Anxiety and sleep after fosazepam.

Activity of fosazepam, a soluble analogue of diazepam.

“…Both diazepam and fosazepam have short plasma half times (equilibration phase), but fosazepam, unlike diazepam, modifies the sleep of the recovery night. Similar observations were reported by Allan & Oswald (1976), and it has been suggested that the hypnotic effect of fosazepam may be due to its long acting metabolite, nordiazepam, which is known to modify the sleep wakefulness cycle of man for about 28-30 h after ingestion (Nicholson, Stone, Clarke & Ferres, 1976). However, though the metabolism of both diazepam and fosazepam in man involves significant plasma levels of nordiazepam (Hoechst AG-Internal Report) it would appear that nordiazepam is a relatively unimportant metabolite of fosazepam in the monkey, and we have used this species difference to investigate the behavioural activity of fosazepam and its principal metabolite, 3-hydroxyfosazepam, uncomplicated by the activity of nordiazepam (Figure 1).…”

Clazepam: pharmacokinetics and effects on performance.

“…Indeed, its half-life during the plasma distribution phase is 90 min and over twothirds of total 24-h excretion of (II) takes place within the first 4 h. In contrast, (III) is a highly lipophilic molecule which accounts for its prolonged stable concentration in the plasma. This phenomenon has moreover been observed with diazepam (Schwartz, Koechlin, Postma, Palmer & Krol, 1965;Schwartz, 1973) and fosazepam (Allen & Oswald, 1976;Nicholson, Stone & Clarke, 1976a) of which (III) is also a metabolite. In view of its presence in the plasma and considering what is known about its metabolism in man (Schwartz et al, 1965;Schwartz, 1973), (III) is, as might be expected, excreted in the urine in two forms, namely (III) itself and particularly (IV).…”

“…The fact that clazepam itself could never be detected in the plasma demonstrates that these late effects are not (Nicholson et al, 1976a). This drug which exhibits late residual effects (Allen & Oswald, 1976;Nicholson et al, 1976a) has a very short elimination half life and most of its activity is related to the formation of desmethyldiazepam, which has a half life of over two days (Tansella, Siciliani, Burti, Schiavon, Zimmermann Tansella, Gerna, Tognoni & Morselli, 1975) and long-lasting effects (Nicholson, Stone, Clarke & Ferres, 1976b (Schwartz et al, 1965;Van der Kleijn, 1969;Nicholson et al, 1976a). But from a quantitative standpoint, whereas (III) is a major metabolite of diazepam (Schwartz, 1973), it is only a minor one for clazepam.…”

Hypnotics: rebound insomnia and residual sequelae.

“…The other study involved fosazepam, an analogue of diazepam with a very short half-life. It has been reported that nightly use leads to changes in sleep on withdrawal, and these have been attributed to a continued effect of the drug (Allen & Oswald, 1976). However, Kales et al (1979) suggest that it is related to its short half-life, and so is essentially a rebound effect.…”