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1.
World J Microbiol Biotechnol ; 35(12): 186, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31728655

RESUMO

The pollution of aquatic environments by drugs is a problem for which scarce research has been conducted in regards of their removal. Amycolatopsis sp. Poz 14 presents the ability to biotransformation naphthalene at high efficiency, therefore, in this work this bacterium was proposed as an assimilator of naproxen and carbamazepine. Growth curves at different concentrations of naproxen and carbamazepine showed that Amycolatopsis sp. Poz 14 is able to utilize these drugs at a concentration of 50 mg L-1 as a source of carbon and energy. At higher concentrations, the bacterial growth was inhibited. The transformation kinetics of naproxen showed the total elimination of the compound in 18 days, but carbamazepine was only eliminated in 19.9%. The supplementation with cometabolites such as yeast extract and naphthalene (structure similar to naproxen) at 50 mg L-1, showed that the yeast extract shortened the naproxen elimination to 6 days and reached a higher global consumption rate compared to the naphthalene cometabolite. The biotransformation of carbamazepine was not improved by the addition of cometabolites. The partial sequencing of the genome of Amycolatopsis sp. Poz 14 detected genes encoding putative enzymes for the degradation of cyclic aromatic compounds and the activities of aromatic monooxygenase, catechol 1,2-dioxygenase and gentisate 1,2-dioxygenase exhibited their involving in the naproxen biodegradation. The HPLC-MS analysis detected the 5-methoxysalicylic acid at the end of the biotransformation kinetics. This work demonstrates that Amycolatopsis sp. Poz 14 utilizes naproxen and transforms it to 5-methoxysalicylic acid which is the initial compound for the catechol and gentisic acid metabolic pathway.


Assuntos
Actinomycetales/enzimologia , Actinomycetales/metabolismo , Redes e Vias Metabólicas , Naproxeno/metabolismo , Actinomycetales/efeitos dos fármacos , Actinomycetales/crescimento & desenvolvimento , Biodegradação Ambiental , Biotransformação , Carbamazepina/metabolismo , Carbamazepina/farmacologia , Carbono/metabolismo , Catecol 1,2-Dioxigenase , Catecóis , Dioxigenases , Poluição Ambiental , Gentisatos , Éteres de Hidroxibenzoatos/metabolismo , Cinética , Oxigenases de Função Mista , Naftalenos/metabolismo , Naproxeno/farmacologia , Salicilatos/metabolismo
2.
Eur J Med Chem ; 183: 111650, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539780

RESUMO

Inspired by the traditional Chinese herbal pair of Polygala tenuifolia-Acori Tatarinowii for treating epilepsy, 33 novel substituted cinnamic α-asaronol esters and analogues were designed by Combination of Traditional Chinese Medicine Molecular Chemistry (CTCMMC) strategy, synthesized and tested systematically not only for anticonvulsant activity in three mouse models but also for LDH inhibitory activity. Thereinto, 68-70 and 75 displayed excellent and broad spectra of anticonvulsant activities with modest ability in preventing neuropathic pain, as well as low neurotoxicity. The protective indices of these four compounds compared favorably with stiripentol, lacosamide, carbamazepine and valproic acid. 68-70 exhibited good LDH1 and LDH5 inhibitory activities with noncompetitive inhibition type, and were more potent than stiripentol. Notably, 70, as a representative agent, was also shown as a moderately positive allosteric modulator at human α1ß2γ2 GABAA receptors (EC50 46.3 ±â€¯7.3 µM). Thus, 68-70 were promising candidates for developing into anti-epileptic drugs, especially for treatment of refractory epilepsies such as Dravet syndrome.


Assuntos
Anisóis/química , Anticonvulsivantes/química , Cinamatos/química , Medicamentos de Ervas Chinesas/química , Ésteres/química , L-Lactato Desidrogenase/antagonistas & inibidores , Polygala/química , Regulação Alostérica , Animais , Anisóis/farmacologia , Anticonvulsivantes/farmacologia , Carbamazepina/química , Carbamazepina/farmacologia , Cinamatos/farmacologia , Dioxolanos/química , Dioxolanos/farmacologia , Desenho de Drogas , Medicamentos de Ervas Chinesas/farmacologia , Ésteres/farmacologia , Humanos , Medicina Tradicional Chinesa , Camundongos , Estrutura Molecular , Neuralgia/prevenção & controle , Receptores de GABA-A/metabolismo , Relação Estrutura-Atividade , Ácido Valproico/química , Ácido Valproico/farmacologia
3.
Int J Mol Sci ; 20(15)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366130

RESUMO

Carbamazepine (CBZ) binds adenosine receptors, but detailed effects of CBZ on astroglial transmission associated with adenosine receptor still need to be clarified. To clarify adenosinergic action of CBZ on astroglial transmission, primary cultured astrocytes were acutely or chronically treated with CBZ, proinflammatory cytokines (interferon γ (IFNγ) and tumor necrosis factor α (TNFα)), and adenosine A2A receptor (A2AR) agonist (CGS21680). IFNγ and TNFα increased basal, adenophostin-A (AdA)-evoked, and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA)-evoked astroglial L-glutamate releases. In physiological condition, CGS21680 increased basal astroglial L-glutamate release but glutamate transporter inhibition prevented this CGS21680 action. CBZ did not affect basal release, whereas glutamate transporter inhibition generated CBZ-induced glutamate release. Furthermore, AdA-evoked and AMPA-evoked releases were inhibited by CBZ but were unaffected by CGS21680. Contrary to physiological condition, chronic administrations of IFNγ and TNFα enhanced basal, AdA-, and AMPA-evoked releases, whereas IFNγ and TNFα decreased and increased CGS21680-evoked releases via modulation A2AR expression. Both chronic administration of CGS21680 and CBZ suppressed astroglial L-glutamate release responses induced by chronic cytokine exposer. Especifically, chronic administration of CBZ and CGS21680 prevented the reduction and elevation of A2AR expression by respective IFNγ and TNFα. These findings suggest that A2AR agonistic effects of CBZ contribute to chronic prevention of pathomechanisms developments of several neuropsychiatric disorders associated with proinflammatory cytokines.


Assuntos
Astrócitos/efeitos dos fármacos , Carbamazepina/farmacologia , Ácido Glutâmico/metabolismo , Receptor A2A de Adenosina/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacologia , Agonistas do Receptor A2 de Adenosina/farmacologia , Animais , Astrócitos/metabolismo , Células Cultivadas , Interferon gama/farmacologia , Fenetilaminas/farmacologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/farmacologia
4.
Neurosci Lett ; 708: 134363, 2019 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-31276728

RESUMO

We previously reported that treatment with levetiracetam (LEV) after status epilepticus (SE) termination by diazepam (DZP) prevents the development of spontaneous recurrent seizures. LEV suppresses increased expression levels of proinflammatory mediators during epileptogenesis after SE, but how LEV acts in neuroinflammatory processes is not yet known. In this study, we examined the effects of LEV on neuroinflammation and phagocytic microglia in vivo and in vitro and compared the effects of LEV with those of representative antiepileptic drugs valproate (VPA) and carbamazepine (CBZ). Repeated treatment with LEV for 30 days after the termination of pilocarpine-induced SE by DZP almost completely prevented the incidence of spontaneous recurrent seizures, while administration of VPA or CBZ showed no effect on the seizures. LEV clearly suppressed phagocytosis of mononuclear phagocytes, and cytokine expression was observed 2 days after SE. VPA attenuated neuroinflammation only, and CBZ showed no effect on changes after SE. Treatment with LEV significantly suppressed BV-2 microglial activation, which was defined by morphological changes, phagocytic activity and cytokine expression. By contrast, VPA and CBZ did not affect BV-2 microglial activity. In summary, LEV directly suppresses excess microglial phagocytosis during epileptogenesis, which might prevent the occurrence of spontaneous recurrent seizures after SE.


Assuntos
Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Levetiracetam/farmacologia , Microglia/efeitos dos fármacos , Fagócitos/efeitos dos fármacos , Estado Epiléptico/tratamento farmacológico , Ácido Valproico/farmacologia , Animais , Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Células Cultivadas , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Levetiracetam/uso terapêutico , Masculino , Camundongos Endogâmicos ICR , Microglia/patologia , Fagócitos/patologia , Estado Epiléptico/patologia , Estado Epiléptico/fisiopatologia , Ácido Valproico/uso terapêutico
5.
Pak J Pharm Sci ; 32(3): 997-1003, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31278712

RESUMO

The aim of this study was to investigate the antiepileptic effects of duloxetine in the maximal electroshock test and convulsions induced by four compounds: Pentylenetetrazole, 3-mercaptopropionic acid, thiosemicarbazide, and bicuculline. Duloxetine exhibited moderate anticonvulsive activity with an ED50 (median effective dose) of 48.21 mg/kg in the maximal electroshock test in mice. The anticonvulsive action of duloxetine was also confirmed in chemical-induced seizure tests, where this drug decreased tonic convulsions. Single administration of duloxetine (6.25-25 mg/kg) significantly increased the anticonvulsant effects of valproate, carbamazepine, and oxcarbazepine in the maximal electroshock test. Furthermore, pretreatment with thiosemicarbazide (an inhibitor of GABA synthesis enzyme) significantly increased the ED50 of duloxetine, suggesting the GABAergic system may contribute to the anticonvulsive action of duloxetine. These results support the use of duloxetine in the treatment of coexisting depression and epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Cloridrato de Duloxetina/farmacologia , Epilepsia/tratamento farmacológico , Ácido 3-Mercaptopropiônico/farmacologia , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Antidepressivos/farmacologia , Carbamazepina/farmacologia , Depressão/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Sinergismo Farmacológico , Cloridrato de Duloxetina/administração & dosagem , Cloridrato de Duloxetina/efeitos adversos , Eletrochoque/efeitos adversos , Fenclonina/farmacologia , GABAérgicos/farmacologia , Masculino , Camundongos , Síndromes Neurotóxicas/etiologia , Oxcarbazepina/farmacologia , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Semicarbazidas/farmacologia , Ácido Valproico/farmacologia
6.
Talanta ; 202: 221-229, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171174

RESUMO

In Western Europe, river water quality can be assessed using sentinel species such as the amphipod Gammarus fossarum. In this work of environmental metabolomics, the objective was to develop suitable chemometrics methods, using a limited number of individuals, to assess the modification of the metabolism of G. fossarum exposed to two human pharmaceuticals. Males and females gammarids were exposed to a mixture of the anxiolytic oxazepam and the antiepileptic carbamazepine (1000 ng L-1) for 14 days under laboratory conditions according to a full factorial design 2² (repeated 5 times). They were analyzed at the single individual scale using a method including a µQuEChERS type extraction followed by a nanoliquid chromatography analysis coupled to high-resolution mass spectrometry. The molecular fingerprints obtained were investigated using XCMS. Several corrections of experimental drifts (by using lock mass and Quality Control samples) were tested prior to using APCA + method for the exploitation of the unbalanced designed data. Signal reproducibility was greatly improved by the lock mass normalisation. From the experimental design, a significant effect of both experimental factors "exposure to the mixture" and "gammarid gender" on the signals measured were highlighted by APCA+. Finally, the results obtained made it possible to identify variables responsible for each of the factor effects.


Assuntos
Anfípodes/efeitos dos fármacos , Carbamazepina/farmacologia , Nanotecnologia , Oxazepam/farmacologia , Anfípodes/metabolismo , Animais , Cromatografia Líquida , Feminino , Humanos , Masculino , Espectrometria de Massas , Análise de Componente Principal
7.
J Thromb Thrombolysis ; 48(3): 528-531, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31041653

RESUMO

Current guidelines recommend caution in prescribing concomitant use of direct-acting oral anticoagulants (DOACs) and antiepileptic drugs due to drug-drug interactions leading to potential risk of DOACs subtherapeutic concentration and treatment failure. Herein we report a significant interaction between carbamazepine (CZP) and apixaban, causing subtherapeutic concentration of the drug in a patient with atrial fibrillation who had a transient ischemic attack (TIA) episode. Another anti-Xa DOAC, edoxaban, administered to the patient after TIA occurrence did not show significant interaction with CZP. In addition to confirm that cautions should be used when antiepileptic and DOACs are concomitantly prescribed, the present case also demonstrates that, in the management of certain subsets of patients who need anticoagulant treatment, measurement of DOAC plasma concentration can help guide a personalized management and avoid adverse clinical outcomes.


Assuntos
Carbamazepina/farmacologia , Inibidores do Fator Xa/farmacologia , Medicina de Precisão/métodos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Carbamazepina/uso terapêutico , Interações de Medicamentos , Monitoramento de Medicamentos , Inibidores do Fator Xa/uso terapêutico , Humanos , Ataque Isquêmico Transitório/tratamento farmacológico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Tiazóis/farmacologia , Tiazóis/uso terapêutico
8.
Pharmacol Rep ; 71(2): 299-305, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826570

RESUMO

BACKGROUND: To assess the effects of 5-(3-chlorobenzyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP427) on the protective anticonvulsant action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the tonic-clonic seizure model in mice, an isobolographic transformation of data was used. METHODS: Electrically-induced tonic-clonic seizures were experimentally evoked in adult male albino Swiss mice. The anticonvulsant effects of TP427, when used singly, were determined by the calculation of the threshold increasing the dose by 20% (TID20 value). The influence of TP427 on the anticonvulsant potency of four various classical antiepileptic drugs was determined with a subthreshold method. Types of interactions between drugs were determined using the isobolographic transformation of data. Additionally, total brain antiepileptic drug concentrations were measured. RESULTS: TP427, when administered separately, significantly increased the threshold for electroconvulsions. The experimentally determined TID20 value for TP427 was 11.71 mg/kg. Moreover, TP427 (10 mg/kg) significantly increased the anticonvulsant activity of valproate (p < 0.01), but not that of carbamazepine, phenobarbital or phenytoin in the mouse tonic-clonic seizure model. Isobolographic transformation of data confirmed that the interaction between TP427 and valproate was synergistic. Pharmacokinetic study revealed that TP427 increased total brain valproate concentrations, and had no impact on total brain concentrations of carbamazepine, phenobarbital or phenytoin in mice. CONCLUSION: The synergistic interaction between TP427 and valproate in the mouse tonic-clonic seizure model might occur favorable for epilepsy patients in future. The combinations of TP427 with carbamazepine, phenobarbital and phenytoin were additive in the mouse tonic-clonic seizure model and also deserves clinical attention.


Assuntos
Anticonvulsivantes/farmacologia , Convulsões/tratamento farmacológico , Ácido Valproico/farmacologia , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Carbamazepina/administração & dosagem , Carbamazepina/farmacocinética , Carbamazepina/farmacologia , Modelos Animais de Doenças , Interações de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Masculino , Camundongos , Fenobarbital/administração & dosagem , Fenobarbital/farmacocinética , Fenobarbital/farmacologia , Fenitoína/administração & dosagem , Fenitoína/farmacocinética , Fenitoína/farmacologia , Convulsões/fisiopatologia , Ácido Valproico/administração & dosagem , Ácido Valproico/farmacocinética
9.
J Pharm Pharmacol ; 71(6): 982-987, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30793320

RESUMO

OBJECTIVES: Fentanyl is a potent analgesic that accounts for an increasing number of overdose deaths in the United States. This study tested whether altered pharmacokinetics plays a pivotal role in the increased fentanyl dose requirements in patients receiving the enzyme-inducing anticonvulsant, carbamazepine. METHODS: Neurosurgical patients receiving carbamazepine for >6 weeks (N = 11) or no carbamazepine (N = 6, controls) received a single bolus dose of fentanyl (200 µg) intravenously. Plasma was collected before and for up to 9 h after the bolus. Fentanyl concentrations were measured using liquid chromatography-mass spectrometry. Pharmacokinetic variables were derived from plasma concentration-time curves best fitted to a two-compartment model. KEY FINDINGS: Fentanyl clearance was significantly higher in the carbamazepine group compared to controls (mean ± SD: 20.1 ± 6.8 vs 13.2 ± 4.8 ml/min per kg, P < 0.05), and area under the plasma concentration curve (AUC) was significantly lower (150 ± 65 vs 233 ± 70 ng/ml × min, P < 0.02). Volume of distribution was larger in the carbamazepine group, but the difference was not statistically significant (5.4 ± 3.1 vs 3.6 ± 1.2 l/kg, P > 0.15). The terminal elimination half-life did not differ between the two groups. CONCLUSIONS: Chronic carbamazepine therapy leads to increased fentanyl clearance and decreased AUC, which may result in decreased duration of therapeutic plasma concentrations of fentanyl and an increased dose requirement. Assuming that carbamazepine does not change fentanyl pharmacodynamics, patients on chronic carbamazepine therapy may require more frequent or higher fentanyl doses to maintain therapeutic plasma concentrations.


Assuntos
Analgésicos Opioides/farmacocinética , Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Fentanila/farmacocinética , Adulto , Idoso , Analgésicos Opioides/administração & dosagem , Anticonvulsivantes/administração & dosagem , Área Sob a Curva , Carbamazepina/administração & dosagem , Cromatografia Líquida , Relação Dose-Resposta a Droga , Interações de Medicamentos , Feminino , Fentanila/administração & dosagem , Meia-Vida , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Distribuição Tecidual
10.
Pharm Biol ; 57(1): 22-28, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30724642

RESUMO

CONTEXT: Epilepsy is a common life-threatening neurological disorder that is often drug-resistant and associated with cognitive impairment. The traditional Chinese patent medicine Songling Xuemaikang capsules (SXC) is clinically used for epilepsy therapy and alleviation of cognitive impairment. OBJECTIVE: This study investigates the neuronal protective effect of SXC combined with carbamazepine (CBZ) on epilepsy and cognitive impairment in kainic acid-kindled SD rats. MATERIALS AND METHODS: Kainic acid-kindled rats were established by injection of 0.45 µg kainic acid and randomly divided into 5 groups (n = 14): saline (sham-operated), control, CBZ, SXC and CBZ + SXC combined group. Rats in the treatment groups received CBZ (50 mg/kg/d), SXC (600 mg/kg/d) or combined CBZ (50 mg/kg/d) + SXC (600 mg/kg/d) via intragastric injection for 60 days. Epileptic behaviours, cognitive impairment, neuronal apoptosis and expression of p-Akt, Akt and caspase-9 were measured, and the alleviation of cognitive damage and neuronal apoptosis was analyzed. RESULTS: The combined administration of SXC and CBZ significantly decreased the frequency of seizures (1.2 ± 0.3) and the number of episodes (1.3 ± 0.5) above stage III (p < 0.05). Neuronal apoptosis was improved (p < 0.01), and cognitive damage was ameliorated (p < 0.05).The level of p-Akt was enhanced (p < 0.01) whereas the expression of caspase-9 was evidently inhibited (p < 0.01) in the combined group. CONCLUSIONS: The present findings confirm that the combined use of SXC with CBZ can effectively control epileptic seizures, alleviate damage to hippocampal neurons and protect against cognitive impairment. The mechanism of action might be related to the upregulation of p-Akt and inhibition of caspase-9 expression.


Assuntos
Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Epilepsia/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Caspase 9/metabolismo , Cognição/efeitos dos fármacos , Quimioterapia Combinada , Epilepsia/induzido quimicamente , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Ácido Caínico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Distribuição Aleatória , Ratos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
11.
Invert Neurosci ; 19(1): 4, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30734144

RESUMO

Primary mechanism of action of local anesthetics and various anticonvulsants is the voltage-gated sodium channel block. Many of these small molecules also have other targets in nervous system of vertebrates. However, little is known about their action on invertebrate nervous system. Nevertheless, insect-based models are suggested for high-throughput screening of antiepileptic drugs. In the present work, we characterized action of lidocaine, carbamazepine, lamotrigine, and phenytoin on the neuromuscular transition of Calliphora vicina fly larvae using conventional voltage-clamp approach. Carbamazepine and lidocaine caused inhibition of synaptic transmission, which has presynaptic origin. This action is in agreement with inhibition of voltage-gated sodium channels that reduces depolarization of nerve terminals and, thus, calcium entry. Surprisingly, phenytoin and lamotrigine produced a prominent increase in the evoked postsynaptic currents without any effect on frequency or amplitude of spontaneous miniature currents. Potassium channel blocker 4-aminopyridine affects synaptic transmission in similar way. Elevation of synaptic quantal content via increase in calcium concentration or via application of 1 mM 4-aminopyridine eliminates the enhancement effect or even turns it to modest inhibition. We propose that lamotrigine and phenytoin act as inhibitors of insect potassium channels that cause the membrane depolarization and thus facilitates calcium entry into the nerve terminal.


Assuntos
Carbamazepina/farmacologia , Lamotrigina/farmacologia , Lidocaína/farmacologia , Fenitoína/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Anestésicos Locais , Animais , Anticonvulsivantes/farmacologia , Dípteros
12.
Behav Brain Res ; 356: 120-126, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30142397

RESUMO

Aggressive behaviors can be considered symptoms of bipolar disorder, schizophrenia, post-traumatic stress, intermittent explosive, and personality disorders. Nociceptin/orphanin FQ (N/OFQ) is a peptide acting as endogenous ligand of the NOP receptor. Preclinical and clinical findings suggest the NOP receptor as an innovative target for the treatment of psychopathologies, such as anxiety, depression, and drug abuse. This study investigated the effects of NOP ligands and the behavioral phenotype of mice lacking the NOP receptor in an animal model of aggressiveness, the resident-intruder test. Mood stabilizers, such as valproate, lithium, and carbamazepine reduced aggressive behaviors of resident mice, while diazepam was inactive. In contrast, para-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis, increased aggressiveness in mice. Similar to PCPA, the treatment with the NOP agonists Ro 65-6570 and AT-090 also increased aggressive behaviors. The systemic administration of the NOP antagonist SB-612111 did not modify the behavior of resident mice, but it prevented the aggressive behavior of Ro 65-6570. NOP receptor knockout mice did not display any behavioral difference compared to wild-type animals in the resident-intruder test. None of the treatments affected non-agonistic behaviors and spontaneous locomotion. In conclusion, NOP receptor agonists increased aggressiveness, while the pharmacological and genetic blockade of NOP receptor signaling did not modify agonistic behaviors. Ultimately, the aggressive profile of action of NOP agonists should be taken into account in the development of innovative psychiatric drugs targeting the NOP receptor.


Assuntos
Agressão/fisiologia , Comportamento Agonístico/fisiologia , Receptores Opioides/fisiologia , Animais , Ansiedade , Transtorno Bipolar , Carbamazepina/farmacologia , Cicloeptanos/farmacologia , Depressão , Transtorno Depressivo , Modelos Animais de Doenças , Fenclonina/farmacologia , Lítio/farmacologia , Masculino , Camundongos , Camundongos Knockout , Peptídeos Opioides/metabolismo , Piperidinas/farmacologia , Receptores Opioides/agonistas , Receptores Opioides/genética , Ácido Valproico/farmacologia
13.
Neurosci Lett ; 690: 48-55, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30312753

RESUMO

Drug-resistant epilepsy (DRE) is present in 20-30% of all patients who develop epilepsy. Growing evidences demonstrated that glutamate released during seizures to increase the brain P-glycoprotein (P-gp) expression. Carbamazepine (CBZ) is known to influence the P-gp and cytochrome P450 (CYP) expression. However, the exact molecular mechanism is still unknown. We investigated that the effects of NF-κB and pregnane X receptor (PXR) activity on P-gp and CYP3A expression in mouse brain endothelial (bEnd.3) cells treated with l-glutamate (mimicking the seizure conditions), CBZ (mimicking the AED treating conditions) or both (l-glutamate plus CBZ) through qPCR and Western blotting assay. Mean fluorescence intensity was used to observe P-gp efflux function by analysis of intracellular Rhodamine123 (Rho123) accumulation. P-gp, CYP3A, PXR and NF-κB p65 were elevated in bEnd.3 cells incubated with l-glutamate, CBZ or CBZ pretreated by l-glutamate for 30 min. Both the mRNA and protein levels of P-gp and CYP3A were remarkably reduced by PXR or NF-κB p65 knock-down by siRNA transfections. The decreased intracellular accumulation of Rho123 suggested that the expression of P-gp was enhanced in bEnd.3 cells. These data suggested that overexpression of P-gp and CYP3A during seizures and treated with CBZ may be regulated by PXR or NF-κB p65 activity and expression, which revealed a mechanism underlying the development of DRE.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Carbamazepina/farmacologia , Sistema Enzimático do Citocromo P-450/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Receptor de Pregnano X/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Ácido Glutâmico/farmacologia , Camundongos , RNA Interferente Pequeno/farmacologia
14.
ISME J ; 13(2): 509-522, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30291330

RESUMO

Antibiotic resistance is a severe global threat for public health, causing around 700,000 deaths per year. Horizontal gene transfer (HGT) is one of the most significant pathways to disseminate antibiotic resistance. It is commonly acknowledged that sub-minimum inhibition concentrations of antibiotics are major contributors in promoting antibiotic resistance through HGT. Pharmaceuticals are occurring in our environments at increased levels, yet little is known whether non-antibiotic pharmaceuticals cause or accelerate the dissemination of antibiotic resistance. Here, we report for the first time that the antiepileptic drug, carbamazepine, promotes conjugative transfer of antibiotic resistance genes. It was seen that environmentally relevant concentrations of carbamazepine (e.g., 0.05 mg/L) significantly enhanced the conjugative transfer of multiresistance genes carried by plasmid within and across bacterial genera. The underlying mechanisms of the enhanced HGT were revealed by detecting oxidative stress and cell membrane permeability, in combination with MinION DNA sequencing, genome-wide RNA sequencing, and proteomic analysis. Carbamazepine induced a series of acute responses, including increased levels of reactive oxygen species, the SOS response; increased cell membrane permeability, and pilus generation. Expressional levels of genes related to these processes were significantly upregulated during carbamazepine exposure. Given that HGT occurs widely among different species in various environments, these findings are an early warning for a wide assessment of the roles of non-antibiotic pharmaceuticals in the spread of antibiotic resistance.


Assuntos
Bactérias/efeitos dos fármacos , Carbamazepina/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Transferência Genética Horizontal/efeitos dos fármacos , Anticonvulsivantes/farmacologia , Bactérias/genética , Resistência Microbiana a Medicamentos/genética , Escherichia coli/genética , Testes de Sensibilidade Microbiana , Plasmídeos , Proteômica
15.
Chemosphere ; 217: 542-549, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30445399

RESUMO

There is increasing knowledge about the presence of psychiatric pharmaceutical substances in the aquatic environment due to increasing number of ecotoxicological studies with sensitive species in addition to improved methods of analysis. Here, we assessed the effects of two psychiatric substances carbamazepine and fluoxetine in the planarian Schmidtea mediterranea using endpoints such as survival, behaviour (feeding, locomotion), DNA damage and regeneration. Also, planarian asexual reproduction by fissioning was used to assess the reproductive effects of these compounds. Whereas for survival, no effect was observed for carbamazepine exposure, fluoxetine exposure was toxic to planarians with an LC50 of 357.93 and 160.01 µg L-1 at 48 and 96 h, respectively. Time for head regeneration in decapitated planarians was not affected by either fluoxetine or carbamazepine exposures. Fluoxetine was more toxic than carbamazepine and caused concentration dependent increase in locomotor activity and DNA damage (LOEC's of 0.1-1.0 µg L-1), and decrease in feeding and fissioning. Despite some alteration on planarian locomotion observed under exposure to intermediate concentrations, no significant effects were observed in the other endpoints in response to carbamazepine. The observations in the present study showed that freshwater planarians such as Schmidtea mediterranea, animal models in neuropharmacology, are sensitive to low concentrations of psychiatric drugs, displaying an array of sensitive sub-lethal endpoints that can be used for the ecological risk assessment of psychiatric substances. Future studies to determine effects of these psychiatric drugs on the levels of neurotransmitters and other biochemical biomarkers in planarians are recommended.


Assuntos
Antidepressivos de Segunda Geração/efeitos adversos , Carbamazepina/efeitos adversos , Fluoxetina/efeitos adversos , Água Doce/química , Planárias/efeitos dos fármacos , Animais , Antidepressivos de Segunda Geração/farmacologia , Carbamazepina/farmacologia , Fluoxetina/farmacologia
16.
Seizure ; 64: 29-33, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30529757

RESUMO

PURPOSE: To describe the retention rates of first antiepileptic drugs (AEDs) in patients with poststroke epilepsy on a nationwide scale. METHODS: The Swedish Stroke Register, which has 94% coverage and high-resolution data on stroke, comorbidities, and disability, was cross-referenced to the National Patient Register, Drug Register, and Cause-of-Death Register. Patients with onset of AED-treated epilepsy after stroke in 2005-2010 were included. An algorithm based on prescription renewal intervals was used to analyze treatment data until the end of 2014. RESULTS: A total of 4991 patients were included. First AEDs analyzed were carbamazepine (n = 2373), valproic acid (n = 943), levetiracetam (n = 555), lamotrigine (n = 519), phenytoin (n = 176), and oxcarbazepine (n = 89). The five-year retention rate was highest for lamotrigine (75%, 95%CI:70.4-79.4), followed by levetiracetam (69%, 95%CI:62.9-74.3), oxcarbazepine (68%, 95%CI:55.2-79.8), valproic acid (62%, 95%CI:57.8-66.4), carbamazepine (60%, 95%CI:57.6-62.4), and phenytoin (55%, 95%CI:45.2-64.0). There were minor differences in baseline characteristics with low levels of disability being slightly more common in patients treated with lamotrigine and levetiracetam. Atrial fibrillation and hypertension were more common in patients treated with levetiracetam, and atrial fibrillation was less common in patients treated with carbamazepine. In a Cox model adjusted for baseline characteristics, the risk of discontinuation was lower for lamotrigine (HR 0.53, 95%CI:0.43-0.67) and levetiracetam (HR 0.75, 95%CI:0.60-0.94) when compared to carbamazepine. CONCLUSIONS: Lamotrigine and levetiracetam have higher retention rates than carbamazepine in poststroke epilepsy. This is in agreement with existing small RCTs in this patient group.


Assuntos
Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Epilepsia/tratamento farmacológico , Lamotrigina/farmacologia , Levetiracetam/farmacologia , Sistema de Registros , Acidente Vascular Cerebral/complicações , Idoso , Idoso de 80 Anos ou mais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Carbamazepina/administração & dosagem , Carbamazepina/efeitos adversos , Epilepsia/epidemiologia , Epilepsia/etiologia , Feminino , Humanos , Lamotrigina/administração & dosagem , Lamotrigina/efeitos adversos , Levetiracetam/administração & dosagem , Levetiracetam/efeitos adversos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Sistema de Registros/estatística & dados numéricos , Acidente Vascular Cerebral/epidemiologia , Suécia/epidemiologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-30376788

RESUMO

Klüver-Bucy syndrome (KBS) is a rare clinical presentation following traumatic brain injury (TBI). Symptoms include visual agnosia, placidity, hyperorality, sexual hyperactivity, changes in dietary behavior, and hypermetamorphosis. The purpose of this article was to identify and synthesize the available evidence from case reports and case series on the treatment profile of KBS among adolescents and adults after TBI. Four bibliographic databases (MEDLINE OVID, EMBASE, PsycINFO, and SCOPUS) were searched for relevant literature. No date or language restrictions were applied. All case reports containing original data on KBS following TBI among adolescents and adults were included. Articles were evaluated, and data were extracted according to predefined criteria. The literature search identified 24 case reports of KBS post-TBI published between 1968 and 2017. Most case subjects were male (70.1%), and the mean age at injury was 25.1 years (range, 13-67 years). Injury to one or both temporal lobes occurred in most cases. Inappropriate sexual hyperactivity was the most common KBS symptom, followed by a change in dietary behavior and hyperorality. Visual agnosia was the least reported. In 50% of cases, the patient fully recovered from KBS. One-half of all participants described pharmacological management; the most common medication prescribed was carbamazepine. Overall, there was a lack of data available on pharmacotherapy initiation and duration. The complex presentation of KBS presents challenges in terms of treatment options. Although overall individuals who were prescribed carbamazepine had positive outcomes, given the reliance on case reports, it is difficult to make a definitive recommendation to guide clinical practice.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Carbamazepina/farmacologia , Fármacos do Sistema Nervoso Central/farmacologia , Síndrome de Kluver-Bucy , Adolescente , Adulto , Idoso , Feminino , Humanos , Síndrome de Kluver-Bucy/tratamento farmacológico , Síndrome de Kluver-Bucy/etiologia , Síndrome de Kluver-Bucy/fisiopatologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
J Immunol Res ; 2018: 5086503, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30302345

RESUMO

Among patients treated with the anticonvulsive and psychotropic drug carbamazepine (CBZ), approximately 10% develop severe and life-threatening adverse drug reactions. These immunological conditions are resolved upon withdrawal of the medicament, suggesting that the drug does not manifest in the body in long term. The HLA allele B∗15:02 has been described to be a genomic biomarker for CBZ-mediated immune reactions. It is not well understood if the immune reactions are triggered by the original drug or by its metabolite carbamazepine-10,11-epoxide (EPX) and how the interaction between the drug and the distinct HLA molecule occurs. Genetically engineered human B-lymphoblastoid cells expressing soluble HLA-B∗15:02 molecules were treated with the drug or its metabolite. Functional pHLA complexes were purified; peptides were eluted and sequenced. Applying mass spectrometric analysis, CBZ and EPX were monitored by analyzing the heavy chain and peptide fractions separately for the presence of the drug. This method enabled the detection of the drug in a biological situation post-pHLA assembly. Both drugs were bound to the HLA-B∗15:02 heavy chain; however, solely EPX altered the peptide-binding motif of B∗15:02-restricted peptides. This observation could be explained through structural insight; EPX binds to the peptide-binding region and alters the biochemical features of the F pocket and thus the peptide motif. Understanding the nature of immunogenic interactions between CBZ and EPX with the HLA immune complex will guide towards effective and safe medications.


Assuntos
Alérgenos/efeitos adversos , Anticonvulsivantes/efeitos adversos , Linfócitos B/efeitos dos fármacos , Carbamazepina/análogos & derivados , Carbamazepina/efeitos adversos , Hipersensibilidade a Drogas/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Alérgenos/química , Alérgenos/uso terapêutico , Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Apresentação do Antígeno , Linfócitos B/fisiologia , Sítios de Ligação , Carbamazepina/química , Carbamazepina/farmacologia , Carbamazepina/uso terapêutico , Linhagem Celular , Antígeno HLA-B15/genética , Antígeno HLA-B15/metabolismo , Humanos , Imunomodulação , Espectrometria de Massas , Fragmentos de Peptídeos/metabolismo , Ligação Proteica
20.
Hum Psychopharmacol ; 33(6): e2676, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30311959

RESUMO

OBJECTIVE: This study aims to describe the prescription patterns of the mood stabilizers most commonly used for the treatment of bipolar I and II disorders (lithium, valproate, and carbamazepine) and to analyze the treatment outcomes. METHODS: Two hundred and thirty-four outpatients with bipolar disorders receiving prophylactic treatment with lithium, valproate, carbamazepine, or their combination were followed up for at least 18 months in two Italian psychiatric centers specialized in mood disorders. RESULTS: The combination of lithium and valproate or carbamazepine was the most common prophylactic treatment (54.3%), followed by valproate or carbamazepine (24%) and lithium monotherapy (22%). Polytherapy was prescribed mainly to patients with bipolar I disorder, a high number of previous episodes and lifetime psychotic symptoms, whereas valproate or carbamazepine monotherapy was prescribed to patients with anxiety comorbidity. The annual frequency of recurrences decreased significantly after entering the study in the overall sample, and the reduction was significantly higher in patients on lithium plus valproate or carbamazepine compared with the valproate or carbamazepine group, but not with the lithium monotherapy group. The number of mixed recurrences during the follow-up was significantly higher in patients on lithium plus valproate or carbamazepine. CONCLUSIONS: Our findings may help clinicians to personalize long-term treatment to prevent relapses of bipolar disorder according to clinical presentation.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Carbamazepina/farmacologia , Compostos de Lítio/farmacologia , Ácido Valproico/farmacologia , Adulto , Prescrições de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Estudos Prospectivos
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