Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0149958 (complex partial seizures)
 2,563 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article highlights studies in three major domains of potential mechanisms of sudden unexplained death in epilepsy (SUDEP): cardiac, respiratory, and autonomic. Ictal cardiac arrest is a clinically rare but well-recognized potential mechanism of SUDEP. Studies have failed to identify preexisting cardiac electrophysiologic or structural abnormalities that distinguish SUDEP persons. Some degree of pulmonary congestion is a common autopsy finding, but severe pulmonary edema occurs very rarely with seizures. In contrast, periictal apnea and hypoxia occur commonly with generalized tonic-clonic seizures and, to a lesser degree, with complex partial seizures. There are several animal models of postictal respiratory arrest. Postictal respiratory arrest in audiogenic seizure mice can be induced by serotonin receptor inhibition or prevented by selective serotonin reuptake inhibitor (SSRI) drugs. Reduced heart rate variability occurs in patients with refractory epilepsy and can be induced in animal seizure models, but its precise role in predisposing persons to sudden death requires further investigation.
 ...
PMID:What is known about the mechanisms underlying SUDEP? 1908 23

Inhibitors of voltage-gated sodium channels (Na(v)) have been used as anticonvulsants since the 1940s, while potassium channel activators have only been investigated more recently. We here describe the discovery of 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a thioanalog of riluzole, as a potent, novel anticonvulsant, which combines the two mechanisms. SKA-19 is a use-dependent NaV channel blocker and an activator of small-conductance Ca(2+)-activated K(+) channels. SKA-19 reduces action potential firing and increases medium afterhyperpolarization in CA1 pyramidal neurons in hippocampal slices. SKA-19 is orally bioavailable and shows activity in a broad range of rodent seizure models. SKA-19 protects against maximal electroshock-induced seizures in both rats (ED50 1.6 mg/kg i.p.; 2.3 mg/kg p.o.) and mice (ED50 4.3 mg/kg p.o.), and is also effective in the 6-Hz model in mice (ED50 12.2 mg/kg), Frings audiogenic seizure-susceptible mice (ED50 2.2 mg/kg), and the hippocampal kindled rat model of complex partial seizures (ED50 5.5 mg/kg). Toxicity tests for abnormal neurological status revealed a therapeutic index (TD50/ED50) of 6-9 following intraperitoneal and of 33 following oral administration. SKA-19 further reduced acute pain in the formalin pain model and raised allodynic threshold in a sciatic nerve ligation model. The anticonvulsant profile of SKA-19 is comparable to riluzole, which similarly affects Na(V) and KCa2 channels, except that SKA-19 has a ~4-fold greater duration of action owing to more prolonged brain levels. Based on these findings we propose that compounds combining KCa2 channel-activating and Na(v) channel-blocking activity exert broad-spectrum anticonvulsant and analgesic effects.
 ...
PMID:The riluzole derivative 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a mixed KCa2 activator and NaV blocker, is a potent novel anticonvulsant. 2525 61