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1.
Gene ; 805: 145907, 2021 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-34411648

RESUMO

The gene polymorphisms of ABCB1, EPHX1, and SCN1A were found to influence carbamazepine (CBZ) metabolism and resistance in epilepsy patients, but the relevance remains controversial. To reveal the relationships among the gene polymorphisms of ABCB1, EPHX1, SCN1A and the metabolism and resistance of CBZ, the databases of PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals, China Biology medicine disc and Wan Fang were retrieved for suitable studies up to April 2021. 18 studies containing 3293 epilepsy patients were included. The result revealed the gene polymorphism of ABCB1 c.3435C > T is significantly associated with altered concentration-dose ratios of CBZ (CDRCBZ) (CC vs. CT, OR = 0.25 (95% CI: 0.08-0.42), P = 0.004), and EPHX c.416A > G gene polymorphism may also significantly adjusted the concentration-dose ratios of carbamazepine-10, 11-trans dihydrodiol (CDRCBZD) (AA vs. GG, OR = 0.48 (95% CI: 0.01-0.96), P = 0.045; AG vs. GG, OR = 0.68 (95% CI: 0.16-1.20), P = 0.010, respectively) and the ratio of CBZD:carbamazepine-10,11-epoxide (CBZE) (CDRCBZD:CDRCBZE) (AG vs GG, OR = 0.83 (95% CI: 0.31-1.36), P = 0.002). Furthermore, ABCB1 c.3435C > T polymorphism was also observed to be significantly influenced CBZ resistance (CC vs TT, OR = 1.78 (95% CI: 1.17-2.72), P = 0.008; CT vs TT, OR = 1.60 (95% CI: 1.12-2.30), P = 0.01; CC + CT vs TT, OR = 1.61 (95% CI: 1.15-2.26), P = 0.006, respectively). Therefore, CBZ metabolism and resistance in patients with epilepsy may be adjusted by the gene polymorphisms of ABCB1 c.3435C > T and EPHX1 c.416A > G which provides the further scientific basis for clinical individualized therapy of epilepsy. However, larger sample size studies are still needed to provide further conclusive evidence.


Assuntos
Carbamazepina/metabolismo , Epóxido Hidrolases/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adulto , Anticonvulsivantes/farmacologia , Carbamazepina/sangue , Carbamazepina/farmacologia , China , Bases de Dados Genéticas , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , Epóxido Hidrolases/metabolismo , Feminino , Genótipo , Humanos , Masculino , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Polimorfismo de Nucleotídeo Único/genética
2.
J Neurosci ; 41(43): 8991-9007, 2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34446571

RESUMO

Different peripheral nerve injuries cause neuropathic pain through distinct mechanisms. Even the site of injury may impact underlying mechanisms, as indicated by the clinical finding that the antiseizure drug carbamazepine (CBZ) relieves pain because of compression injuries of trigeminal but not somatic nerves. We leveraged this observation in the present study hypothesizing that because CBZ blocks voltage-gated sodium channels (VGSCs), its therapeutic selectivity reflects differences between trigeminal and somatic nerves with respect to injury-induced changes in VGSCs. CBZ diminished ongoing and evoked pain behavior in rats with chronic constriction injury (CCI) to the infraorbital nerve (ION) but had minimal effect in rats with sciatic nerve CCI. This difference in behavior was associated with a selective increase in the potency of CBZ-induced inhibition of compound action potentials in the ION, an effect mirrored in human trigeminal versus somatic nerves. The increase in potency was associated with a selective increase in the efficacy of the NaV1.1 channel blocker ICA-121431 and NaV1.1 protein in the ION, but no change in NaV1.1 mRNA in trigeminal ganglia. Importantly, local ICA-121431 administration reversed ION CCI-induced hypersensitivity. Our results suggest a novel therapeutic target for the treatment of trigeminal neuropathic pain.SIGNIFICANCE STATEMENT This study is based on evidence of differences in pain and its treatment depending on whether the pain is above (trigeminal) or below (somatic) the neck, as well as evidence that voltage-gated sodium channels (VGSCs) may contribute to these differences. The focus of the present study was on channels underlying action potential propagation in peripheral nerves. There were differences between somatic and trigeminal nerves in VGSC subtypes underlying action potential propagation both in the absence and presence of injury. Importantly, because the local block of NaV1.1 in the trigeminal nerve reverses nerve injury-induced mechanical hypersensitivity, the selective upregulation of NaV1.1 in trigeminal nerves suggests a novel therapeutic target for the treatment of pain associated with trigeminal nerve injury.


Assuntos
Analgésicos não Narcóticos/uso terapêutico , Carbamazepina/uso terapêutico , Neuralgia/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Neuralgia do Trigêmeo/tratamento farmacológico , Analgésicos não Narcóticos/farmacologia , Animais , Carbamazepina/farmacologia , Feminino , Masculino , Canal de Sódio Disparado por Voltagem NAV1.1/biossíntese , Neuralgia/metabolismo , Medição da Dor/métodos , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Neuralgia do Trigêmeo/metabolismo
3.
Am J Physiol Renal Physiol ; 320(5): F963-F971, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33843270

RESUMO

Psychotropic drugs may be associated with hyponatremia, but an understanding of how they induce water retention in the kidney remains elusive. Previous studies have postulated that they may increase vasopressin production in the hypothalamus without supporting evidence. In this study, we investigated the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis using haloperidol, sertraline, and carbamazepine. Haloperidol, sertraline, or carbamazepine were treated in inner medullary collecting duct (IMCD) suspensions and primary cultured IMCD cells prepared from male Sprague-Dawley rats. The responses of intracellular cAMP production, aquaporin-2 (AQP2) protein expression and localization, vasopressin-2 receptor (V2R) and AQP2 mRNA, and cAMP-responsive element-binding protein (CREB) were tested with and without tolvaptan and the protein kinase A (PKA) inhibitors H89 and Rp-cAMPS. In IMCD suspensions, cAMP production was increased by haloperidol, sertraline, or carbamazepine and was relieved by tolvaptan cotreatment. In primary cultured IMCD cells, haloperidol, sertraline, or carbamazepine treatment increased total AQP2 and decreased phosphorylated Ser261-AQP2 protein expression. Notably, these responses were reversed by cotreatment with tolvaptan or a PKA inhibitor. AQP2 membrane trafficking was induced by haloperidol, sertraline, or carbamazepine and was also blocked by cotreatment with tolvaptan or a PKA inhibitor. Furthermore, upregulation of V2R and AQP2 mRNA and phosphorylated CREB was induced by haloperidol, sertraline, or carbamazepine and was blocked by tolvaptan cotreatment. We conclude that, in the rat IMCD, psychotropic drugs upregulate AQP2 via V2R-cAMP-PKA signaling in the absence of vasopressin stimulation. The vasopressin-like action on the kidney appears to accelerate AQP2 transcription and dephosphorylate AQP2 at Ser261.NEW & NOTEWORTHY It is unclear whether antipsychotic drugs can retain water in the kidney in the absence of vasopressin. This study demonstrates that haloperidol, sertraline, and carbamazepine can produce nephrogenic syndrome of inappropriate antidiuresis because they directly upregulate vasopressin-2 receptor and aquaporin-2 (AQP2) via cAMP/PKA signaling. We showed that, in addition to AQP2 trafficking, AQP2 protein abundance was rapidly increased by treatment with antipsychotic drugs in association with dephosphorylation of AQP2 at Ser261 and accelerated AQP2 transcription.


Assuntos
Aquaporina 2/metabolismo , Fármacos do Sistema Nervoso Central/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Túbulos Renais Coletores/citologia , Receptores de Vasopressinas/metabolismo , Animais , Carbamazepina/administração & dosagem , Carbamazepina/farmacologia , Fármacos do Sistema Nervoso Central/administração & dosagem , AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Quimioterapia Combinada , Regulação da Expressão Gênica/efeitos dos fármacos , Haloperidol/administração & dosagem , Haloperidol/farmacologia , Masculino , Fosforilação , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Vasopressinas/genética , Sertralina/administração & dosagem , Sertralina/farmacologia , Vasopressinas/administração & dosagem , Vasopressinas/farmacologia
4.
Biomed Res Int ; 2021: 6685806, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33816628

RESUMO

Carbamazepine (CBZ) is an antiepileptic drug having low bioavailability due to its hydrophobic nature. In the current study, efforts are made to investigate the effect of dicarboxylic acid coformer spacer groups (aliphatic chain length) on physicochemical properties, relative humidity (RH) stability, and oral bioavailability of CBZ cocrystals. Slurry crystallization technique was employed for the preparation of CBZ cocrystals with the following coformers: adipic (AA), glutaric (GA), succinic (SA), and malonic acid (MA). Powder X-ray diffractometry and Fourier-transform infrared spectroscopy confirmed cocrystal preparation. Physicochemical properties, RH stability, and oral bioavailability of cocrystals were investigated. Among the prepared cocrystals, CBZ-GA showed maximum solubility as well as improved dissolution profile (CBZ-GA > CBZ-MA > CBZ-AA > pure CBZ > CBZ-SA) in ethanol. Maximum RH stability was shown by CBZ-AA, CBZ-SA, and CBZ-MA. In vivo studies confirmed boosted oral bioavailability of cocrystals compared to pure CBZ. Furthermore, in vivo studies depicted the oral bioavailability order of cocrystals as CBZ-GA > CBZ-MA > Tegral® > CBZ-AA > CBZ-SA > pure CBZ. Thus, pharmaceutical scientists can effectively employ cocrystallization technique for tuning physicochemical properties of hydrophobic drugs to achieve the desired oral bioavailability. Overall, results reflect no consistent effect of spacer group on physicochemical properties, RH stability, and oral bioavailability of cocrystals.


Assuntos
Carbamazepina , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Carbamazepina/química , Carbamazepina/farmacocinética , Carbamazepina/farmacologia , Cristalização , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Coelhos
5.
Biochem Biophys Res Commun ; 554: 151-157, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33798941

RESUMO

It has been suggested that the intelligence quotient of children born to pregnant women taking 1000 mg or more of valproic acid per day is lower than that of children born to pregnant women taking other antiepileptic drugs. However, the mechanism whereby intelligence quotient is decreased in children exposed to valproic acid during the fetal period has not yet been elucidated. Therefore, we used the human neuroblastoma cell line SH-SY5Y to evaluate the effects of antiepileptic drugs containing valproic acid on nerve cells. We assessed the anti-proliferative effects of drugs in these cells via WST-8 colorimetric assay, using the Cell Counting Kit-8. We also quantified drug effects on axonal elongation from images using ImageJ software. We also evaluated drug effects on mRNA expression levels on molecules implicated in nervous system development and folic acid uptake using real-time PCR. We observed that carbamazepine and lamotrigen were toxic to SH-SY5Y cells at concentrations >500 µM. In contrast, phenytoin and valproic acid were not toxic to these cells. Carbamazepine, lamotrigen, phenytoin, and valproic acid did not affect axonal outgrowth in SH-SY5Y cells. Sodium channel neuronal type 1a (SCN1A) mRNA expression-level ratios increased when valproic acid was supplemented to cells. The overexpression of SCN1A mRNA due to high valproic acid concentrations during the fetal period may affect neurodevelopment. However, since detailed mechanisms have not yet been elucidated, it is necessary to evaluate it by comparing cell axon elongation and SCN1A protein expression due to high-concentration valproic acid exposure.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia/tratamento farmacológico , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Neuroblastoma/tratamento farmacológico , Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Carbamazepina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Criança , Epilepsia/complicações , Epilepsia/metabolismo , Feminino , Humanos , Lamotrigina/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Neuroblastoma/complicações , Neuroblastoma/metabolismo , Fenitoína/farmacologia , Gravidez , Ácido Valproico/farmacologia
6.
Invest Ophthalmol Vis Sci ; 62(1): 2, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33393968

RESUMO

Purpose: To test the effect of different sodium channel blockers on the electrical activity of corneal nociceptors in intact and surgically injured corneas. Methods: In anesthetized guinea pigs, a 4-mm diameter corneal flap was performed in one eye at a midstromal depth using a custom-made microkeratome. At different times after surgery (3 hours to 15 days), the electrical activity of corneal nociceptor fibers was recorded from ciliary nerve filaments in the superfused eye in vitro. Mechanical threshold was measured using calibrated von Frey hairs; chemical stimulation was performed applying 30-second CO2 gas pulses. The characteristics of the spontaneous and stimulus-evoked activity of corneal nociceptors recorded from intact and lesioned corneas, before and after treatment with the sodium channel blockers lidocaine, carbamazepine, and amitriptyline, were compared. Results: No spontaneous or stimulus-evoked impulse activity was detected inside the flap at any of the studied time points. However, both were recorded from mechanonociceptor and polymodal nociceptors fibers in the surrounding corneal tissue, being significantly higher (sensitization) 24 to 48 hours after surgery. In these fibers, none of the tested drugs affected mechanical threshold, but they significantly reduced the CO2 response of polymodal nociceptors of intact and injured corneas. Likewise, they diminished significantly the transient increase in spontaneous and stimulus-evoked activity of sensitized polymodal nociceptors. Conclusions: Na+ channel blockers decrease the excitability of intact and sensitized corneal nociceptor fibers, thus acting as potential tools to attenuate their abnormal activity, which underlies the spontaneous pain, hyperalgesia, and allodynia often accompanying surgical corneal lesions, as occurs after photorefractive surgery.


Assuntos
Córnea/inervação , Regeneração Nervosa/fisiologia , Nociceptores/metabolismo , Nervo Oftálmico/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Amitriptilina/farmacologia , Animais , Carbamazepina/farmacologia , Dióxido de Carbono/toxicidade , Córnea/cirurgia , Substância Própria/cirurgia , Eletrofisiologia , Feminino , Cobaias , Lidocaína/farmacologia , Masculino , Fibras Nervosas/fisiologia , Retalhos Cirúrgicos
7.
Epilepsia ; 62(1): 163-175, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33258489

RESUMO

OBJECTIVE: Following surgery, focal seizures relapse in 20% to 50% of cases due to the difficulty of delimiting the epileptogenic zone (EZ) by current imaging or electrophysiological techniques. Here, we evaluate an unbiased metabolomics approach based on ex vivo and in vivo nuclear magnetic resonance spectroscopy (MRS) methods to discriminate the EZ in a mouse model of mesiotemporal lobe epilepsy (MTLE). METHODS: Four weeks after unilateral injection of kainic acid (KA) into the dorsal hippocampus of mice (KA-MTLE model), we analyzed hippocampal and cortical samples with high-resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS). Using advanced multivariate statistics, we identified the metabolites that best discriminate the injected dorsal hippocampus (EZ) and developed an in vivo MEGAPRESS MRS method to focus on the detection of these metabolites in the same mouse model. RESULTS: Multivariate analysis of HRMAS data provided evidence that γ-aminobutyric acid (GABA) is largely increased in the EZ of KA-MTLE mice and is the metabolite that best discriminates the EZ when compared to sham and, more importantly, when compared to adjacent brain regions. These results were confirmed by capillary electrophoresis analysis and were not reversed by a chronic exposition to an antiepileptic drug (carbamazepine). Then, using in vivo noninvasive GABA-edited MRS, we confirmed that a high GABA increase is specific to the injected hippocampus of KA-MTLE mice. SIGNIFICANCE: Our strategy using ex vivo MRS-based untargeted metabolomics to select the most discriminant metabolite(s), followed by in vivo MRS-based targeted metabolomics, is an unbiased approach to accurately define the EZ in a mouse model of focal epilepsy. Results suggest that GABA is a specific biomarker of the EZ in MTLE.


Assuntos
Epilepsia do Lobo Temporal/metabolismo , Hipocampo/metabolismo , Metabolômica , Ácido gama-Aminobutírico/metabolismo , Animais , Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Modelos Animais de Doenças , Eletroforese Capilar , Epilepsia do Lobo Temporal/induzido quimicamente , Agonistas de Aminoácidos Excitatórios/toxicidade , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Ácido Caínico/toxicidade , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética/métodos , Masculino , Camundongos , Análise Multivariada , Espectroscopia de Prótons por Ressonância Magnética/métodos , Esclerose , Ácido gama-Aminobutírico/efeitos dos fármacos
8.
Ann Neurol ; 89(2): 199-211, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33159466

RESUMO

Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin-associated proteins, transcription factors, and RNA-binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach originally developed for cancer called "transcriptome reversal" for these neurodevelopmental disorders. This approach attempts to identify compounds that reverse gene-expression signatures associated with disease states. ANN NEUROL 2021;89:199-211.


Assuntos
Regulação da Expressão Gênica/genética , Células-Tronco Neurais/efeitos dos fármacos , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Neurônios/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anticonvulsivantes/farmacologia , Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Carbamazepina/farmacologia , Simulação por Computador , Descoberta de Drogas , Epirizol/farmacologia , Perfilação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas , Células MCF-7 , Camundongos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Células-Tronco Neurais/metabolismo , Transtornos do Neurodesenvolvimento/genética , Neurônios/metabolismo , Células PC-3 , Perfenazina/farmacologia , Cultura Primária de Células , RNA-Seq , Risperidona/farmacologia , Análise de Célula Única , Trazodona/farmacologia , Trimipramina/farmacologia
9.
Gene ; 771: 145359, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33333223

RESUMO

PURPOSE: Drug-resistant epilepsy is a problem worldwide. Xenobiotic receptors may play a significant role in the establishment of resistance to antiepileptic agents. Previous studies have confirmed that the metabolism and efficacy of carbamazepine (CBZ) can be influenced by xenobiotic receptors, especially pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AHR). Therefore, this study intends to elucidate the pharmacogenomic associations of polymorphisms of these xenobiotic receptors with the CBZ response in epilepsy patients, and these genetic data may be useful for the treatment of clinical prophylaxis and individualized treatment of intractable epilepsy. METHODS: Adult patients with epilepsy who were on CBZ-based monotherapy and combination therapy (n = 257) were genotyped, and the patients were divided into drug-responsive and drug-resistant groups according to the International League Against Epilepsy criteria. We sought to tag single-nucleotide polymorphisms (SNPs) of PXR, CAR and AHR that principally represent alleles associated with drug resistance risk; in addition, a gene interaction analysis reference panel was constructed for SNP-based imputation. RESULTS: No significant effects of PXR or AHR polymorphisms were observed. However, an interaction between the CAR rs2502815 variant and CBZ response was observed: in CBZ-based monotherapy and combination therapy patients, the GG genotype of the CAR rs2502815 variant (vs. wild-type homozygous) was independently associated with CBZ response after adjusting for variables [odds ratio (OR) = 0.389, 95% confidence interval (CI) 0.203-0.743, p = 0.004]. The results of the haplotype and gene interaction case-control analyses of the CBZ response were negative. Our results provide clinical data regarding the genetic possibilities of drug responses related to CAR variation in epilepsy patients. CONCLUSION: This study is the first to indicate a potentially relevant interaction between the CAR rs2502815 polymorphism and the CBZ response in epilepsy patients.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carbamazepina/administração & dosagem , Resistência a Medicamentos , Epilepsia/tratamento farmacológico , Receptor de Pregnano X/genética , Receptores de Hidrocarboneto Arílico/genética , Receptores Citoplasmáticos e Nucleares/genética , Adolescente , Adulto , Carbamazepina/farmacologia , Estudos de Casos e Controles , Criança , Epilepsia/genética , Feminino , Estudos de Associação Genética , Haplótipos , Humanos , Masculino , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Medicina de Precisão , Resultado do Tratamento , Adulto Jovem
10.
Neurosurg Rev ; 44(2): 1119-1125, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32333283

RESUMO

OBJECTIVE: To determine whether diabetes mellitus (DM) contributes to the drug resistance of carbamazepine (CBZ), we investigated the correlation between the blood glucose status and the CBZ resistance condition in patients with trigeminal neuralgia (TN). PATIENTS AND METHODS: A total of 155 TN patients treated with the CBZ monotherapy were selected at Shanghai General Hospital and Shanghai Xinhua Hospital from September 2018 to January 2020. Among them, 15 were diagnosed with DM. Patients' CBZ resistance levels were evaluated according to progression-free survival. We utilized ordered multiple classification logistic regression to determine the dominant factors leading to CBZ resistance. We analyzed the correlation between hemoglobin A1c (HbA1c) and progression-free survival using the Pearson correlation analysis. RESULTS: The regression analysis showed that DM was the only factor affecting CBZ resistance (p = 0.035; OR = 0.327; 95% CI, 0.115-0.926). Progression-free survival was 28.5 ± 21.2 months in the DM group and 66.0 ± 33.2 months in the non-DM group. The concentration of HbA1c in the blood was negatively correlated with progression-free survival (r = - 0.197; p = 0.014). CONCLUSIONS: This study shows that blood glucose status is a significant factor contributing to the CBZ resistance in the treatment of TN. The progression-free survival of patients is affected by the status of DM and blood HbAlc levels.


Assuntos
Carbamazepina/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Resistência a Medicamentos/fisiologia , Neuralgia do Trigêmeo/tratamento farmacológico , Neuralgia do Trigêmeo/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos não Narcóticos/farmacologia , Analgésicos não Narcóticos/uso terapêutico , Carbamazepina/farmacologia , China/epidemiologia , Estudos de Coortes , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neuralgia do Trigêmeo/diagnóstico
11.
Int J Mol Sci ; 21(23)2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33297570

RESUMO

Fragile X syndrome (FXS) is a leading genetic disorder of intellectual disability caused by the loss of the functional fragile X mental retardation protein (FMRP). To date, there is no efficacious mechanism-based medication for FXS. With regard to potential disease mechanisms in FXS, it is widely accepted that the lack of FMRP causes elevated protein synthesis and deregulation of neuronal signaling. Abnormal enhancement of the ERK½ (extracellular signal-regulated kinase ½) and PI3K-Akt (Phosphoinositide 3 kinase-protein kinase B) signaling pathways has been identified in both FXS patients and FXS mouse models. In this study, we show that carbamazepine, which is an FDA-approved drug and has been mainly used to treat seizure and neuropathic pain, corrects cognitive deficits including passive avoidance and object location memory in FXS mice. Carbamazepine also rescues hyper locomotion and social deficits. At the cellular level, carbamazepine dampens the elevated level of ERK½ and Akt signaling as well as protein synthesis in FXS mouse neurons. Together, these results advocate repurposing carbamazepine for FXS treatment.


Assuntos
Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Neurônios/efeitos dos fármacos , Animais , Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Células Cultivadas , Cognição , Reposicionamento de Medicamentos , Locomoção , Sistema de Sinalização das MAP Quinases , Masculino , Memória , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
12.
Epilepsy Behav ; 113: 107580, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33242771

RESUMO

BACKGROUND: Cognitive and psychiatric problems are common in people with epilepsy. They can have multiple causes, including structural brain lesions, the active epilepsy, and the effect of anti-epileptic therapy. Since patients' treatment compliance and quality of life are affected by cognitive and emotional status, it is crucial for clinicians to understand how anti-seizure medications (ASMs) affect cognition and mood, and to choose the proper ASM. OBJECTIVE: To conduct a literature review of the impact on cognition and mood status of lacosamide (LCM) in people with epilepsy. METHODS: Wesearched PubMed, the Cochrane Database of Systematic Reviews and reference lists of articles for all types of articles with no limitations on publication date. RESULTS: A total of 251 records were obtained, including 247 articles in PubMed and 4 articles from reference lists. We included 2 meta-analyses, one randomized controlled trials and 14 observational studies after the screening process. Most studies agree LCM has low risk of treatment-emergent adverse events (TEAEs) on cognition. Comparisons with other ASMs, LCM may be preferable to carbamazepine, topiramate and perampanel, and not inferior to lamotrigine. In spite of low incident rate, depression is the most common psychiatric change of LCM. There are no consistent positive or negative psychiatric effects of LCM. CONCLUSION: Lacosamide has limited impact on cognitive and mood status in this review. Several factors including mechanism of co-administration of ASMs and personal history of psychiatric disorder should be considered as important in the development of cognitive and psychiatric side effects. However, the heterogeneity between studies make the quality of evidence weaker and further trials are needed.


Assuntos
Anticonvulsivantes/farmacologia , Cognição/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Lacosamida/farmacologia , Adulto , Afeto/efeitos dos fármacos , Anticonvulsivantes/uso terapêutico , Carbamazepina/farmacologia , Carbamazepina/uso terapêutico , Epilepsia/psicologia , Humanos , Lacosamida/uso terapêutico , Lamotrigina/farmacologia , Lamotrigina/uso terapêutico , Nitrilas , Piridonas , Qualidade de Vida , Topiramato/farmacologia , Topiramato/uso terapêutico
13.
Ann Clin Transl Neurol ; 7(9): 1488-1501, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32750235

RESUMO

OBJECTIVE: We identified a novel de novo SCN2A variant (M1879T) associated with infantile-onset epilepsy that responded dramatically to sodium channel blocker antiepileptic drugs. We analyzed the functional and pharmacological consequences of this variant to establish pathogenicity, and to correlate genotype with phenotype and clinical drug response. METHODS: The clinical and genetic features of an infant boy with epilepsy are presented. We investigated the effect of the variant using heterologously expressed recombinant human NaV 1.2 channels. We performed whole-cell patch clamp recording to determine the functional consequences and response to carbamazepine. RESULTS: The M1879T variant caused disturbances in channel inactivation including substantially depolarized voltage dependence of inactivation, slower time course of inactivation, and enhanced resurgent current that collectively represent a gain-of-function. Carbamazepine partially normalized the voltage dependence of inactivation and produced use-dependent block of the variant channel at high pulsing frequencies. Carbamazepine also suppresses resurgent current conducted by M1879T channels, but this effect was explained primarily by reducing the peak transient current. Molecular modeling suggests that the M1879T variant disrupts contacts with nearby residues in the C-terminal domain of the channel. INTERPRETATION: Our study demonstrates the value of conducting functional analyses of SCN2A variants of unknown significance to establish pathogenicity and genotype-phenotype correlations. We also show concordance of in vitro pharmacology using heterologous cells with the drug response observed clinically in a case of SCN2A-associated epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Epilepsia , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Idade de Início , Fenômenos Eletrofisiológicos/fisiologia , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Epilepsia/genética , Epilepsia/fisiopatologia , Estudos de Associação Genética , Humanos , Lactente , Masculino
14.
Eur J Pharmacol ; 886: 173413, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758572

RESUMO

The antiepileptic sodium channel blocker, carbamazepine, has long been known to be able to attenuate cAMP signals. This could be of clinical importance since cAMP signaling has been shown to be involved in epileptogenesis and seizures. However, no information on the ability to affect cAMP signaling is available for the marketed structural derivatives, oxcarbazepine and eslicarbazepine acetate or their dominating metabolite, licarbazepine. Thus, we employed a HEK293 cell line stably expressing a cAMP biosensor to assess the effect of these two drugs on cAMP accumulation. We find that oxcarbazepine does not affect cAMP accumulation whereas eslicarbazepine acetate, surprisingly, is able to enhance cAMP accumulation. Since the transcription of ADCY8 (adenylyl cyclase isoform 8; AC8) has been found to be elevated in epileptic tissue from patients, we subsequently expressed AC8 in the HEK293 cells. In the AC8-expressing cells, oxcarbazepine was now able to attenuate whereas eslicarbazepine maintained its ability to increase cAMP accumulation. However, at all concentrations tested, licarbazepine demonstrated no effect on cAMP accumulation. Thus, we conclude that the effects exerted by carbamazepine and its derivatives on cAMP accumulation do not correlate with their clinical efficacy in epilepsy. However, this does not disqualify cAMP signaling per se as a potential disease-modifying drug target for epilepsy since more potent and selective inhibitors may be of therapeutic value.


Assuntos
Anticonvulsivantes/farmacologia , Carbamazepina/análogos & derivados , Carbamazepina/farmacologia , AMP Cíclico , Epilepsia/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Adenilil Ciclases/biossíntese , Adenilil Ciclases/efeitos dos fármacos , Anticonvulsivantes/química , Sinalização do Cálcio/efeitos dos fármacos , Carbamazepina/química , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dibenzazepinas/farmacologia , Células HEK293 , Humanos , Oxcarbazepina/farmacologia , Convulsões/tratamento farmacológico , Resultado do Tratamento
15.
Epilepsia ; 61(9): 2022-2034, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32757210

RESUMO

OBJECTIVE: Initial identification of new investigational drugs for the treatment of epilepsy is commonly conducted in well-established mouse acute and chronic seizure models: for example, maximal electroshock (MES), 6 Hz, and corneal kindling. Comparison of the median effective dose (ED50) of approved antiseizure drugs (ASDs) vs investigational agents in these models provides evidence of their potential for clinical efficacy. Inbred and outbred mouse strains exhibit differential seizure susceptibility. However, few comparisons exist of the ED50 or median behaviorally impairing dose (TD50) of prototype ASDs in these models in inbred C57Bl/6 vs outbred CF-1 mice, both of which are often used for ASD discovery. METHODS: We defined the strain-related ED50s and TD50s of several mechanistically distinct ASDs across established acute seizure models (MES, 6 Hz, and corneal-kindled mouse). We further quantified the strain-related effect of the MES ED50 of each ASD on gross behavior in a locomotor activity assay. Finally, we describe a novel pharmacoresistant corneal-kindling protocol that is suitable for moderate-throughput ASD screening and demonstrates highly differentiated ASD sensitivity. RESULTS: We report significant strain-related differences in the MES ED50 of valproic acid (CF-1 ED50: 90 mg/kg [95% confidence interval (CI) 165-214] vs C57Bl/6: 276 mg/kg [226-366]), as well as significant differences in the ED50 of levetiracetam in the pharmacoresistant 6 Hz test (CF-1: 22.5 mg/kg [14.7-30.2] vs C57Bl/6: >500 mg/kg [CI not defined]). There were no differences in the calculated TD50 of these ASDs between strains. Furthermore, the MES ED50 of phenobarbital significantly enhanced locomotor activity of outbred CF-1, but not C57Bl/6, mice. SIGNIFICANCE: Altogether, this study provides strain-related information to differentiate investigational agents from ASD standards-of-care in commonly employed preclinical discovery models and describes a novel kindled seizure model to further explore the mechanisms of drug-resistant epilepsy.


Assuntos
Animais não Endogâmicos , Anticonvulsivantes/farmacologia , Modelos Animais de Doenças , Epilepsia Resistente a Medicamentos/fisiopatologia , Locomoção/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Convulsões/fisiopatologia , Animais , Anticonvulsivantes/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Carbamazepina/farmacologia , Carbamazepina/uso terapêutico , Córnea , Diazepam/farmacologia , Diazepam/uso terapêutico , Relação Dose-Resposta a Droga , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Eletrochoque , Excitação Neurológica , Lamotrigina/farmacologia , Lamotrigina/uso terapêutico , Levetiracetam/farmacologia , Levetiracetam/uso terapêutico , Camundongos , Camundongos Endogâmicos , Teste de Campo Aberto , Fenobarbital/farmacologia , Fenobarbital/uso terapêutico , Convulsões/tratamento farmacológico , Resultado do Tratamento , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico
16.
Lancet Neurol ; 19(9): 784-796, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32822636

RESUMO

Trigeminal neuralgia is a very painful neurological condition with severe, stimulus-evoked, short-lasting stabbing pain attacks in the face. The past decade has offered new insights into trigeminal neuralgia symptomatology, pathophysiology, and treatment, leading to a change in the classification of the condition. An accurate diagnosis is crucial because neuroimaging interpretation and clinical management differ among the various forms of facial pain. MRI using specific sequences should be a part of the diagnostic workup to detect a possible neurovascular contact and exclude secondary causes. Demonstration of a neurovascular contact should not be used to confirm a diagnosis but rather to facilitate surgical decision making. Carbamazepine and oxcarbazepine are drugs of first choice for long-term treatment, whereas microvascular decompression is the first-line surgery in medically refractory patients. Advances in neuroimaging techniques and animal models will provide further insight into the causes of trigeminal neuralgia and its pathophysiology. Development of more efficacious treatment options is highly warranted.


Assuntos
Gerenciamento Clínico , Neuralgia do Trigêmeo/diagnóstico por imagem , Neuralgia do Trigêmeo/fisiopatologia , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Carbamazepina/farmacologia , Carbamazepina/uso terapêutico , Descompressão Cirúrgica/métodos , Humanos , Neuroimagem/métodos , Oxcarbazepina/farmacologia , Oxcarbazepina/uso terapêutico , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Neuralgia do Trigêmeo/classificação , Neuralgia do Trigêmeo/terapia
18.
Neurosci Lett ; 736: 135248, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32673692

RESUMO

Trigeminal neuralgia (TN) is a type of neuropathic pain characterized by intense pain; although anticonvulsants are used as an option to relieve pain, adverse side effects can decrease patient adherence. In this context, a low dose of naltrexone is effective in relieving pain in other pain conditions. Thus, the objective of the present study was to evaluate the analgesic effect of low-dose naltrexone on facial mechanical allodynia in a rat model of TN, as well as its effect(s) on biomarkers in the central nervous system (tumor necrosis factor-alpha, brain-derived neurotrophic factor [BDNF], interleukin [IL]-10, and toll-like receptor-4). Fifty-nine adult male Wistar rats (CEUA-HCPA#2017-0575) were allocated to following groups: control; sham-pain + vehicle; sham-pain + carbamazepine (100 mg/kg); sham-pain + naltrexone (0.5 mg/kg); pain + vehicle; pain + carbamazepine; and pain + naltrexone. TN was induced using chronic constriction of the infraorbital nerve. Facial allodynia was assessed using von Frey test. Drugs were administered by gavage 14 days after surgery for 10 days. At baseline, the mechanical threshold was similar between groups (P > 0.05; generalized estimating equation). Seven days after surgery, facial allodynia was observed in sham-TN and pain-TN groups (P < 0.05). Fourteen days after surgery, only pain-TN groups exhibited facial allodynia. The first dose of low-dose naltrexone or carbamazepine partially reversed facial allodynia. After 10 days of treatment, both drugs completely reversed it. Spinal cord levels of BDNF and IL-10 were modulated by low-dose naltrexone. Thus, low-dose naltrexone may be suitable to relieve TN; however, the exact mechanisms need to be clarified.


Assuntos
Hiperalgesia , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Neuralgia do Trigêmeo , Analgésicos não Narcóticos/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carbamazepina/farmacologia , Modelos Animais de Doenças , Dor Facial/metabolismo , Hiperalgesia/metabolismo , Masculino , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Neuralgia do Trigêmeo/metabolismo
19.
Arch Pharm Res ; 43(7): 724-734, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32676893

RESUMO

This work tested the role of carbamazepine in alleviating alloxan-induced diabetic neuropathy and the enhancement of spinal plasticity. Mice were randomized into four groups: normal, control, carbamazepine (25-mg/kg) and carbamazepine (50-mg/kg). Nine weeks after induction of diabetes, symptoms of neuropathy were confirmed and carbamazepine (or vehicle) was given every other day for five weeks. After completing the treatment period, mice were sacrificed and the pathologic features in the spinal cord and the sciatic nerves were determined. The spinal cords were evaluated for synaptic plasticity (growth associated protein-43, GAP43), microglia cell expression (by CD11b) and astrocyte expression (glial fibrillary acidic protein, GFAP). Further, sciatic nerve expression of Nav1.5 was measured. Results revealed that carbamazepine 50 mg/kg prolonged the withdrawal threshold of von-Frey filaments and increased the hot plate jumping time. Carbamazepine improved the histopathologic pictures of the sciatic nerves and spinal cords. Spinal cord of carbamazepine-treated groups had enhanced expression of GAP43 but lower content of CD11b and GFAP. Furthermore, specimens from the sciatic nerve indicated low expression of Nav1.5. In conclusion, this work provided evidence, for the first time, that the preventive effect of carbamazepine against diabetic neuropathy involves correction of spinal neuronal plasticity and glia cell expression.


Assuntos
Carbamazepina/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Proteína GAP-43/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Medula Espinal/efeitos dos fármacos , Aloxano/administração & dosagem , Animais , Carbamazepina/administração & dosagem , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Proteína GAP-43/genética , Hiperalgesia , Injeções Intraperitoneais , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Medula Espinal/química , Medula Espinal/metabolismo
20.
Rev Neurol ; 71(2): 54-60, 2020 Jul 16.
Artigo em Espanhol | MEDLINE | ID: mdl-32627160

RESUMO

INTRODUCTION: Although carbamazepine (CBZ) has strong enzyme-inducing properties, oxcarbazepine (OXC) and eslicarbazepine acetate (ESL) are thought to have a milder effect. These drugs are known to have effects on lipid metabolism and may cause hyponatremia and changes in blood cell counts and liver function tests. AIM: To compare the long-term effects of three antiepileptic drugs (CBZ, OXC and ESL) on these variables. PATIENTS AND METHODS: Retrospective cohort study of consecutive patients treated with CBZ, OXC or ESL. Natremia, lipid concentrations, blood cell counts and liver function tests were compared before, during and at the end of the study period. RESULTS: A total of 292 patients were included. Of these, 143 were treated with CBZ, 55 with OXC and 94 with ESL. CBZ showed a greater impact on lipid metabolism, while OXC was correlated with lower mean sodium levels and a higher frequency of hyponatremia. Lifestyle recommendations related to diet, physical activity and water intake were helpful in overcoming these side effects. No other statistically significant differences were detected. CONCLUSIONS: While CBZ showed a greater impact on lipid metabolism, OXC displayed a higher frequency of hyponatremia. Lifestyle recommendations may be helpful in overcoming these side effects. No other statistically significant differences were found.


Assuntos
Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Dibenzazepinas/farmacologia , Metabolismo/efeitos dos fármacos , Oxcarbazepina/farmacologia , Adulto , Idoso , Alanina Transaminase/sangue , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Aspartato Aminotransferases/sangue , Carbamazepina/efeitos adversos , Carbamazepina/uso terapêutico , Dibenzazepinas/efeitos adversos , Dibenzazepinas/uso terapêutico , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/metabolismo , Feminino , Seguimentos , Estilo de Vida Saudável , Humanos , Hiponatremia/induzido quimicamente , Contagem de Leucócitos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/antagonistas & inibidores , Oxcarbazepina/efeitos adversos , Oxcarbazepina/uso terapêutico , Estudos Retrospectivos , Sódio/sangue , Canais de Sódio Disparados por Voltagem/efeitos dos fármacos , gama-Glutamiltransferase/sangue
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