CNS 7056: A Novel Ultra-short-acting Benzodiazepine

Background: A new benzodiazepine derivative, CNS 7056, has been developed to permit a superior sedative profile to current agents, i.e., more predictable fast onset, short duration of sedative action, and rapid recovery profile. This goal has been achieved by rendering the compound susceptible to metabolism via esterases. The authors now report on the profile of CNS 7056 in vitro and in vivo.

Methods: The affinity of CNS 7056 and its carboxylic acid metabolite, CNS 7054, for benzodiazepine receptors and their selectivity profiles were evaluated using radioligand binding. The activity of CNS 7056 and midazolam at subtypes ([alpha]1[beta]2[gamma]2, [alpha]2[beta]2[gamma]2, [alpha]3[beta]2[gamma]2, [alpha]5[beta]2[gamma]2) of the [gamma]-aminobutyric acid type A (GABAA) receptor was evaluated using the whole cell patch clamp technique. The activity of CNS 7056 at brain benzodiazepine receptors in vivo was measured in rats using extracellular electrophysiology in the substantia nigra pars reticulata. The sedative profile was measured in rodents using the loss of righting reflex test.

Results: CNS 7056 bound to brain benzodiazepine sites with high affinity. The carboxylic acid metabolite, CNS 7054, showed around 300 times lower affinity. CNS 7056 and CNS 7054 (10 [mu]m) showed no affinity for a range of other receptors. CNS 7056 enhanced GABA currents in cells stably transfected with subtypes of the GABAA receptor. CNS 7056, like midazolam and other classic benzodiazepines, did not show clear selectivity between subtypes of the GABAA receptor. CNS 7056 (intravenous) caused a dose-dependent inhibition of substantia nigra pars reticulata neuronal firing and recovery to baseline firing rates was reached rapidly. CNS 7056 (intravenous) induced loss of the righting reflex in rodents. The duration of loss of righting reflex was short (< 10 min) and was inhibited by pretreatment with flumazenil.     

Neonatal septicaemia due to non-capsulate Haemophilus influenzae in three siblings.

I report the case of a woman who, in three successive pregnancies, gave birth to premature infants with septicaemia due to non-capsulate Haemophilus influenzae. All three infants displayed characteristic features of the disease. Maternal antenatal and postnatal management is discussed.     

Frozen algae as food for Daphnia magna Straus in toxicity testing.

As EC validity criteria for the production of Daphnia magna neonates in standard toxicity tests set fecundity minima which must be attained, it is important that culture conditions provide an adequate ration of high quality food. Maintaining a steady supply of fresh algae can be problematical so the possibility of using frozen food was investigated. The performance of three generations of D. magna fed on diets of fresh or frozen Chlorella was compared. There were no significant effects on fecundity due to food type or generation. Cumulative fecundity (over 21 days) on fresh or frozen food exceeded 120 neonates per female and satisfied that EC validity criterion (60 neonates per female). In addition criteria relating to survival and variability were met. We conclude that frozen Chlorella are an acceptable substitute for fresh algae.     

Cerebrovascular accidents complicating pregnancy and the puerperium

The decreasing incidence of direct causes of maternal death over the past half century has led to a heightened awareness of nonobstetric factors responsible for maternal mortality. For example, cerebrovascular accidents are an important nonobstetric cause of maternal morbidity and mortality. During the 6.5-year period from 1984 to mid-1990, we encountered 15 women in whom pregnancy or the puerperium was complicated by an acute cerebrovascular accident. Six of these women had hemorrhagic strokes and nine had ischemic strokes. During this same time, approximately 90,000 women were delivered at Parkland Memorial Hospital, and thus the incidence of stroke was about one in 6000 pregnancies. Chronic hypertension or preeclampsia was causative in three cases of hemorrhagic stroke. It is important that 20% of the women died as a result of stroke, and of the 12 survivors, 40% have residual neurologic deficits. An aggressive work-up to define the etiology of stroke is necessary in order to implement cause-specific management, with subsequent reduction in morbidity and mortality.