Update on the management of neuromuscular block: focus on sugammadex

Steroidal neuromuscular blocking agents (NMBAs), such as rocuronium, are widely used in clinical anesthesia and emergency medicine to facilitate endotracheal intubation and artificial ventilation and to allow surgical access to body cavities. Reversal of neuromuscular blockade is important for the acceleration of patient recovery and prevention of postoperative residual neuromuscular blockade and reduces the incidence of severe morbidity and mortality associated with anesthesia management. Sugammadex is the first selective relaxant binding agent (SRBA) and has been designed to reverse the steroidal neuromuscular blocking drug rocuronium. Encapsulation of the rocuronium molecule by sugammadex results in a rapid decrease in free rocuronium in the plasma and subsequently at the nicotinic receptor at the motor endplate. After encapsulation, rocuronium is not available to bind to the nicotinic receptor in the neuromuscular junction. This promotes the liberation of acetylcholine receptors, and muscle activity reappears. This new concept of reversal of neuromuscular block induced by rocuronium (or vecuronium) led to impressive results in animal and phase 1 and 2 studies. Sugammadex is currently in phase 3 clinical studies and may be commercially available by 2008.     

Check size tuning of the pattern electroretingoram: a reappraisal

The pattern electroretinogram was recorded to checkerboard stimuli with a wide range of check sizes and two stimulus field sizes. Check sizes ranged from 0.25° to 7° (field size, 16°×14°) and 0.25° to 15° (field size, 32°×27°) in 14 and seven subjects, respectively. Reversal rate was 4.5/s. For minimal intrusion of blink artifacts the interrupted stimulation technique was employed. The P50 and N95 components of the pattern electroretinogram were evaluated separately. With both stimulus field sizes amplitude of P50 and N95 was maximal between 0.75° and 1°. With smaller check sizes the amplitude dropped monotonically. With larger check sizes field size played a role: with the 16°×14° field, P50 gradually dropped to 89% from 1° to 7°, which was paralleled by N95 only up to 7°, where N95 dropped to 81% (p<0.05). With the 32°×27° field, there was no significant difference in size dependency between P50 and N95 for large checks, both components staying constant from 1° to 15° We conclude that there is only minor large-check attenuation of the pattern electroretinogram, especially with a large field. The apparent field-size dependency may explain previous discrepancies in the literature.     

Proteolytic processing of the Plasmodium falciparum merozoite surface protein-1 produces a membrane-bound fragment containing two epidermal growth factor-like domains.

The amino-terminal sequence has been obtained for 2 fragments of the Plasmodium falciparum T9/94 merozoite surface protein precursor (PfMSP1) and these have been compared with the sequence predicted from the gene. These data define the position of these fragments in the precursor and indicate that the C-terminal sequence which is carried into the red cell during invasion consists of 2 epidermal growth factor (EGF)-like domains. A homologous cleavage sequence and domain structure can be identified in the MSP1 molecules of other malarial species. In addition the results suggest that the smaller fragment is not N-glycosylated.     

Candida albicans growth studies: a hypothesis for the pathogenesis of Candida infections in burns.

The proteolytic environment in which Candida albicans exists strongly affects its virulence. To determine whether virulence might be related to C. albicans growth in different proteolytic environments, we measured renal fungal load in burned mice and found significantly greater Candida census in kidneys from mice that were challenged with a high proteinase-generating parent C. albicans (MY 1044) versus those that were challenged with its low proteinase-generating mutant (MY 1049). In vitro, MY 1044 cells grew faster than MY 1049 cells in media that contained sera from burned mice as the only nitrogen source. Augmentation of media with proteinase or a mixture of amino acids increased growth of MY 1049 cells, whereas augmentation with proteinase inhibitor decreased MY 1044 growth. In conclusion, in vitro growth of both the mutant and its parent strain was affected by the proteolytic environment in which they existed; thus, virulence differences for MY 1044 and MY 1049 could be due in part to growth differences between these two strains in different proteolytic environments. These results were combined with existing observations, and we proposed a theory for the pathogenesis of C. albicans in burns.     

Incompatibility of contrast agents with intravascular medications. Work in progress

In vitro and in vivo precipitation of iodinated contrast agents when ioxaglate and papaverine are given together has been reported. To verify these reports and to investigate other medications not previously tested, the authors analyzed mixtures of contrast agents and medications in vitro with a light spectrophotometer and observed them for visible precipitates for up to 120 minutes. Previously reported incompatibilities between ionic or low-osmolality contrast media and medications were verified, and several new incompatibilities were discovered. No incompatibilities were found when the drugs tested were mixed with the new nonionic contrast media.     

Metabolism of doxylamine succinate in Fischer 344 rats. Part II: Nonconjugated urinary and fecal metabolites

Elimination and metabolic profiles of doxylamine and its nonconjugated metabolites were determined after the oral administration of [14C]-doxylamine succinate (13.3 mg/kg and 133 mg/kg doses) to male and female Fischer 344 rats. Total urine and fecal recovery of the administered dose was greater than 90% regardless of sex or dose. The cumulative urinary and fecal elimination of these nonconjugated doxylamine metabolites at the 13.3 mg dose was 44.4 +/- 4.4% and 36.0 +/- 5.8% of the total recovered dose for male and female rats, respectively. The cumulative urinary and fecal elimination of the doxylamine nonconjugated metabolites at the 133 mg/kg dose was 38.7 +/- 2.7% and 41.4 +/- 1.0% of the total recovered dose for male and female rats, respectively. In order to determine the contribution of mammalian and bacterial enzymes in the overall metabolism and excretion patterns for doxylamine, two in vitro techniques were investigated. Incubation of [14C]-doxylamine succinate with human and rat intestinal microflora indicated that anaerobic bacteria were not capable of effecting the degradation of [14C]-doxylamine succinate. However, the incubation of [14C]-doxylamine succinate with isolated rat hepatocytes generated several metabolites similar to those observed in vivo. The nonconjugated doxylamine metabolites isolated and identified include: doxylamine N-oxide, desmethyldoxylamine, didesmethyldoxylamine and ring-hydroxylated products of doxylamine and desmethyldoxylamine. The studies demonstrate the role of hepatic metabolism in the elimination of doxylamine succinate in the rat.     

Retinoic acid stimulates neurite outgrowth in the amphibian spinal cord.

There is increasing evidence that retinoic acid (RA), a vitamin A metabolite, plays a role in the development of the nervous system. Here we specifically test this notion by examining the effect of RA on neurite outgrowth from explanted segments of the axolotl spinal cord. We show that there is a threshold concentration in the region of 0.1-1 nM above which neurite outgrowth is stimulated 4-5 fold. Retinol, by contrast, only stimulated the migration of glial cells from the explants. Using HPLC we demonstrate that RA and retinol are present endogenously in the axolotl spinal cord. In addition, we have identified by immunocytochemistry with antipeptide antibodies the cells of the spinal cord that contain the binding proteins for RA (cellular RA-binding protein; CRABP) and retinol (cellular retinol-binding protein; CRBP). CRABP is found in the axons and CRBP is found in the ependyma and glial cells. These results provide strong evidence for a role for RA in the developing nervous system, and we propose a specific hypothesis involving CRBP, CRABP, retinol, and RA in the control of axon outgrowth in the spinal cord.     

The role of 3D CT in the assessment of acetabular fractures.

A total of 16 patients with acetabular fractures were evaluated by plain radiography, axial computed tomography (CT) and three dimensional (3D) CT. It was possible to classify the fracture type in each case from the plain radiographs alone. Axial CT gave additional detail in certain areas, notably the region of the teardrop, the obturator foramen and the acetabular roof. Intra-articular and impacted roof fragments and associated soft tissue injuries were also shown. 3D CT provided the best and most easily interpreted overall assessment of the fractures. In addition to projections equivalent to the plain radiographs, two other views were of particular clinical value in demonstrating surgically inaccessible areas, namely the view of the pelvis from above and the view of the inner aspect of the fractured hemipelvis. However, fracture lines demonstrated on plain radiographs and axial CT were not always apparent on the 3D CT scans. Although 3D CT is a valuable addition to the imaging of acetabular fractures, it is not a substitute for good quality plain radiography and analysis of the axial CT images.