RESUMEN
Painful diabetic neuropathy is difficult to treat. Single analgesics often have insufficient efficacy and poor tolerability. Combination therapy may therefore be of particular benefit, because it might provide optimal analgesia with fewer adverse effects. This study aimed to examine the type of interaction between levetiracetam, a novel anticonvulsant with analgesic properties, and commonly used analgesics (ibuprofen, aspirin and paracetamol) in a mouse model of painful diabetic neuropathy. Diabetes was induced in C57BL/6 mice with a single high dose of streptozotocin, applied intraperitoneally (150 mg/kg). Thermal (tail-flick test) and mechanical (electronic von Frey test) nociceptive thresholds were measured before and three weeks after diabetes induction. The antinociceptive effects of orally administered levetiracetam, analgesics, and their combinations were examined in diabetic mice that developed thermal/mechanical hypersensitivity. In combination experiments, the drugs were co-administered in fixed-dose fractions of single drug ED50 and the type of interaction was determined by isobolographic analysis. Levetiracetam (10-100 mg/kg), ibuprofen (2-50 mg/kg), aspirin (5-75 mg/kg), paracetamol (5-100 mg/kg), and levetiracetam-analgesic combinations produced significant, dose-dependent antinociceptive effects in diabetic mice in both tests. In the tail-flick test, isobolographic analysis revealed 15-, and 19-fold reduction of doses of both drugs in the combination of levetiracetam with aspirin/ibuprofen, and paracetamol, respectively. In the von Frey test, approximately 7- and 9-fold reduction of doses of both drugs was detected in levetiracetam-ibuprofen and levetiracetam-aspirin/levetiracetam-paracetamol combinations, respectively. These results show synergism between levetiracetam and ibuprofen/aspirin/paracetamol in a model of painful diabetic neuropathy and might provide a useful approach to the treatment of patients suffering from painful diabetic neuropathy.
Asunto(s)
Analgésicos/farmacología , Neuropatías Diabéticas/complicaciones , Dolor/tratamiento farmacológico , Dolor/etiología , Piracetam/análogos & derivados , Acetaminofén/uso terapéutico , Animales , Aspirina/uso terapéutico , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Calor , Ibuprofeno/uso terapéutico , Levetiracetam , Masculino , Ratones , Ratones Endogámicos C57BL , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Estimulación Física , Piracetam/farmacología , Equilibrio Postural/efectos de los fármacosRESUMEN
This study investigated the impact of modulating the gamma-aminobutyric acid(A) (GABA)(A)-benzodiazepine receptor complex activity on the rat frontal cortex slices oxygen consumption (QO(2)), polarographically determined using the biological oxygen monitor. Throughout the study, diazepam, flumazenil and picrotoxin were administered i.p. 30 min before sacrificing animals and obtaining slice preparations, while GABA was added directly into the medium in the reaction chamber. GABA decreased QO(2) in concentrations of 5 x 10(-4), 10(-2) and 5 x 10(-2)mol l(-1), while 10(-5) and 10(-6)mol l(-1) GABA had no effect, as well as diazepam, flumazenil and picrotoxin. All diazepam doses (1, 2.5 and 5 mg kg(-1)) increased action of 5 x 10(-4)mol l(-1) GABA, whereas 2.5 mg kg(-1) dose amplified the effect of 10(-6)mol l(-1) GABA. Flumazenil and picrotoxin (5 mg kg(-1) both) blocked diazepam's effects. Flumazenil augmented 10(-6)mol l(-1) GABA effects, while picrotoxin and flumazenil abolished the effects of 5 x 10(-4)mol l(-1) GABA. To our knowledge, this is the first study to examine the influence of modulation of GABA(A)-benzodiazepine receptor function on cerebral metabolism of oxygen in in vitro settings. The results are in accordance with those obtained in numerous in vivo studies, pointing to the moderate level of influence of GABA(A)-benzodiazepine receptor complex on QO(2) regulation.