Clonazepam in a focal-motor monkey model: efficacy, tolerance, toxicity, withdrawal, and management.
Since the clinical data have been equivocal in regard to the effects of clonazepam (CZP) in focal-motor seizures, an alumina gel monkey model was used to evaluate quantitatively its efficacy with respect to this seizure category. The insolubility of CZP and its short biological half-life in monkey necessitated its evaluation in the model via constant-rate intravenous administration in a solution of polyethylene glycol 400 (PEG). Two groups of monkeys were given CZP in PEG (N = 6) or a PEG solution alone as a control compound (N = 5) for 6 weeks; these treatments were bordered at both ends by 3 weeks of treatment with saline only in order to establish a baseline. CZP was administered at a concentration sufficient to achieve a plasma level of 30 ng/ml in drug step I (3 weeks) and at least double that level in drug step II (3 weeks). As a solute for CZP, and when given by itself, PEG was always administered at a concentration of 35%. The results indicate that CZP is effective for focal-motor seizures and secondarily generalized tonic-clonic seizures, particularly when its concentration in plasma is higher than 60 ng/ml. Withdrawal seizures were evident on cessation of CZP administration. CZP appears to be a useful broad-spectrum anticonvulsant when managed carefully. An unexpected finding was the irreversibility of the pharmacological effect of PEG. Cessation of PEG administration significantly reduced seizure frequency in subsequent weeks to a level below the initial baseline level.
D000536:Aluminum Hydroxide / Q000633:toxicity; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001570:Benzodiazepinones / Q000627:therapeutic use*; D002998:Clonazepam / Q000097:blood / Q000627:therapeutic use*; D004361:Drug Tolerance; D004569:Electroencephalography; D005071:Evoked Potentials / Q000187:drug effects; D000882:Haplorhini; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008959:Models, Neurological; D011092:Polyethylene Glycols / Q000008:administration & dosage; D012640:Seizures / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D012894:Sleep Stages / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000209:etiology*
D001570:Benzodiazepinones; D011092:Polyethylene Glycols; D002998:Clonazepam; D000536:Aluminum Hydroxide