seizure frequencies of 50.00% (p = .0002; patients with DS) and 17.08% (p = .1160; patients with LGS), respectively, were observed. TEAE incidences were similar between the soticlestat (80.3%) and placebo (74.3%) groups and were mostly mild or moderate in severity. Serious TEAEs were reported by 15.5% and 18.6% of participants receiving soticlestat and placebo, respectively. TEAEs reported in soticlestat-treated patients with ≥5% difference from placebo were lethargy and constipation. No deaths were reported. SIGNIFICANCE: Soticlestat treatment resulted in statistically significant, clinically meaningful reductions from baseline in median seizure frequency (combined patient population) and in convulsive seizure frequency (DS cohort). Drop seizure frequency showed a nonstatistically significant numerical reduction in children with LGS. Soticlestat had a safety profile consistent with previous studies.
Asunto(s)
Epilepsias Mioclónicas , Síndrome de Lennox-Gastaut , Espasmos Infantiles , Anticonvulsivantes/efectos adversos , Niño , Método Doble Ciego , Epilepsias Mioclónicas/inducido químicamente , Epilepsias Mioclónicas/tratamiento farmacológico , Síndromes Epilépticos , Humanos , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Piperidinas , Piridinas , Convulsiones/tratamiento farmacológico , Espasmos Infantiles/inducido químicamente , Espasmos Infantiles/tratamiento farmacológico , Resultado del TratamientoRESUMEN
PURPOSE OF REVIEW: Summarize evidence on Developmental and Epileptic Encephalopathies (DEEs) treatments focusing on new and emerging pharmacologic therapies (see Video, http://links.lww.com/CONR/A61, Supplementary Digital Content 1, which provides an overview of the review). RECENT FINDINGS: Advances in the fields of molecular genetics and neurobiology have led to the recognition of underlying pathophysiologic mechanisms involved in an increasing number of DEEs that could be targeted with precision therapies or repurposed drugs, some of which are currently being evaluated in clinical trials. Prompt, optimal therapy is critical, and promising therapies approved or in clinical trials for tuberous sclerosis complex, Dravet and Lennox-Gastaut Syndromes including mammalian target of rapamycin inhibitors, selective membrane channel and antisense oligonucleotide modulation, and repurposed drugs such as fenfluramine, stiripentol and cannabidiol, among others, may improve seizure burden and neurological outcomes. There is an urgent need for collaborative efforts to evaluate the efficacy and safety of emerging DEEs therapies. SUMMARY: Development of new therapies promise to address unmet needs for patients with DEEs, including improvement of neurocognitive function and quality of life.
Asunto(s)
Epilepsias Mioclónicas , Síndrome de Lennox-Gastaut , Anticonvulsivantes/uso terapéutico , Epilepsias Mioclónicas/inducido químicamente , Epilepsias Mioclónicas/tratamiento farmacológico , Fenfluramina/farmacología , Fenfluramina/uso terapéutico , Humanos , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Calidad de VidaRESUMEN
OBJECTIVE: The number, unpredictability, and severity of seizures experienced by patients with Dravet syndrome (DS) negatively impact quality of life (QOL) for patients, caregivers, and families. Metrics are needed to assess whether patients with residual seizures have moved meaningfully toward seizure freedom after treatment with new antiseizure medications. METHODS: We evaluated the time required postrandomization for each patient to experience the same number of seizures experienced during baseline (i.e., time-to-nth seizure), using a post hoc time-to-event (TTE) analysis of data from two Phase 3 placebo-controlled trials of adjunctive fenfluramine for DS (Study 1, N = 119; Study 2, N = 87). Patients aged 2-19 years were randomized to placebo or adjunctive fenfluramine (Study 1: .7 mg/kg/day or .2 mg/kg/day; Study 2: .4 mg/kg/day with stiripentol). Data were analyzed by Kaplan-Meier TTE curves and waterfall plots. RESULTS: The proportion of patients who never reached baseline seizure frequency was greater with fenfluramine than with placebo (Study 1: fenfluramine .7 mg/kg/day, 60%; fenfluramine .2 mg/kg/day, 31%; placebo, 13%; Study 2: fenfluramine .4 mg/kg/day, 58%; placebo, 2%). Median time-to-nth seizure was longer after fenfluramine than after placebo (Study 1: fenfluramine .7 mg/kg/day, 13 weeks; .2 mg/kg/day, 10 weeks; placebo, 7 weeks; Study 2: fenfluramine .4 mg/kg/day, 13 weeks; placebo, 5 weeks; p < .001). Longest duration of convulsive seizure-free days was increased in active groups versus the placebo group (Study 1: fenfluramine .7 and .2 mg/kg/day, 25.0 and 15.0 days; placebo, 9.5 days [p = .0001; p = .0352]; Study 2: fenfluramine .4 mg/kg/day, 22.0 days; placebo, 13.0 days [p = .004]). The most common adverse events included decreased appetite, pyrexia, upper respiratory tract infection, diarrhea, and fatigue. SIGNIFICANCE: These data demonstrate that fenfluramine can significantly reduce day-to-day seizure burden in patients with DS, providing prolonged periods of convulsive seizure-free days, which may help reduce the physical and emotional disease toll while improving health-related QOL for patients and caregivers.
Asunto(s)
Epilepsias Mioclónicas , Calidad de Vida , Anticonvulsivantes/efectos adversos , Epilepsias Mioclónicas/inducido químicamente , Epilepsias Mioclónicas/complicaciones , Epilepsias Mioclónicas/tratamiento farmacológico , Síndromes Epilépticos , Fenfluramina/efectos adversos , Humanos , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Espasmos Infantiles , Resultado del TratamientoRESUMEN
OBJECTIVE: Dravet syndrome (DS) is a rare but severe drug-resistant epilepsy. Before the approval of fenfluramine (FFA) for the treatment of seizures in DS, patients in Germany could receive treatment under a compassionate use program (CUP). METHODS: We conducted a multicenter, retrospective, observational study to describe the efficacy, tolerability, and retention of FFA within the CUP. Patients received add-on therapy with oral FFA gradually titrated to a target dose between .13 and .7 mg/kg/day. RESULTS: Overall, 78 patients with DS (median age = 8.0 years, range = 2.1-46.0; 53% female, median concomitant antiseizure medications [ASMs] = 3) were treated with FFA for a median duration of 255.5 days (range = 31-572). Responder rates (a ≥50% reduction; n = 78) and seizure-freedom rates at 3 months were 68% and 14% for total seizures, respectively, and 67% and 23% for generalized tonic-clonic seizures. Responder rates were consistent at 6 and 12 months (n = 66 and n = 43, respectively). Median seizure days per month significantly decreased from 10.0 (range = .5-30) to 3.0 (range = 0-30) in the 3-month period before and after FFA treatment (p < .001). Significantly fewer patients reported at least one episode of status epilepticus (28% vs. 14% patients before and after FFA initiation, p = .005). During FFA treatment, 35 (45%) patients were able to discontinue a concomitant ASM. At the last follow-up date, 66 (85%) patients remained on treatment with FFA. The most common adverse events were somnolence (36%), decreased appetite (22%), and ataxia (8%). Forty-eight (62%) patients were reported as having a meaningful global clinical improvement. SIGNIFICANCE: In a large cohort of patients, FFA demonstrated efficacy across a range of outcomes including clinically significant reductions in convulsive seizures, and was well tolerated, providing valuable information for real-world practice.
Asunto(s)
Ensayos de Uso Compasivo , Epilepsias Mioclónicas , Adolescente , Adulto , Anticonvulsivantes/efectos adversos , Niño , Preescolar , Epilepsias Mioclónicas/inducido químicamente , Epilepsias Mioclónicas/complicaciones , Epilepsias Mioclónicas/tratamiento farmacológico , Síndromes Epilépticos , Femenino , Fenfluramina/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Convulsiones/complicaciones , Espasmos Infantiles , Resultado del Tratamiento , Adulto JovenRESUMEN
We report a case of cefepime neurotoxicity characterised by myoclonic status epilepticus with coma, in a context of acute renal failure and requiring one discontinuous conventional haemodialysis. Cefepime is a fourth-generation broad-spectrum cephalosporin mainly used to treat hospital-acquired Gram-negative infections. Acute neurotoxicity is an increasingly reported adverse effect which occurs predominantly in patients with renal impairment. Renal replacement therapy has been proposed to treat this condition.
Asunto(s)
Lesión Renal Aguda/terapia , Antibacterianos/efectos adversos , Cefepima/efectos adversos , Epilepsias Mioclónicas/inducido químicamente , Estado Epiléptico/inducido químicamente , Lesión Renal Aguda/inducido químicamente , Anciano de 80 o más Años , Antibacterianos/toxicidad , Bronquiectasia/tratamiento farmacológico , Cefepima/toxicidad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Epilepsias Mioclónicas/fisiopatología , Resultado Fatal , Femenino , Humanos , Síndromes de Neurotoxicidad/complicaciones , Síndromes de Neurotoxicidad/diagnóstico , Diálisis Renal , Estado Epiléptico/fisiopatologíaRESUMEN
Dravet syndrome (DS) is a refractory epileptic syndrome. Vaccination is the trigger of the first seizure in about 50% of cases. Fever remains a trigger of seizures during the course of the disease. We compared ex vivo cytokine responses to a combined aluminium-adjuvanted vaccine of children with DS to sex- and age-matched heathy children. Using ex vivo cytokine responses of peripheral-blood mononuclear cells and monocytes, we found that vaccine responsiveness is biased toward a proinflammatory profile in DS with a M1 phenotype of monocytes. We provide new insight into immune mechanisms associated with DS that might guide research for the development of new immunotherapeutic agents in this epilepsy syndrome.
Asunto(s)
Citocinas/inmunología , Epilepsias Mioclónicas/inmunología , Leucocitos Mononucleares/inmunología , Vacunación/efectos adversos , Vacunas/efectos adversos , Vacunas/inmunología , Niño , Preescolar , Citocinas/metabolismo , Epilepsias Mioclónicas/inducido químicamente , Epilepsias Mioclónicas/metabolismo , Femenino , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , MasculinoRESUMEN
The serpinopathies are human pathologies caused by mutations that promote polymerisation and intracellular deposition of proteins of the serpin superfamily, leading to a poorly understood cell toxicity. The dementia FENIB is caused by polymerisation of the neuronal serpin neuroserpin (NS) within the endoplasmic reticulum (ER) of neurons. With the aim of understanding the toxicity due to intracellular accumulation of neuroserpin polymers, we have generated transgenic neural progenitor cell (NPC) cultures from mouse foetal cerebral cortex, stably expressing the control protein GFP (green fluorescent protein), or human wild type, G392E or delta NS. We have characterised these cell lines in the proliferative state and after differentiation to neurons. Our results show that G392E NS formed polymers that were mostly retained within the ER, while wild type NS was correctly secreted as a monomeric protein into the culture medium. Delta NS was absent at steady state due to its rapid degradation, but it was easily detected upon proteasomal block. Looking at their intracellular distribution, wild type NS was found in partial co-localisation with ER and Golgi markers, while G392E NS was localised within the ER only. Furthermore, polymers of NS were detected by ELISA and immunofluorescence in neurons expressing the mutant but not the wild type protein. We used control GFP and G392E NPCs differentiated to neurons to investigate which cellular pathways were modulated by intracellular polymers by performing RNA sequencing. We identified 747 genes with a significant upregulation (623) or downregulation (124) in G392E NS-expressing cells, and we focused our attention on several genes involved in the defence against oxidative stress that were up-regulated in cells expressing G392E NS (Aldh1b1, Apoe, Gpx1, Gstm1, Prdx6, Scara3, Sod2). Inhibition of intracellular anti-oxidants by specific pharmacological reagents uncovered the damaging effects of NS polymers. Our results support a role for oxidative stress in the cellular toxicity underlying the neurodegenerative dementia FENIB.
Asunto(s)
Demencia/metabolismo , Epilepsias Mioclónicas/metabolismo , Trastornos Heredodegenerativos del Sistema Nervioso/metabolismo , Neuronas/metabolismo , Neuropéptidos/toxicidad , Estrés Oxidativo/fisiología , Polímeros/toxicidad , Serpinas/toxicidad , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Demencia/inducido químicamente , Demencia/patología , Epilepsias Mioclónicas/inducido químicamente , Epilepsias Mioclónicas/patología , Trastornos Heredodegenerativos del Sistema Nervioso/inducido químicamente , Trastornos Heredodegenerativos del Sistema Nervioso/patología , Humanos , Ratones , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/patología , Estrés Oxidativo/efectos de los fármacos , NeuroserpinaRESUMEN
A wide variety of drugs can cause myoclonus. To illustrate this, we first discuss two personally observed cases, one presenting with generalized, but facial-predominant, myoclonus that was induced by amantadine; and the other presenting with propriospinal myoclonus triggered by an antibiotic. We then review the literature on drugs that may cause myoclonus, extracting the corresponding clinical phenotype and suggested underlying pathophysiology. The most frequently reported classes of drugs causing myoclonus include opiates, antidepressants, antipsychotics, and antibiotics. The distribution of myoclonus ranges from focal to generalized, even amongst patients using the same drug, which suggests various neuro-anatomical generators. Possible underlying pathophysiological alterations involve serotonin, dopamine, GABA, and glutamate-related processes at various levels of the neuraxis. The high number of cases of drug-induced myoclonus, together with their reported heterogeneous clinical characteristics, underscores the importance of considering drugs as a possible cause of myoclonus, regardless of its clinical characteristics.
Asunto(s)
Mioclonía/inducido químicamente , Anciano , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/uso terapéutico , Discinesia Inducida por Medicamentos/etiología , Epilepsias Mioclónicas/inducido químicamente , Epilepsias Mioclónicas/etiología , Femenino , Humanos , Masculino , Mioclonía/etiología , Enfermedad de Parkinson/tratamiento farmacológico , Neumonía/tratamiento farmacológicoRESUMEN
Increasing evidence suggests that plant-derived extracts and their isolated components are useful for treatment of seizures and, hence, constitute a valuable source of new antiepileptic drugs with improved efficacy and better adverse effect profile. ß-Caryophyllene is a natural bicyclic sesquiterpene that occurs in a wide range of plant species and displays a number of biological actions, including neuroprotective activity. In the present study, we tested the hypothesis that ß-caryophyllene displays anticonvulsant effects. In addition, we investigated the effect of ß-caryophyllene on behavioral parameters and on seizure-induced oxidative stress. Adult C57BL/6 mice received increasing doses of ß-caryophyllene (0, 10, 30, or 100mg/kg). After 60 min, we measured the latencies to myoclonic and generalized seizures induced by pentylenetetrazole (PTZ, 60 mg/kg). We found that ß-caryophyllene increased the latency to myoclonic jerks induced by PTZ. This result was confirmed by electroencephalographic analysis. In a separate set of experiments, we found that mice treated with an anticonvulsant dose of ß-caryophyllene (100mg/kg) displayed an improved recognition index in the object recognition test. This effect was not accompanied by behavioral changes in the open-field, rotarod, or forced swim tests. Administration of an anticonvulsant dose of ß-caryophyllene (100mg/kg) did not prevent PTZ-induced oxidative stress (i.e., increase in the levels of thiobarbituric acid-reactive substances or the decrease in nonprotein thiols content). Altogether, the present data suggest that ß-caryophyllene displays anticonvulsant activity against seizures induced by PTZ in mice. Since no adverse effects were observed in the same dose range of the anticonvulsant effect, ß-caryophyllene should be further evaluated in future development of new anticonvulsant drugs.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Convulsivantes , Pentilenotetrazol , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Sesquiterpenos/uso terapéutico , Animales , Relación Dosis-Respuesta a Droga , Electroencefalografía/efectos de los fármacos , Epilepsias Mioclónicas/inducido químicamente , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Mioclónicas/psicología , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Sesquiterpenos Policíclicos , Equilibrio Postural/efectos de los fármacos , Reconocimiento en Psicología , Convulsiones/psicología , Natación/psicologíaAsunto(s)
Encefalopatías/inducido químicamente , Encéfalo/fisiopatología , Cilastatina/efectos adversos , Epilepsias Mioclónicas/inducido químicamente , Imipenem/efectos adversos , Síndrome de Activación Macrofágica/tratamiento farmacológico , Trastornos por Fotosensibilidad/inducido químicamente , Anciano , Encefalopatías/fisiopatología , Cilastatina/uso terapéutico , Combinación Cilastatina e Imipenem , Combinación de Medicamentos , Electroencefalografía , Epilepsias Mioclónicas/fisiopatología , Femenino , Humanos , Imipenem/uso terapéutico , Síndrome de Activación Macrofágica/fisiopatología , Trastornos por Fotosensibilidad/fisiopatologíaRESUMEN
BACKGROUND: The incidence rate of depression among patients with epilepsy is relatively high. The basis of proper therapy is knowledge of drug interactions, which may enable to maximize therapeutic effects and minimize undesired effects of the combined treatment. The purpose of this study was to evaluate the influence of reboxetine, a selective norepinephrine reuptake inhibitor, on the seizure threshold and anticonvulsant effects of four classic antiepileptic drugs: valproate, phenobarbital, ethosuximide, and clonazepam. Moreover, we assessed the adverse effects of reboxetine and combinations of reboxetine with antiepileptic drugs on motor coordination and long-term memory. METHODS: The subcutaneous pentylenetetrazole (PTZ) test in mice was used to determine effects of anticonvulsant activity of antiepileptic drugs and reboxetine. Undesired effects of either reboxetine or and its combinations with antiepileptics were evaluated in the chimney test (motor coordination) and the step-through passive-avoidance task (long-term memory). RESULTS: Analysis of obtained results revealed that reboxetine given at doses of 10 and 15 mg/kg doses exhibits anticonvulsant activity expressed by increasing the median convulsive dose (CD(50)) for pentylenetetrazole (p < 0.01). However, the antidepressant did not affect the anticonvulsant action of antiepileptic drugs studied in this seizure model. Moreover, no adverse reactions were found after administration of reboxetine alone or in combinations. CONCLUSION: If further research confirms the obtained results, reboxetine may be categorized as an antidepressant which can be safely administered to epileptic patients treated with valproate, phenobarbital, ethosuximide or clonazepam.
Asunto(s)
Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Epilepsias Mioclónicas/tratamiento farmacológico , Morfolinas/farmacología , Morfolinas/uso terapéutico , Animales , Antidepresivos/efectos adversos , Reacción de Prevención/efectos de los fármacos , Clonazepam/farmacología , Clonazepam/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada/efectos adversos , Epilepsias Mioclónicas/inducido químicamente , Etosuximida/farmacología , Etosuximida/uso terapéutico , Masculino , Ratones , Morfolinas/efectos adversos , Destreza Motora/efectos de los fármacos , Pentilenotetrazol , Fenobarbital/farmacología , Fenobarbital/uso terapéutico , Reboxetina , Ácido Valproico/farmacología , Ácido Valproico/uso terapéuticoRESUMEN
INTRODUCTION: Alpha lipoic acid is a powerful antioxidant widely used for the supplementary treatment of diabetic neuropathy. Intoxication with alpha lipoic acid is very rare. There is no reported dose of safety in children. CASE REPORT: A 14-month-old previously healthy girl was referred to our hospital with the diagnosis of drug intoxication. She was admitted to the emergency department with lethargy and continuing involuntary movements for several hours after she had ingested an unknown amount of alpha lipoic acid. On admission she was lethargic and had myoclonic seizures involving all extremities. She had no fever and laboratory examinations were normal except for mild metabolic acidosis. The seizures were unresponsive to bolus midazolam, phenytoin infusion and levetiracetam infusion. She was taken to the pediatric intensive care unit with the diagnosis of status epilepticus. After failure of the treatment with midazolam infusion she was intubated and thiopental sodium infusion was started. Her myoclonic seizures were controlled with thiopental sodium infusion. After 48 h intubation and mechanical ventilation thiopental sodium was gradually reduced and then stopped. Following the withdraw of thiopental sodium, she was seizure free on her discharge on the 8th day. CONCLUSION: Alpha lipoic acid and derivatives cause side effects in children like refractory convulsions. They are frequently rendered as vitamins by diabetic patients and are left at places where children can easily access them. Therefore, when faced with refractory convulsions in children who have had no disease before, intoxication by medicaments with alpha lipoic acid should be taken into consideration.