Assuntos
Anticonvulsivantes/efeitos adversos , Coreia/induzido quimicamente , Lateralidade Funcional/fisiologia , Ácido Valproico/efeitos adversos , Encéfalo/patologia , Coreia/diagnóstico , Epilepsia/tratamento farmacológico , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-IdadeRESUMO
Paroxysmal autonomic instability with dystonia, an under-recognized and poorly understood phenomenon of episodic central dysautonomia is associated with various cerebral insults. Treatment options include benzodiazepines, opioids, and gabapentin. Using an illustrative case, we discuss presentation, pathomechanisms, and management of this condition.
Assuntos
Doenças do Sistema Nervoso Autônomo/fisiopatologia , Distonia/fisiopatologia , Adulto , Aminas/uso terapêutico , Doenças do Sistema Nervoso Autônomo/tratamento farmacológico , Benzodiazepinas/uso terapêutico , Lesões Encefálicas/complicações , Ácidos Cicloexanocarboxílicos/uso terapêutico , Distonia/tratamento farmacológico , Gabapentina , Humanos , Masculino , Síndrome , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.