In acute stroke, the therapeutic time window is a critical factor which may have contributed to the failure of several phase III clinical trials with so-called neuroprotective agents. Since cerebral glutamate levels are elevated for many hours in progressing stroke, we investigated the novel AMPA glutamate receptor antagonist ZK 187638 in rodent models of stroke using up to 12 h delays in the start of therapy after permanent occlusion of the middle cerebral artery (MCA). In rats, ZK 187638 reduced total infarct volume by 43% and 33% when therapy was started immediately or with a delay of 6 h, respectively, but no effect was observed after a 12 h delay. Dose-dependent decreases of total infarct volume (up to 42%) were measured in mice given the first injection of ZK 187638 6 h after permanent MCA occlusion. In conclusion, the AMPA receptor antagonist ZK 187638 has a therapeutic time window of at least 6 h after permanent focal cerebral ischemia in rodents.

AbstractDurch Umsetzung der 5‐Aryloxazole 2a–e sowie der substituierten Vertreter 8a–c und 10 mit 4‐Phenyl‐4H‐1,2,4‐triazol‐3,5‐dion (3) lassen sich die neuen 7‐Aroyl‐1H,7Hs‐triazolo[1,2‐a]‐s‐ triazol‐1,3(2H)‐dione 5a–e, 9a–c und 11 herstellen. Die Struktur wird aus den 13C‐NMR‐spektroskopischen Daten von 5b, 9a und 11 abgeleitet. Der Mechanismus der Bildung wird kurz diskutiert.

Tilorone hydrochloride, an interferon inducer in small laboratory animals, was demonstrated to elicit formation of macrophage migration affecting and microbial growth inhibitory cytokines after peroral drug administration to mice. Serum kinetics of the migration inhibitory cytokine resembled those of interferon, exhibiting a peak after about 24 h, whereas the bactericidal cytokine showed a steady increase up to 48 h after drug treatment. Both the factors were found to have molecular weights of 10,000–30,000 daltons as determined by Sephadex G-200 chromatography, to be stable at pH 2 and at 56°C for 30 min, sensitive to chymotrypsin and resistant to RNase digestion. The migration enhancing serum activity could not finally be characterized so far. The physicochemical data are discussed in comparison to those of lymphocyte-derived cytokines. It is suggested that cytokine production may be, at least partially, responsible for the immunological effects of tilorone and possibly contribute to its antiviral action.