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.     

Multicenter Pilot Study of a Serpentine Balloon-Expandable Stent (beStentTM): Acute Angiographic and Clinical Results

The beStent is a new stainless steel, balloon-expandable mesh stent which has a unique serpentine design. Rotation of the unique low stress junctions upon expansion leads to orthogonal locking of the wires, maximizing radial strength and assuring zero shortening. The stent has delineating gold markers which assure precise positioning. We aim to present the initial acute results in a pilot registry for stent evaluation. Two hundred eighty-four stents were used in a total of 217 patients (age 57.9 ± 3.10 years; 178 males; 39 females) in seven centers, for variable indications. Stents of 15-, 25-, and 35-mm length were used. The arteries treated were the left anterior descending (n = 112, 42%), circumflex (n = 54, 20.2%), right coronary (n = 95, 35.5%), left main (n = 1, 0.4%), and vein graft (n = 5, 1.9%). Lesion types were: A in 42 patients (16.5%); B1 in 53 patients (20.7%); B2 in 81 patients (31.8%); and C in 79 patients (31%). One hundred fifty-nine patients required one stent, 40 patients required two stents, and 18 patients required three or more stents. Anticoagulation protocol included procedural heparin with aspirin with/without ticlopidine. Smooth angiographie results were obtained in all cases with no plaque herniation. Acute angiographic success was obtained in 97% of the patients, and acute clinical success in 95% of the patients. Complications within 30 days were: 3 deaths (1.4%) (2 noncardiac); 2 (0.9%) myocardial infarctions; and 2 (0.9%) stent thromboses. Therefore, the beStent is useful in treatment of complex lesions of variable length and complexity, providing excellent acute results with a low complication rate, in spite of unfavorable basic clinical and angiographie characteristics.     

Chronic Administration of Glucocorticoids Directly Upregulates Prepro-Neuropeptide Y and Y1-Receptor mRNA Levels in the Arcuate Nucleus of the Rat

The complete sequence of the cDNA encoding the neuropeptide Y (NPY) Y₁-receptor has recently been deduced from a rat brain library, and the presence of messenger ribonucleic acid (mRNA) encoding Y₁-receptor protein has been demonstrated within the brain. Using quantitative in situ hybridization histochemistry, the content and distribution of Y₁receptor and preproNPY mRNAs have been investigated in the hypothalamic arcuate nucleus of adrenalectomized rats receiving glucocorticoid replacement therapy for 12 days by means of either high doses of dexamethasone in their drinking water or by subcutaneous corticosterone pellets. Basal metabolic parameters such as weight gain or loss, blood glucose and plasma insulin were monitored: Dexamethasone treatment induced weight loss and a state of hyperinsulinemia with normoglycemia, while corticosterone treated animals displayed metabolic parameters identical to sham ADX animals. Within the arcuate nucleus of glucocorticoid treated animals, levels of Y₁receptor and preproNPY mRNAs were increased. In contrast, adrenalectomy itself had no effect upon Y₁-receptor mRNA levels or preproNPY mRNA levels in the arcuate nucleus. These studies demonstrate that glucocorticoids exert a stimulatory action on levels of Y₁-receptor mRNA and preproNPY mRNA levels in the hypothalamic arcuate nucleus. This is the first evidence to suggest that the expression of a neuropeptide-receptor gene in the central nervous system may be directly sensitive to peripheral hormonal signals.