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Neuropathic pain constitutes a serious therapeutic problem. In most cases polytherapy is necessary. Tramadol and antidepressants have common mechanisms of action and are frequently used together in clinical practice, thus interaction between them is very important. In the present study isobolographic analysis for equivalent doses of drugs was applied to examine the nature of interaction between tramadol and doxepin or venlafaxine in a neuropathic pain model in rats. Allodynia and hyperalgesia were assessed after intraperitoneal administration of each drug alone or in combination. Dose response curves were obtained and ED50 doses were calculated. All drugs were effective in reducing thermal hyperalgesia and mechanical allodynia, however doxepin was more effective than venlafaxine. Combined administration of tramadol and doxepin demonstrated synergistic action in reducing thermal hyperalgesia and additive action in reducing mechanical allodynia. Combined administration of tramadol and venlafaxine showed additive action in reducing hyperalgesia and allodynia. Moreover, combined administration of tramadol and doxepin was more effective than combined administration of tramadol and venlafaxine. The experiments demonstrated that the nature of interaction between tramadol and doxepin is synergistic, which is not the case for tramadol and venlafaxine, what provides a valuable information referring to clinical practice, rationalizing administration of such drug combination.
The aim of the present study was to characterize the anticonvulsant effects of levetiracetam in combination with ethosuximide in the mouse 6 Hz psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes; type II isobolographic analysis was used to characterize the consequent anticonvulsant interactions between the drug combinations for fixed-ratios of 1:1, 1:2, 1:5 and 1:10. With type II isobolographic analysis, the combinations of levetiracetam with ethosuximide for the fixed-ratios of 1:5 and 1:10 were supra-additive (synergistic; P<0.05 and P<0.01, respectively) in terms of seizure suppression, while the combinations for the fixed-ratios of 1:1 and 1:2 were additive in the mouse 6 Hz psychomotor seizure model. The combinations of levetiracetam with ethosuximide for the fixed-ratios of 1:5 and 1:10 appear to be particularly favorable combinations exerting supra-additive interaction in the mouse 6 Hz psychomotor seizure model. Finally, it may be concluded that because of the synergistic interactions between levetiracetam and ethosuximide, the combination might be useful in clinical practice.
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