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Rotenone-induced parkinsonism in rats is a widely used animal model of parkinsonism for studies of the antiparkinsonism activity of new substances. The guanidine derivatives of adamantane 1-adamantylguanidine hydrochloride (IEM-2151) and 3,5-dimethyl-1-adamantylguanidine hydrochloride (IEM-2163) given p.o. at a dose of 10 mg/kg had signifi cantly greater antiparkinsonism effects than levodopa at a dose of 20 mg/kg and memantine at a dose of 5 mg/kg, as they reduced the proportion of rats with severe oligokinesia 1.5–3 times more effectively than memantine and levodopa and, in contrast to memantine and levodopa, completely eliminated severe catalepsy in rats with rotenone-induced parkinsonism. IEM-2151 was the safest substance, as it prevented lethality among rats throughout the experiment, while memantine and levodopa increased lethality among the animals towards the end of the experiment. Combined p.o. administration of levodopa with IEM-2151 at the low doses of 10 and 5 mg/kg, respectively, produced a maximal synergistic antiparkinsonism effect, which was greater than the effects of each drug alone at twice the dose. The combination of IEM-2151 with levodopa at low therapeutic doses is a potentially effective and safe approach to the treatment of levodopa-refractory parkinsonism. [ABSTRACT FROM AUTHOR]

Chronic oral administration of the selective AMPA receptor blocker IEM-1676 and the combined NMDA and AMPA receptor blocker IEM-1913 decreased the severity of convulsions kindled by corasol (pentylenetetrazole) and also the number of rats with full kindling by 20–40% more than the standard antiepileptic sodium valproate and the selective NMDA receptor blocker memantine. IEM-1913 and IEM-1676 induced anticonvulsant effects over wide dose ranges, of 0.03–1 and 3–40 mg/kg, respectively, while memantine and sodium valproate were effective only in narrow dose ranges, of 12–20 and 100–200 mg/kg, respectively. Sodium valproate, memantine, and IEM-1676 had low therapeutic indexes (TD50/ED50), of 1.7, 2.0, and 8.0, respectively, evidencing the high chronic toxicity and low safety of these agents. IEM-1913 had a therapeutic index of 1600, which is evidence of low toxicity and high safety in the chronic use of IEM-1913. Thus, the selective blockade of AMPA receptors induced by IEM-1676 is sufficient to achieve a maximum anticonvulsant effect in rats with corasol kindling, though only combined blockade of NMDA and AMPA receptors provide both the maximal anticonvulsant activity and the safety of using IEM-1913 over a wide range of effective doses. [ABSTRACT FROM AUTHOR]

Chronic oral administration of IEM-2062 [1-(6-aminohexylamino)-1-phenylcyclohexyl dihydrochloride], which produces combined blockade of NMDA and AMPA receptors, at a dose of 3 mg/kg was found to induce a maximal anticonvulsant effect in rats with corasol kindling, producing a 100% decrease in the number of rats demonstrating corasol kindling and a 3.3-fold reduction in the mean severity of clonic-tonic kindled seizures. IEM-2062 induced significant anticonvulsant effects over a wide range of doses (1-48 mg/kg), which was 22-24 times greater than that of memantine (12-20 mg/kg) and sodium valproate (100-200 mg/kg). Sodium valproate and memantine induced significant impairment to movement activity in an open field at the doses having maximal anticonvulsant effects in rats with corasol kindling. At the same time, IEM-2062 induced impairments to movement activity only at a very high dose, 92 mg/kg, which was 30.7 times greater than the dose producing the maximal anticonvulsant effect in rats with corasol kindling. Thus, IEM-2062 decreases the severity of kindled seizures 1.7-1.9 times more effectively than sodium valproate and memantine, and has a range of therapeutic doses 22-24 times wider, as well as a 30.7 times greater level of safety than sodium valproate and memantine. [ABSTRACT FROM AUTHOR]

Intramuscular administration of the central analgesics fentanyl and Analgin (dipyrone) along with the pain mediators cholecystokinin (CCK), glutamate, ATP, and adrenaline, and the analgesia mediator adenosine, which have weak penetration into the CNS, induced maximal analgesic effects at minimally effective doses in the tailflick test in rats. The minimal effective doses of Analgin and fentanyl decreased by factors of 50–220 in response to combined i.m. administration of each of the analgesics with CCK, glutamate, ATP, adrenaline, and adenosine at subthreshold does which were ineffective when given alone. Intragastric administration of lidocaine and subdiaphragmatic gastric vagotomy completely blocked the analgesic effects of these combinations. These data lead to the conclusion that peripherally acting pain and analgesia mediators given systemically potentiate the central analgesic actions of Analgin and fentanyl via stimulation of the chemoreceptors of vagal afferents in the gastric mucosa. [ABSTRACT FROM AUTHOR]