Ralitoline: a reevaluation of anticonvulsant profile and determination of "active" plasma concentrations in comparison with prototype antiepileptic drugs in mice.
Ralitoline (RLT) is a new thiazolidinone derivative with potent anticonvulsant activity in different seizure models. During Phase I studies, RLT was well tolerated in human volunteers and showed linear pharmacokinetics in the dose range tested (up to 150 mg). Since RLT will soon be entering clinical Phase II studies, we were interested in obtaining predictive data for effective plasma concentrations in patients. For this purpose, the anticonvulsant potency of RLT was determined in four seizure models in mice, and plasma levels were measured at time of peak drug effect. The four models were the threshold for maximal (tonic extension) electroshock seizures (MES), the threshold for clonic seizures determined by i.v. infusion of pentylenetetrazol (PTZ), the traditional MES test with supramaximal (50 mA) stimulation, and generalized clonic seizures induced by s.c. administration of PTZ. Furthermore, median minimal "neurotoxic" doses (TD50s) were determined by the rotorod and chimney test for calculation of protective indices. All data obtained for RLT were compared with data obtained with standard antiepileptic drugs: phenobarbital, phenytoin, valproate, and diazepam. The onset of anticonvulsant action after i.p. injection of RLT was very rapid, and the peak drug effect was already obtained after 2 min. In the MES models, RLT was the most potent compound. "Active" plasma levels ranged from approximately 300 ng/ml in the MES threshold test to approximately 1,300 ng/ml in the MES test. RLT was also capable of increasing the PTZ threshold, whereas, possibly because of its short duration of action in mice, it was not very active in the s.c. PTZ seizure test.(ABSTRACT TRUNCATED AT 250 WORDS)
Löscher
W
W
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, F.R.G.
von Hodenberg
A
A
Nolting
B
B
Fassbender
C P
CP
Taylor
C
C
D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004353:Drug Evaluation, Preclinical; D004597:Electroshock; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole; D010634:Phenobarbital / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D013844:Thiazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D013844:Thiazoles; D014635:Valproic Acid; D010672:Phenytoin; D003975:Diazepam; C054894:Ralitoline; D010433:Pentylenetetrazole; D010634:Phenobarbital