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Clobazam is a benzodiazepine; it is chemically substituted as the 1 and 5 positions, in contrast to the 1,4-benzodiazepines. The drug is under evaluation in Canada as an add-on drug for epileptic seizures which do not respond to conventional antiepileptic treatments. Clobazam produces fewer cognitive side effects than the 1,4-benzodiazepines, and is generally well tolerated. Three cases are now reported, however, in which the addition of clobazam to a phenytoin-based (the drug, Dilantin) regimen resulted in the development of phenytoin toxicity. All three patients developed lethargy within a few weeks of the introduction of clobazam, in two cases the patients also became ataxic. However, seizure activity improved in all three cases. Blood analysis revealed that the phenytoin levels for the three patients were 29.0, 31.6, and 33.1 milligrams per liter, well above the therapeutic level for this drug. The phenytoin dose was reduced or eliminated and the symptoms resolved. In two cases, the dose of clobazam was eventually increased without ill effect. The results suggest that the introduction of clobazam may have adversely affected the patients' abilities to metabolize the phenytoin. The molar levels of clobazam are thought to be too small to replace phenytoin bound to plasma proteins and produce higher blood levels in this fashion. Rather, it seems likely that the clobazam interfered with the breakdown of phenytoin in the liver, a process which may already have been close to saturation in these patients. (Consumer Summary produced by Reliance Medical Information, Inc.)

Animal data suggest that the widely abused psychostimulant methamphetamine can damage brain dopamine neurones by causing dopamine-dependent oxidative stress; however, the relevance to human methamphetamine users is unclear. We measured levels of key antioxidant defences [reduced (GSH) and oxidized (GSSG) glutathione, six major GSH system enzymes, copper­zinc superoxide dismutase (CuZnSOD), uric acid] that are often altered after exposure to oxidative stress, in autopsied brain of human methamphetamine users and matched controls. Changes in the total (n 1/4 20) meth- amphetamine group were limited to the dopamine-rich caudate (the striatal subdivision with the most severe dopamine loss) in which only activity of CuZnSOD (+ 14%) and GSSG levels (+ 58%) were changed. In the six methamphetamine users with severe (- 72 to ) 97%) caudate dopamine loss, caudate CuZnSOD activity (+ 20%) and uric acid levels (+ 63%) were increased with a trend for decreased () 35%) GSH concentration. Our data suggest that brain levels of many antioxidant systems are preserved in methampheta- mine users and that GSH depletion, commonly observed during severe oxidative stress, might occur only with severe dopamine loss. Increased CuZnSOD and uric acid might reflect compensatory responses to oxidative stress. Future studies are necessary to establish whether these changes are associated with oxidative brain damage in human metham- phetamine users. [ABSTRACT FROM AUTHOR]