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.     

MEASUREMENTS OF INTERFACE PRESSURE BETWEEN BODY SITES AND THE SURFACES OF FOUR SPECIALISED AIR MATTRESSES

SUMMARY Four specialised air mattresses had interface pressure measured under six body sites prone to pressure sores in 10 subjects, supine and sitting. The mattresses were the Clinirest (SSI) and FirstStep (KCI) continuous airflow mattress overlays, and Airwave (Pegasus) and Nimbus (Huntleigh) alternating pressure air mattresses. On the mattress overlays, average supine interface pressures were 2.33 kPa (scapula), 4.15 kPa (elbow), 1.94 kPa (sacrum) and 2.79 kPa (buttock), although they were higher at the occiput (7.97 kPa) and heel (11.7 kPa). The alternating pressure air mattresses had an average minimum interface pressure close to zero for three sites, rising to 4.28 kPa under the heel. Average maximum interface pressures were 8.61 kPa (occiput), 5.21 kPa (scapula), 4.90 (elbow), 4.85 kPa (sacrum), 4.61 kPa (buttock) and 13.2 kPa (heel). No accepted scientific method exists for comparing the two types of mattress. Our data suggest a clinical benefit at the occiput and heel (supine) in using an alternating pressure air mattress and a benefit in using a continuous airflow mattress overlay at other sites.     

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.     

Anesthesia and/or Sedation for Pulsed Dye Laser Therapy

One of the most exciting developments in pediatric dermatology has been the use of the flashlamp-pumped, 585-nm, pulsed dye laser for treatment of vascular birthmarks. In many cases the results are miraculous. The increase in self-esteem and happiness of many children and adolescents has been overwhelming; for some, depression has been lifted, stuttering has ceased, social involvement has increased, and antidepressants have been discontinued. There are many success stories to tell.
Despite the remarkable effects of the pulsed dye laser and the medical and psychosocial indications for its use, the issue of pain control remains significant. We have no perfect outpatient pediatric anesthetic. Most methods carry either some risk or, if not hazardous, often are not very effective for controlling pain. Needless to say, a diversity of opinions exist on how to manage discomfort from this treatment modality. Therefore, we thought it would be useful to share the experiences and opinions of several dermatologists who have extensive experience with the pulsed dye laser.