Keywords
valproate
combination
central effects
analgesia
hypoxia
Abstract
The cardiac glycoside digoxin, at a sub-cardiotonic dose, has been proven to be an effective adjuvant to classical antiepileptic drugs (AEDs) in controlling seizures that are poorly responsive to conventional pharmacotherapy. However, the accompanying pharmacological properties of low-dose digoxin remain unclear, particularly its central effects, as well as its influence on pain and hypoxia sensitivity – both per se and in combination with the widely used AED sodium valproate.
The aim of thе study was to investigate the central, analgesic, and antihypoxic properties of low-dose digoxin and its combination with sodium valproate. Experiments were conducted on 162 albino mice. Central effects were assessed using the light/dark box test, the rotarod test, and the horizontal bar test. Analgesic potential was evaluated with the hot plate test. Antihypoxic properties were studied in models of normobaric hypoxic hypoxia with hypercapnia (closed-space hypoxia) and hemic hypoxia. Sodium valproate was administered intragastrically at 150 mg/kg (1/2 ED50) 30 minutes prior to testing; digoxin was administered subcutaneously at a previously established effective anticonvulsant dose of 0.8 mg/kg (1/10 LD50) 15–20 minutes before experiments. It was found that neither digoxin per se, nor its combination with valproate produced adverse effects on muscle tone or motor coordination in the rotarod and horizontal bar tests. The absence of muscle relaxant activity in these tests may be considered a marker of the neuro-safety of digoxin and its combination with valproate, since impaired skeletal muscle tone and motor coordination are regarded as leading indicators of neurotoxicity. Furthermore, the tested drugs – both individually and in combination – exhibited no significant effects on anxiety or behavioral responses in the light/dark box test. In the hot plate test, digoxin demonstrated distinct analgesic properties, and its co-administration with valproate did not abolish the analgesic potential of the cardiac glycoside. Digoxin and its combination with valproate also displayed pronounced antihypoxic properties under conditions of normobaric hypoxic hypoxia with hypercapnia, but not under hemic hypoxia. The results obtained provide experimental justification for the safety of combining low-dose digoxin with sodium valproate in terms of central effects, which may be beneficial in the treatment of refractory epilepsy.
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