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1.
Neuroscience ; 87(4): 905-11, 1998 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9759978

RESUMO

Modafinil is a novel wake-promoting compound for which the mechanism and sites of action are unknown. We examined the neural substrates in the brain for the actions of modafinil using 2-deoxyglucose autoradiography and compared the findings to those obtained with amphetamine. Modafinil showed a relatively restricted pattern of changes in brain regional metabolic activity, while amphetamine altered glucose utilization in a wide variety of brain regions. Both modafinil and amphetamine increased glucose utilization in all subregions of the hippocampus (subiculum, CA1-CA3 and dentate gyrus) and in the centrolateral nucleus of the thalamus. Modafinil also increased glucose utilization in the central nucleus of the amygdala, but amphetamine had no effect in this region. Brain structures in which amphetamine increased metabolic rate but modafinil had no effect included regions of the basal ganglia, other nuclei of the thalamus, the frontal cortex, the nucleus accumbens, the ventral tegmental area and the pontine reticular fields. These findings suggest that, while both modafinil and amphetamine promote wakefulness, they act via distinctly different mechanisms. Modafinil appears to act on a specific subset of brain pathways which regulate sleep and wakefulness, whereas amphetamine affects a greater number of cerebral structures involved in the regulation of these behavioral states. Modafinil also lacks the pronounced effects on the extrapyramidal motor system which are characteristic of amphetamine and other psychomotor stimulants, implying that the effects of modafinil are not mediated by the dopamine system and that modafinil may selectively increase wakefulness with fewer side effects.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Desoxiglucose , Dextroanfetamina/farmacologia , Hipocampo/efeitos dos fármacos , Vigília/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Metabolismo Energético , Glucose/metabolismo , Hipocampo/metabolismo , Masculino , Modafinila , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Ratos Sprague-Dawley , Sono/fisiologia
2.
Neurosci Lett ; 241(2-3): 95-8, 1998 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-9507929

RESUMO

We examined the neuronal targets in the rat brain for the novel wakefulness-promoting agent modafinil and for amphetamine using c-Fos immunohistochemistry. Both modafinil and amphetamine induced neuronal expression of c-Fos-like immunoreactivity in the paraventricular nucleus of the hypothalamus, anterior hypothalamus and central nucleus of the amygdala. Modafinil also increased c-Fos-like immunoreactivity in the suprachiasmatic nucleus, while amphetamine had no effect. Brain regions in which amphetamine increased c-Fos-like immunoreactivity, but modafinil had no effect, included frontal cortex, striatum, lateral habenula, supraoptic nucleus and basolateral nucleus of the amygdala. These findings suggest that the mechanism of action of modafinil is different from that of amphetamine and that the neuronal targets for modafinil in the brain include nuclei of the hypothalamus and amygdala.


Assuntos
Anfetamina/farmacologia , Compostos Benzidrílicos/farmacologia , Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Proteínas Proto-Oncogênicas c-fos/biossíntese , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Imuno-Histoquímica , Masculino , Modafinila , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Vigília
3.
BMC Infect Dis ; 1: 24, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11749671

RESUMO

BACKGROUND: Acyclovir (ACV) resistant herpes simplex virus (HSV) isolates can be readily selected in animal infection models receiving suboptimal ACV treatment, however no comparative studies of the emergence of resistance following suboptimal treatment with valacyclovir (VCV) or famciclovir (FCV), the prodrugs of acyclovir and penciclovir, respectively, have been reported. METHODS: Mice (n = 30) were infected with HSV type 1 or 2 in the ear pinnae and administered oral prodrugs at one fifth a dose previously shown to be effective. To select and amplify drug-resistant HSV, a total of seven consecutive in vivo passages with suboptimal treatment were performed for each virus sample and progeny virus from each passage was characterized by the plaque reduction (PRA) and plating efficiency assays (PEA). RESULTS: No drug-resistant HSV-2 and only a single drug-resistant HSV-1 variant were identified. Virus recovered from the first three sequential passages of this HSV-1 sample was susceptible by PRA, although the proportion of resistant virus recovered gradually increased upon passage. The resistant HSV-1 phenotype was confirmed by PRA after four sequential passages in mice. Unexpectedly, this in vivo-selected drug-resistant HSV-1 failed to yield an infection completely refractory to treatment in subsequent passages. CONCLUSIONS: Sub-optimal therapy of immunocompetent mice with either VCV or FCV did not readily select for HSV-mutants resistant to either ACV or PCV, suggesting that selection of resistance with either prodrug remains difficult using this system. Futhermore, this study suggests that the PEA may represent a useful adjunct to the PRA for monitoring alterations in the proportion of drug-resistant virus even when no change in IC50 is apparent.


Assuntos
Aciclovir/análogos & derivados , Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Herpes Simples/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Simplexvirus/efeitos dos fármacos , Aciclovir/farmacologia , Administração Oral , Animais , Antivirais/farmacologia , Modelos Animais de Doenças , Farmacorresistência Viral , Feminino , Guanina , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Simplexvirus/fisiologia , Carga Viral
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