Hier noch das Abstract zu CNS 7056, das vor einigen Tagen extra als eines der Besten ausgezeichnet wurde.
A Phase I SAD Study Evaluating the Safety, Pharmacokinetics and Pharmacodynamics of CNS 7056
* L.J. Antonik, M.D., D.R. Goldwater, M.D., G.J. Kilpatrick, Ph.D., G.S. Tilbrook, Ph.D., K.M. Borkett, B.S.
Anesthesia & Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland
Introduction: A new benzodiazepine derivative, CNS 7056, has been developed to permit a predictable fast-onset, short duration of action and fast recovery profile. This has been achieved by rendering the compound susceptible to hydrolysis via non-specific tissue esterases. We report the first human study with CNS 7056.
Methods: A Phase 1, single center, double-blind, randomized, single-dose escalation study was conducted. Up to 10 cohorts of healthy volunteers were scheduled to receive a single 1-min IV infusion of CNS 7056, midazolam, or placebo. In the 10 possible cohorts, CNS 7056 doses were 0.01, 0.025, 0.05, 0.075, 0.10, 0.15, 0.20, 0.25, 0.30 and 0.35 mg/kg. In cohorts 1-3, six subjects received CNS 7056 and 1 placebo. From cohort 4, an additional 3 subjects in each cohort received midazolam (0.075mg/kg). Safety (bloods, vital signs, ECG, pulse oximetry, AEs), pharmacokinetics (to 12 hrs) and pharmacodynamics (modified observers' assessment of alertness/sedation [MOAA/S] and bispectral index) were monitored. A stopping criteria of loss of consciousness (LOC, defined as a MOAA/S score of < 2, observed for ≥ 5 minutes in > 50% of subjects) was pre-defined.
Results: The LOC stopping criteria was reached in cohort 9 (0.30 mg/kg CNS 7056), hence 9 cohorts were completed and a total of 81 volunteers enrolled. CNS 7056 was well tolerated in all dose cohorts. No serious adverse events were reported. Two cases of mild (SpO 2 88%) hypoxia resolved spontaneously and one case of moderate hypoxia (SpO 2 75%) resolved with a chin lift in the higher dose groups. O 2 saturation remained stable throughout and there were no reports of respiratory compromise. Vital signs remained stable throughout. There were no reports of hypo- or hypertension.
The plasma clearance of CNS 7056 was approx 3 times greater than that for midazolam. The average % dose cleared from plasma for CNS 7056 was 80-90% in 1 hr, compared with 50% for midazolam. The pharmacokinetic behaviour of CNS 7056 was linear with dose.
Dose dependent sedation, with a rapid onset of effect, was observed after administration of CNS 7056 at 0.05 mg/kg and higher. CNS 7056 at 0.075 – 0.20 mg/kg induced peak sedation levels similar to or greater than those achieved with midazolam (0.075 mg/kg) and showed a short duration of sedative effect with recovery within approximately 10 min compared to approx. 40 min for midazolam (figure 1). For CNS 7056, onset of sedation was observed after approx. 1 min and peak sedative effect was reached within 4 min in these dose groups. For midazolam, the peak effect was reached after approx. 15 min. Doses of 0.25 - 0.30 mg/kg CNS 7056 induced loss of consciousness with a longer recovery time but still earlier than observed with midazolam.[figure1] Conclusions: CNS 7056 provided sedation with rapid onset and offset. There were no significant changes in hemodynamics and minimal changes in oxygenation even at doses that produced LOC. Based on these data further studies on the potential utility of CNS 7056 for sedation/anesthesia are warranted.
From Proceedings of the 2009 Annual Meeting of the American Society Anesthesiologists.