RESUMO
OBJECTIVES: The objective of this study was to evaluate the effectiveness of the combined use of empagliflozin (EMPA) and topiramate (TPM) versus a placebo in overweight/obese individuals without diabetes on a calorie-restricted diet. METHODS: In this study, 44 non-diabetic and overweight/obese subjects who were on a calorie restricted diet were randomly assigned into 2 groups: (1) Participants received a 10 mg EMPA tablet daily plus TPM tablet (at the 1st week 25 mg once a day and from the second week 25 mg twice a day); (2) Participants received an empagliflozin placebo (daily) plus a topiramate placebo (as mentioned for topiramate tablet in group 1), for 12 weeks. At baseline and weeks 4, 8, 12, weight, height, body mass index (BMI), waist circumference (WC), and body composition were evaluated. Before and after the intervention, blood pressure, C reactive protein, and glucose and lipid profile parameters were measured. RESULTS: The EMPA/TPM group, compared to placebo, had a greater percent change of weight at week 12 (- 8.92 ± 1.80 vs. - 4.93 ± 1.17). The intervention group had a greater percent change of fat mass and fat percent at week 12 (P < 0.05). However, there was no difference in the percent of change in fat-free percent between the two groups at week 12 (P = 0.577). Within-group analysis found a significant reduction in SBP, DBP, FBS, insulin, HOMA-IR, TC, LDL, HDL, TG, and CRP in both groups (P < 0.05). At week 12, no statistically significant difference was observed between the two groups in any of mentioned variables (P > 0.05). CONCLUSION: In non-diabetic overweight/obese individuals, the combination of EMPA/TPM and calorie restriction led to a notable decrease in body weight and was generally well-tolerated. Further research is required to evaluate the potential advantages of utilizing this combination for sustained weight management in the long run. LEVEL I: Randomized clinical trial.
Assuntos
Compostos Benzidrílicos , Restrição Calórica , Glucosídeos , Obesidade , Sobrepeso , Topiramato , Humanos , Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Masculino , Feminino , Adulto , Obesidade/tratamento farmacológico , Obesidade/dietoterapia , Obesidade/complicações , Sobrepeso/tratamento farmacológico , Sobrepeso/dietoterapia , Topiramato/uso terapêutico , Pessoa de Meia-Idade , Índice de Massa Corporal , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Quimioterapia Combinada , Método Duplo-Cego , Fármacos Antiobesidade/uso terapêutico , Composição Corporal/efeitos dos fármacos , Circunferência da Cintura/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Resultado do Tratamento , Redução de Peso/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoAssuntos
Fármacos Antiobesidade , Receptor do Peptídeo Semelhante ao Glucagon 1 , Obesidade , Sobrepeso , Fentermina , Topiramato , Redução de Peso , Humanos , Fentermina/administração & dosagem , Fentermina/efeitos adversos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Redução de Peso/efeitos dos fármacos , Sobrepeso/complicações , Obesidade/tratamento farmacológico , Obesidade/complicações , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/efeitos adversos , Topiramato/administração & dosagem , Adulto , Combinação de Medicamentos , Agonistas do Receptor do Peptídeo 1 Semelhante ao GlucagonRESUMO
The rising prevalence of obesity is of major concern. There are currently 5 Food and Drug Administration-approved medications for the treatment of obesity: orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide 3.0 mg, and semaglutide 2.4 mg. Surgical options such as bariatric surgery and endoscopic surgery induce more durable weight loss than pharmacotherapy or lifestyle interventions alone. However, patients often experience weight regain and weight loss plateau after surgery. The addition of multimodal or multihormonal pharmacotherapy is a promising tool to address these challenges. The optimal timing of obesity pharmacotherapy with surgical and endoscopic interventions requires further investigation.
Assuntos
Fármacos Antiobesidade , Naltrexona , Obesidade , Redução de Peso , Humanos , Fármacos Antiobesidade/uso terapêutico , Naltrexona/uso terapêutico , Cirurgia Bariátrica/métodos , Orlistate/uso terapêutico , Fentermina/uso terapêutico , Liraglutida/uso terapêutico , Bupropiona/uso terapêutico , Topiramato/uso terapêutico , Peptídeos Semelhantes ao Glucagon/uso terapêuticoRESUMO
This work provides insight into carbamazepine polymorphs (Forms I, II, III, IV, and V), with reports on the cytoprotective, exploratory, motor, CNS-depressant, and anticonvulsant properties of carbamazepine (CBZ), carbamazepine formulation (CBZ-F), topiramate (TOP), oxcarbazepine (OXC), and diazepam (DZP) in mice. Structural analysis highlighted the significant difference in molecular conformations, which directly influence the physicochemical properties; and density functional theory description provided indications about CBZ reactivity and stability. In addition to neuron viability assessment in vitro, animals were treated orally with vehicle 10 mL/kg, as well as CBZ, CBZ-F, TOP, OXC, and DZP at the dose of 5 mg/kg and exposed to open-field, rotarod, barbiturate sleep induction and pentylenetetrazol (PTZ 70 mg/kg)-induced seizure. The involvement of GABAergic mechanisms in the activity of these drugs was evaluated with the intraperitoneal pretreatment of flumazenil (2 mg/kg). The CBZ, CBZ-F, and TOP mildly preserved neuronal viability. The CBZ-F and the reference AEDs potentiated barbiturate sleep, altered motor activities, and attenuated PTZ-induced convulsion. However, flumazenil pretreatment blocked these effects. Additional preclinical assessments could further establish the promising utility of CBZ-F in clinical settings while expanding the scope of AED formulations and designs.
Assuntos
Anticonvulsivantes , Carbamazepina , Carbamazepina/farmacologia , Carbamazepina/análogos & derivados , Animais , Camundongos , Anticonvulsivantes/farmacologia , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oxcarbazepina/farmacologia , Diazepam/farmacologia , Masculino , Pentilenotetrazol , Sobrevivência Celular/efeitos dos fármacos , Topiramato/farmacologia , Barbitúricos/farmacologiaRESUMO
Oral Topiramate therapy is associated with systemic adverse effects including paresthesia,abdominal pain, and fluctuations in plasma levels. The purpose of this research was to develop an intranasal in situ gel based system comprising Topiramate polymeric nanoparticles and evaluate its potential both in vitro and in vivo. Poly (lactic-co-glycolic acid) (PLGA)nanoparticles prepared by nanoprecipitation method were added into the in situ gelling system of Poloxamer 407 and HPMC K4M. Selected formulation (TG5) was evaluated for physicochemical properties, nasal permeation and in vivo pharmacokinetics in rats. PLGAnanoparticles (O1) exhibited low particle size (~ 144.4 nm), good polydispersity index (0.202), negative zeta potential (-12.7 mV), and adequate entrapment efficiency (64.7%). Developed in situ gel showed ideal pH (6.5), good gelling time (35 s), gelling temperature(37â), suitable viscosity (1335 cP)and drug content of 96.2%. In vitro drug release conformedto Higuchi release kinetics, exhibiting a biphasic pattern of initial burst release and sustained release for 24 h. Oral administration of the drug to Sprague-Dawley rats (G3) showed higher plasma Cmax(504 ng/ml, p < 0.0001) when compared to nasal delivery of in situ gel (G4) or solution (G5). Additionally, AUC0-α of G3 (8786.82 ng/ml*h) was considerably higher than othergroups. Brain uptake data indicates a higher drug level with G4 (112.47 ng /ml) at 12 h when compared to G3. Histopathological examination of groups; G1 (intranasal saline), G2(intranasal placebo), G3, G4, and G5 did not show any lesions of pathological significance. Overall, the experimental results observed were promising and substantiated the potential of developed in situ gel for intranasal delivery.
Assuntos
Administração Intranasal , Encéfalo , Géis , Nanopartículas , Mucosa Nasal , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos Sprague-Dawley , Topiramato , Animais , Topiramato/administração & dosagem , Topiramato/farmacocinética , Nanopartículas/química , Ratos , Administração Intranasal/métodos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Mucosa Nasal/metabolismo , Mucosa Nasal/efeitos dos fármacos , Masculino , Tamanho da Partícula , Frutose/administração & dosagem , Frutose/farmacocinética , Frutose/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Sistemas de Liberação de Medicamentos/métodos , Ácido Láctico/química , Ácido Láctico/administração & dosagem , Ácido Poliglicólico/química , Administração OralRESUMO
A man in his 40s with a known history of alcohol dependence syndrome was admitted with presenting symptoms of alcohol withdrawal. During his admission, he developed breathlessness, cough and wheezing. Investigations revealed raised absolute eosinophil count and serum IgE levels. Chest imaging showed ill-defined opacities and fibreoptic bronchoscopy with bronchoalveolar lavage confirmed eosinophilic pneumonia. Extensive workup for the cause of eosinophilia was negative. The patient's medicines were reviewed, and it was realised that the onset of eosinophilia occurred after starting topiramate for an alcohol withdrawal seizure. The drug was stopped, leading to the complete resolution of symptoms and radiological abnormalities. This case highlights the importance of considering drug-induced causes of eosinophilic pneumonia.
Assuntos
Anticonvulsivantes , Frutose , Eosinofilia Pulmonar , Topiramato , Humanos , Masculino , Topiramato/efeitos adversos , Eosinofilia Pulmonar/induzido quimicamente , Eosinofilia Pulmonar/diagnóstico , Anticonvulsivantes/efeitos adversos , Adulto , Frutose/análogos & derivados , Frutose/efeitos adversos , Síndrome de Abstinência a Substâncias , Doença Aguda , Alcoolismo/complicações , Alcoolismo/tratamento farmacológicoRESUMO
OBJECTIVE: To develop machine learning models using patient and migraine features that can predict treatment responses to commonly used migraine preventive medications. BACKGROUND: Currently, there is no accurate way to predict response to migraine preventive medications, and the standard trial-and-error approach is inefficient. METHODS: In this cohort study, we analyzed data from the Mayo Clinic Headache database prospectively collected from 2001 to December 2023. Adult patients with migraine completed questionnaires during their initial headache consultation to record detailed clinical features and then at each follow-up to track preventive medication changes and monthly headache days. We included patients treated with at least one of the following migraine preventive medications: topiramate, beta-blockers (propranolol, metoprolol, atenolol, nadolol, timolol), tricyclic antidepressants (amitriptyline, nortriptyline), verapamil, gabapentin, onabotulinumtoxinA, and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) (erenumab, fremanezumab, galcanezumab, eptinezumab). We pre-trained a deep neural network, "TabNet," using 145 variables, then employed TabNet-embedded data to construct prediction models for each medication to predict binary outcomes (responder vs. non-responder). A treatment responder was defined as having at least a 30% reduction in monthly headache days from baseline. All model performances were evaluated, and metrics were reported in the held-out test set (train 85%, test 15%). SHapley Additive exPlanations (SHAP) were conducted to determine variable importance. RESULTS: Our final analysis included 4260 patients. The responder rate for each medication ranged from 28.7% to 34.9%, and the mean time to treatment outcome for each medication ranged from 151.3 to 209.5 days. The CGRP mAb prediction model achieved a high area under the receiver operating characteristics curve (AUC) of 0.825 (95% confidence interval [CI] 0.726, 0.920) and an accuracy of 0.80 (95% CI 0.70, 0.88). The AUCs of prediction models for beta-blockers, tricyclic antidepressants, topiramate, verapamil, gabapentin, and onabotulinumtoxinA were: 0.664 (95% CI 0.579, 0.745), 0.611 (95% CI 0.562, 0.682), 0.605 (95% CI 0.520, 0.688), 0.673 (95% CI 0.569, 0.724), 0.628 (0.533, 0.661), and 0.581 (95% CI 0.550, 0.632), respectively. Baseline monthly headache days, age, body mass index (BMI), duration of migraine attacks, responses to previous medication trials, cranial autonomic symptoms, family history of headache, and migraine attack triggers were among the most important variables across all models. A variable could have different contributions; for example, lower BMI predicts responsiveness to CGRP mAbs and beta-blockers, while higher BMI predicts responsiveness to onabotulinumtoxinA, topiramate, and gabapentin. CONCLUSION: We developed an accurate prediction model for CGRP mAbs treatment response, leveraging detailed migraine features gathered from a headache questionnaire before starting treatment. Employing the same methods, the model performances for other medications were less impressive, though similar to the machine learning models reported in the literature for other diseases. This may be due to CGRP mAbs being migraine-specific. Incorporating medical comorbidities, genomic, and imaging factors might enhance the model performance. We demonstrated that migraine characteristics are important in predicting treatment responses and identified the most crucial predictors for each of the seven types of preventive medications. Our results suggest that precision migraine treatment is feasible.
Assuntos
Aprendizado de Máquina , Transtornos de Enxaqueca , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Antidepressivos Tricíclicos/uso terapêutico , Estudos de Coortes , Medicina de Precisão , Antagonistas Adrenérgicos beta/uso terapêutico , Topiramato/administração & dosagem , Topiramato/farmacologia , Resultado do TratamentoRESUMO
Aim: This study aimed to develop and validate a GC-NPD method for quantifying topiramate (TPM) in capillary dried plasma spots (DPS).Materials & methods: Extraction involved three 6 mm DPS with albumin 0.1%, alkaline liquid extraction with tert-Butyl methyl ether and TMAH methylation. The method was validated and applied to 15 paired samples of capillary DPS and venous plasma from chemical dependency patients.Results: The method was linear from 1 to 50 µg/ml (r >0.99), precise (CV% 3.62-8.29%) accurate (98.1-107.7%). TPM stability was confirmed in DPS stored at 4, 23 and 45°C for 21 days. DPS TPM measurements were highly correlated plasma concentrations (rs = 0.96), representing on average 102% of the venous plasma measurements.Conclusion: The method was fully validated, demonstrating potential for clinical application.
[Box: see text].
Assuntos
Teste em Amostras de Sangue Seco , Topiramato , Topiramato/sangue , Humanos , Teste em Amostras de Sangue Seco/métodos , Cromatografia Gasosa/métodos , Frutose/análogos & derivados , Frutose/sangueRESUMO
BACKGROUND/AIM: The most commonly prescribed anti-seizures medications (ASMs) for the treatment of epilepsy are currently topiramate, zonisamide, lacosamide, carbamazepine and levetiracetam. The objective of this study was to examine the correlation between preoperative, intraoperative, and postoperative metabolic acidosis and the use of ASMs prior to craniotomy operations. MATERIALS AND METHODS: This retrospective cross-sectional study evaluated patients who underwent intracranial surgery with craniotomy under general anaesthesia between May 2020 and April 2023 and used ASMs. The patients were classified into four groups based on the pharmacological mechanisms of action of the ASMs administered before intracranial surgery (Group-I, zonisamide or topiramate; Group-II, lacosamide; Group-III, carbamazepine; Group-IV, levetiracetam). Metabolic acidosis severity was defined based on base excess (BE) levels: mild (-3 to -5), moderate (-5 to -10), and severe (below - 10). The study investigated the correlation between ASMs and the severity of metabolic acidosis in preoperative, intraoperative, and postoperative blood gas measurements. RESULTS: Out of 35 patients, 24 patients underwent intracranial surgery and 11 patients underwent epilepsy surgery. There were statistically significant differences in the severity of metabolic acidosis between preoperative (p < 0.001), intraoperative (p < 0.001) and postoperative (p = 0.01) groups. The preoperative mean BE of group-I was - 4.7, which was statistically lower than that of group-III (p = 0.01) and group-IV (p < 0.001). Intraoperatively and postoperatively, group-I had a mean BE of -7.5 and - 3.2, respectively, which was statistically lower than that of groups II (p = 0.007; p = 0.04), III (p = 0.002; p = 0.03), and IV (p < 0.001; p = 0.009). There was no statistically significant difference in BE between groups II, III and IV at all three time points. Group I had the lowest BE at all three time points. Intraoperative bicarbonate was administered to all patients in group I, whereas no intraoperative bicarbonate was required in the other groups. In group I, 50% of patients required postoperative intensive care. CONCLUSION: The use of ASMs in patients undergoing surgery is important in terms of mortality and morbidity. Topirimat and zonisamide are ASMs that can cause preoperative, intraoperative and postoperative metabolic acidosis. Patients receiving topirimat or zonisamide are particularly susceptible to metabolic acidosis. Special care should be taken in the management of anaesthesia in patients receiving these drugs, and monitoring of the perioperative metabolic status is essential.
Assuntos
Acidose , Anticonvulsivantes , Craniotomia , Topiramato , Zonisamida , Humanos , Craniotomia/efeitos adversos , Topiramato/administração & dosagem , Acidose/induzido quimicamente , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Estudos Retrospectivos , Feminino , Masculino , Estudos Transversais , Pessoa de Meia-Idade , Adulto , Complicações Pós-Operatórias/epidemiologia , Idoso , Epilepsia/cirurgia , Epilepsia/tratamento farmacológicoAssuntos
Anticonvulsivantes , Complicações na Gravidez , Topiramato , Humanos , Gravidez , Topiramato/uso terapêutico , Feminino , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Complicações na Gravidez/prevenção & controle , Complicações na Gravidez/tratamento farmacológico , Frutose/análogos & derivados , Frutose/efeitos adversosRESUMO
BACKGROUND: Topiramate is often considered as a second-line medication for the treatment of pseudotumor cerebri syndrome (PTCS), but limited studies exist that evaluate its efficacy in children. METHODS: Retrospective study of patients aged <21 years with PTCS who were treated with topiramate alone or in combination with acetazolamide was performed. Data regarding clinical courses and visual outcomes were recorded. RESULTS: A total of 46 patients were identified. Three (6.5%) patients were treated with topiramate alone, 31 (67.4%) transitioned to topiramate from acetazolamide, and 12 (26.1%) took both topiramate and acetazolamide concurrently. The median time to resolution of papilledema on topiramate was 0.57 years (interquartile range 0.32 to 0.84). Among eyes with papilledema graded on the Frisen scale at topiramate initiation, 40 of 57 (70.2%) were grade 1, nine of 57 (15.8%) were grade 2, and eight of 57 (14.0%) were grade 3. Twenty-seven of 46 (58.7%) reported headache improvement after starting topiramate. The mean dose of topiramate was 1.3 ± 0.8 mg/kg/day. The most common side effect was patient report of cognitive slowing (10 of 46 [21.7%]). All patients on topiramate monotherapy who were compliant with treatment and follow-up had resolution of papilledema with no evidence of visual function loss. CONCLUSIONS: Topiramate can effectively treat PTCS in children with mild to moderate papilledema or in those unable to tolerate acetazolamide. More research is needed to assess the efficacy of topiramate for higher grade papilledema.
Assuntos
Acetazolamida , Pseudotumor Cerebral , Topiramato , Humanos , Topiramato/administração & dosagem , Topiramato/efeitos adversos , Topiramato/farmacologia , Pseudotumor Cerebral/tratamento farmacológico , Pseudotumor Cerebral/induzido quimicamente , Criança , Feminino , Masculino , Estudos Retrospectivos , Acetazolamida/efeitos adversos , Acetazolamida/uso terapêutico , Acetazolamida/administração & dosagem , Adolescente , Papiledema/tratamento farmacológico , Papiledema/induzido quimicamente , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/administração & dosagem , Pré-Escolar , Resultado do Tratamento , Quimioterapia Combinada , Inibidores da Anidrase Carbônica/efeitos adversos , Inibidores da Anidrase Carbônica/administração & dosagem , Frutose/análogos & derivados , Frutose/efeitos adversos , Frutose/uso terapêutico , Frutose/administração & dosagemRESUMO
Importance: Obesity affects approximately 19% of women and 14% of men worldwide and is associated with increased morbidity. Antiobesity medications (AOMs) modify biological processes that affect appetite and significantly improve outcomes, such as type 2 diabetes, hypertension, and dyslipidemia. Observations: AOMs should be administered in combination with lifestyle interventions and can be classified according to their mechanisms of action. Orlistat modifies digestive tract absorption and causes gastrointestinal adverse effects, such as oily fecal spotting and urgency, in more than 25% of patients. Centrally acting drugs, such as phentermine-topiramate and naltrexone-bupropion, regulate appetite in the brain and are associated with constipation in approximately 20% of patients, although the incidence of other adverse effects (eg, paresthesia, nausea) varies by medication. Nutrient-stimulated hormone-based medications, such as liraglutide, semaglutide, and tirzepatide, mimic the actions of enteropancreatic hormones that modify central appetite regulation and provide multiple cardiometabolic weight-loss benefits. Adverse effects of these drugs include nausea (28%-44%), diarrhea (21%-30%), and constipation (11%-24%). The relative potency of adult obesity medications has been studied in meta-analyses. Compared with placebo, orlistat was associated with 3.1% greater weight loss (52 randomized clinical trials [RCTs]; 16â¯964 participants), phentermine-topiramate was associated with 8.0% greater weight loss (5 RCTs; 3407 participants), naltrexone-bupropion was associated with 4.1% greater weight loss (6 RCTs; 9949 participants), liraglutide was associated with 4.7% greater weight loss (18 RCTs; 6321 participants), semaglutide was associated with 11.4% greater weight loss (5 RCTs; 4421 participants), and tirzepatide 15 mg was associated with 12.4% greater weight loss (6 RCTs; 1972 participants). Conclusion and Relevance: Obesity is associated with increased morbidity. Antiobesity medications are effective adjunctive therapy to lifestyle changes for improved weight loss and health outcomes.
Assuntos
Fármacos Antiobesidade , Dieta Saudável , Obesidade , Feminino , Humanos , Masculino , Fármacos Antiobesidade/uso terapêutico , Fármacos Antiobesidade/efeitos adversos , Bupropiona/uso terapêutico , Bupropiona/efeitos adversos , Combinação de Medicamentos , Frutose/análogos & derivados , Frutose/uso terapêutico , Frutose/efeitos adversos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Lactonas/uso terapêutico , Lactonas/efeitos adversos , Liraglutida/uso terapêutico , Liraglutida/efeitos adversos , Naltrexona/uso terapêutico , Naltrexona/efeitos adversos , Obesidade/dietoterapia , Obesidade/tratamento farmacológico , Orlistate/uso terapêutico , Fentermina/uso terapêutico , Fentermina/efeitos adversos , Topiramato/uso terapêutico , Topiramato/efeitos adversos , Redução de Peso/efeitos dos fármacos , Terapia Combinada/métodosAssuntos
Anticonvulsivantes , Lamotrigina , Topiramato , Ácido Valproico , Humanos , Lamotrigina/uso terapêutico , Lamotrigina/efeitos adversos , Topiramato/uso terapêutico , Topiramato/efeitos adversos , Ácido Valproico/uso terapêutico , Ácido Valproico/efeitos adversos , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/efeitos adversos , Feminino , Transtorno Autístico/tratamento farmacológico , Masculino , Criança , Frutose/análogos & derivados , Frutose/efeitos adversos , Frutose/uso terapêutico , Triazinas/uso terapêutico , Triazinas/efeitos adversos , Pré-EscolarRESUMO
Prescriptions for antiseizure medications (ASMs) have been rapidly growing over the last several decades due, in part, to an expanding list of clinical indications for which they are now prescribed. This trend has raised concern for potential adverse neurodevelopmental outcomes in ASM-exposed pregnancies. Recent large scale population studies have suggested that the use of topiramate (TOPAMAX, Janssen-Cilag), when prescribed for seizure control, migraines, and/or weight management, is associated with an increased risk for autism spectrum disorder (ASD), intellectual disability, and attention-deficit/hyperactivity disorder (ADHD) in exposed offspring. Here, we critically review epidemiologic evidence demonstrating the neurobehavioral teratogenicity of topiramate and speculate on the neuromolecular mechanisms by which prenatal exposure may perturb neurocognitive development. Specifically, we explore the potential role of topiramate's pharmacological interactions with ligand- and voltage-gated ion channels, especially GABAergic signaling, its effects on DNA methylation and histone acetylation, whether topiramate induces oxidative stress, and its association with fetal growth restriction as possible mechanisms contributing to neurodevelopmental toxicity. Resolving this biology will be necessary to reduce the risk of adverse pregnancy outcomes caused by topiramate or other ASMs.
Assuntos
Anticonvulsivantes , Topiramato , Topiramato/toxicidade , Humanos , Gravidez , Anticonvulsivantes/toxicidade , Feminino , Efeitos Tardios da Exposição Pré-Natal , Transtornos do Neurodesenvolvimento/induzido quimicamente , Animais , Frutose/análogos & derivados , Frutose/toxicidadeRESUMO
The lithium-pilocarpine model is commonly used to recapitulate characteristics of human intractable focal epilepsy. In the current study, we explored the impact of topiramate (TPM) alone and in combination with pregabalin and lacosamide administration for 6 weeks on the evolution of spontaneous recurrent seizures (SRS) and disease-modifying potential on associated neuropsychiatric comorbidities. In addition, redox impairments and neurodegeneration in hippocampus regions vulnerable to temporal lobe epilepsy (TLE) were assessed by cresyl violet staining. Results revealed that acute electrophysiological (EEG) profiling of the ASD cocktail markedly halted sharp ictogenic spikes as well as altered dynamics of brain wave oscillations thus validating the need for polytherapy vs. monotherapy. In TLE animals, pharmacological intervention for 6 weeks with topiramate 10 mg/kg in combination with PREG and LAC at the dose of 20 mg/kg exhibited marked protection from SRS incidence, improved body weight, offensive aggression, anxiety-like behavior, cognitive impairments, and depressive-like behavior (p < 0.05). Moreover, combination therapy impeded redox impairments as evidenced by decreased MDA and AchE levels and increased activity of antioxidant SOD, GSH enzymes. Furthermore, polytherapy rescued animals from SE-induced neurodegeneration with increased neuronal density in CA1, CA3c, CA3ab, hilus, and granular cell layer (GCL) of the dentate gyrus. In conclusion, early polytherapy with topiramate in combination with pregabalin and lacosamide prompted synergy and prevented epileptogenesis with associated psychological and neuropathologic alterations.
Assuntos
Modelos Animais de Doenças , Eletroencefalografia , Lacosamida , Fármacos Neuroprotetores , Pregabalina , Topiramato , Animais , Lacosamida/farmacologia , Lacosamida/uso terapêutico , Topiramato/farmacologia , Topiramato/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Masculino , Pregabalina/farmacologia , Pregabalina/uso terapêutico , Ratos , Comportamento Animal/efeitos dos fármacos , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Quimioterapia Combinada , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Hipocampo/patologia , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/fisiopatologia , Ratos Wistar , Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/fisiopatologia , Epilepsia do Lobo Temporal/induzido quimicamenteRESUMO
BACKGROUND: Acupuncture has been used for the treatment of chronic migraine, but high-quality evidence is scarce. We aimed to evaluate acupuncture's efficacy and safety compared to topiramate for chronic migraine. METHODS: This double-dummy randomized controlled trial included participants aged 18-65 years diagnosed with chronic migraine. They were randomly assigned (1:1) to receive acupuncture (three sessions/week) plus topiramate placebo (acupuncture group) or topiramate (50-100â mg/day) plus sham acupuncture (topiramate group) over 12 weeks, with the primary outcome being the mean change in monthly migraine days during weeks 1-12. RESULTS: Of 123 screened patients, 60 (mean age 45.8, 81.7% female) were randomly assigned to acupuncture or topiramate groups. Acupuncture demonstrated significantly greater reductions in monthly migraine days than topiramate (weeks 1-12: -2.79 [95% CI: -4.65 to -0.94, p = 0.004]; weeks 13-24: -3.25 [95% CI: -5.57 to -0.92, p = 0.007]). No severe adverse events were reported. CONCLUSIONS: Acupuncture may be safe and effective for treating chronic migraine. The efficacy of 12 weeks of acupuncture was sustained for 24 weeks and superior to that of topiramate. Acupuncture can be used as an optional preventive therapy for chronic migraine. TRIAL REGISTRATION: ISRCTN.org Identifier 13563102.
Assuntos
Terapia por Acupuntura , Transtornos de Enxaqueca , Topiramato , Humanos , Topiramato/uso terapêutico , Topiramato/administração & dosagem , Transtornos de Enxaqueca/prevenção & controle , Transtornos de Enxaqueca/terapia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Terapia por Acupuntura/métodos , Doença Crônica , Resultado do Tratamento , Método Simples-Cego , Adulto Jovem , Terapia Combinada/métodos , Adolescente , IdosoRESUMO
The R-type voltage-gated calcium channel CaV2.3 is predominantly located in the presynapse and is implicated in distinct types of epileptic seizures. It has consequently emerged as a molecular target in seizure treatment. Here, we determined the cryo-EM structure of the CaV2.3-α2δ1-ß1 complex in the topiramate-bound state at a 3.0 Å resolution. We provide a snapshot of the binding site of topiramate, a widely prescribed antiepileptic drug, on a voltage-gated ion channel. The binding site is located at an intracellular juxtamembrane hydrophilic cavity. Further structural analysis revealed that topiramate may allosterically facilitate channel inactivation. These findings provide fundamental insights into the mechanism underlying the inhibitory effect of topiramate on CaV and NaV channels, elucidating a previously unseen modulator binding site and thus pointing toward a route for the development of new drugs.
Assuntos
Anticonvulsivantes , Canais de Cálcio Tipo R , Microscopia Crioeletrônica , Topiramato , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Topiramato/química , Topiramato/farmacologia , Humanos , Regulação Alostérica/efeitos dos fármacos , Canais de Cálcio Tipo R/química , Canais de Cálcio Tipo R/metabolismo , Sítios de Ligação , Modelos Moleculares , Células HEK293 , Conformação Proteica , Frutose/química , Frutose/análogos & derivados , Frutose/metabolismo , Animais , Proteínas de Transporte de CátionsAssuntos
Anticonvulsivantes , Complicações na Gravidez , Topiramato , Humanos , Feminino , Gravidez , Topiramato/efeitos adversos , Topiramato/uso terapêutico , Anticonvulsivantes/efeitos adversos , Complicações na Gravidez/tratamento farmacológico , Frutose/análogos & derivados , Frutose/efeitos adversosAssuntos
Gabapentina , Ketamina , Topiramato , Humanos , Gabapentina/uso terapêutico , Gabapentina/administração & dosagem , Ketamina/uso terapêutico , Ketamina/administração & dosagem , Topiramato/uso terapêutico , Topiramato/administração & dosagem , Adulto , Masculino , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Feminino , Quimioterapia CombinadaRESUMO
Topiramate (TPM) is an antiepileptic drug used for treating epilepsy in children, and migraine in teenagers. In this context, preclinical studies with adult female rats observed reproductive system abnormalities following treatment with TPM. Additionally, exposure to endocrine disruptors during developmental plasticity periods, such as childhood and adolescence, may influence characteristics in the adult individual. This study evaluated whether treatment with TPM during developmental periods influences the reproductive system of female rats either immediately or in adult life. Female Wistar rats were treated with TPM (41â¯mg/Kg/day) by oral gavage from postnatal day (PND) 16-28, or PND 28-50, which correspond to childhood and adolescence, respectively, and euthanized either 24â¯h after the final administration or during adulthood. Treatment with TPM during adolescence induced short-term increase in uterus and ovary weights and reduction in endometrial stroma thickness. Adult animals treated during adolescence displayed reduced primordial ovarian follicles' numbers, and increased primary and pre-antral ovarian follicles' numbers. Treatment during childhood induced no short or long-term differences. These results indicate TPM treatment during adolescence is capable of inducing short and long-term alterations on the reproductive system of female Wistar rats.