Rational polytherapy in the treatment of cholinergic seizures.

The initiation and maintenance phases of cholinergic status epilepticus (SE) are associated with maladaptive trafficking of synaptic GABAA and glutamate receptors. The resulting pharmacoresistance reflects a decrease in synaptic GABAA receptors and increase in NMDA and AMPA receptors, which tilt the balance between inhibition and excitation in favor of the latter. If these changes are important to the pathophysiology of SE, both should be treated, and blocking their consequences should have therapeutic potential. We used a model of benzodiazepine-refractory SE (RSE) (Tetz et al., 2006) and a model of soman-induced SE to test this hypothesis. Treatment of RSE with combinations of the GABAAR agonists midazolam or diazepam and the NMDAR antagonists MK-801 or ketamine terminated RSE unresponsive to high-dose monotherapy with benzodiazepines, ketamine or other antiepileptic drugs (AEDs). It also reduced RSE-associated neuronal injury, spatial memory deficits and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of sc soman-induced SE similarly showed much greater reduction of EEG power by a combination of midazolam with ketamine, compared to midazolam monotherapy. When treating late (40 min after seizure onset), there may not be enough synaptic GABAAR left to be able to restore inhibition with maximal GABAAR stimulation, and further benefit is derived from the addition of an AED which increases inhibition or reduces excitation by a non-GABAergic mechanism. The midazolam-ketamine-valproate combination is effective in terminating RSE. 3-D isobolograms demonstrate positive cooperativity between midazolam, ketamine and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index is increased by combination therapy between GABAAR agonist, NMDAR antagonist and selective AEDs. We compared this drug combination based on the receptor trafficking hypothesis to treatments based on clinical practice. The midazolam-ketamine-valproate combination is far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines. Furthermore, sequential administration of midazolam, ketamine and valproate is far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that we should re-evaluate our traditional treatment of RSE, and that treatment should be based on pathophysiology. The search for a better drug has to deal with the fact that most monotherapy leaves half the problem untreated. The search for a better benzodiazepine should acknowledge the main cause of pharmacoresistance, which is loss of synaptic GABAAR. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm.

Estudo da viabilidade da iontoforese na infusão de medicamentos, utilizando eletrodos móveis / Study of the viability of iontophoresis for compounds infusion using mobile electrodes

A iontoforese utiliza corrente elétrica com a fi nalidade de aumentar a penetração de substâncias polares através da pele. O objetivo do trabalho foi avaliar os efeitos da iontoforese utilizando eletrodos fi xos e móveis. Foram utilizados 6 ratos Wistar machos (300 g), dos quais 1 animal serviu como controle e 5 animais receberam a ionização (Ibramed) de sulfato de estricnina (20 ml; 10 mg/ml), com intensidade de 30 mA por 10 minutos, separados conforme o tratamento: R1 (controle): o animal foi submetido apenas à injeção de sulfato de estricnina (10 mg/kg, i.p.), R2: ionização com eletrodo fi xo (+), R3: ionização com eletrodo fi xo (-), R4: (ionização simulada fi xo): ionização com eletrodos fi xos e o aparelho desligado, R5: ionização com eletrodos móveis, R6: ionização simulada móvel) ionização com eletrodo móvel e o aparelho desligado. Resultados: o animal R1 apresentou crises convulsivas imediatamente após a injeção da droga. O animal R2 apresentou convulsões dois minutos após o início da aplicação da corrente. Os animais R3, R4 e R6 não apresentaram crises. O animal R5 apresentou crise convulsiva 12 minutos após o início do tratamento. Concluímos que os eletrodos móveis possuem menor eficácia que os eletrodos fixos na aplicação transdermal de drogas com base nos parâmetros utilizados.

Iontophoresis is a method in which are used electrical currents to increase the penetration of polarized compounds through the skin. In this study we compared the eff ects of iontophoresis using mobile and fi xed electrodes. We used 6 male Wistar rats (300 g), trichotomized in the dorsal region of the body. One animal was injected with saline and used as control and 5 received the ionization through an iontophoresis device (Ibramed). Animals were gently immobilized, then received strychnine sulfate (20 ml; 10 mg/kg), using the current intensity of 30 mA during 10 minutes. Th e controlrat (R1) received an injection of strychnine sulfate (10 mg/kg; i.p.). Another animal (R2) was submitted to ionization with a fi xed electrode and the drug located at the positive pole. Th e rat 3 (R3) was also submitted to ionization with a fi xed electrode, but the drug was placed at the negative pole. Th e rat 4 (R4) was submitted tothe same protocol as R2, but the device was turned off . Finally the rat 5 (R5) received ionization with mobile electrodes. Results: The animal R1 presented convulsive seizures immediately after the drug injection. Th e animal R2 presented convulsions 2 minutes after the beginning of the current application. Th e animals R3, R4 and R6 did not present seizures. The animal R5 presented a convulsive seizure at 12 minutes. We concluded that using the parameters applied in this work, the mobile electrodes have fewer effi cacies than the fixed ones for the transdermal application of drugs.