Doughnuts and holes: molecules and muscle relaxants

Canadian Journal of Anesthesia/Journal canadien d'anesthésie -     

Effect of dry powder inhaler resistance on the inspiratory flow rates and volumes of cystic fibrosis patients of six years and older.

Several inhaled drugs for use by cystic fibrosis (CF) patients are formulated for nebulizer use only. This therapy is time consuming and includes the risk of contamination of the nebulizers. Dry powder inhalers (DPI) can be an attractive alternative for CF drugs. Inhaled flow rate and volume, and the device resistance are important determinants for optimal dispersion of drug from a DPI. It is important to understand how these variables interact in the CF population in order to properly design a new DPI formulation targeted for these patients. The objective of this study was to assess the inspiratory variables of a representative population of CF subjects 6 years and older with varying degrees of lung disease while inhaling through resistances that simulate DPI devices. Ninety-six stable CF patients were enrolled, ages 6-54 years, FEV(1) 19-126% predicted. Subjects inhaled forcefully through four different resistances (0.019, 0.024, 0.038, and 0.048 kP(0.5)/LPM, respectively), while inspiratory time (IT(DPI)), peak inspiratory flow (PIF(DPI)), and volumes (V(DPI)) were measured. For any resistance, inspired V(DPI) increased with the older age groups; PIF(DPI) was similar between adults and adolescents but lower in the children. Subjects with lower FEV(1) had lower V(DPI) and PIF(DPI). As resistance increased, PIF(DPI) decreased, IT(DPI) increased, with no significant change in V(DPI). At the lowest resistance mean PIF(DPI) was 105 LPM (range 45-163) for all patients; 112 LPM (range 75-163) in adults; and 89 LPM (45-126) in children. Mean inspired V(DPI) was 1.75 L for all patients; 2.2 L (0.8-3.7) in adults; and 1.2 L (0.5-1.8) in children. At the lowest resistance a minimal flow rate of 30, 45, and 60 LPM was attained in 100%, 99%, and 96% of all patients. Volumes of 1.0, 1.5, and 2.0 L were attained by 85%, 57%, and 30% of the patients. At the highest resistance mean PIF(DPI) was 52 LPM (range 26-70) for all patients; 55 LPM (40-70) in adults; and 47 LPM (26-62) in children. Mean inspired V(DPI) was 1.5 L in all patients; 1.9 L (0.9-3.5) in adults and 1.1 L (0.5-2.3) in children. At the highest resistance, a minimal flow rate of 30, 45, and 60 LPM was attained in 99%, 80%, and 22% of all patients. Volumes of 1, 1.5, and 2 L were attained in 84%, 45%, and 23% of the patients. We defined ranges for inspiratory variables in a diverse CF population for a range of device resistances that bracket those of current DPIs. The recorded inspiratory patterns can be used on the bench to design and test new dry powder formulations and devices to target the largest proportion of the CF population.     

Effects of insulin on diacylglycerol-protein kinase C signaling in rat diaphragm and soleus muscles and relationship to glucose transport

Insulin was found to provoke rapid increases in diacylglycerol (DAG) content and [3H]glycerol incorporation into DAG and other lipids during incubations of rat hemidiaphragms and soleus muscles. Insulin also rapidly increased phosphatidic acid and total glycerolipid labeling by [3H]glycerol, suggesting that insulin increases DAG production at least partly through stimulation of the de novo pathway. Increased DAG production may activate protein kinase C (PKC) as reported previously in the rat diaphragm. We also observed apparent insulin-induced translocation of PKC from cytosol to membrane in the rat soleus muscle. The importance of insulin-induced increases in DAG-PKC signaling in the stimulation of glucose transport in rat diaphragm and soleus muscles was suggested by 1) PKC activators phorbol esters and phospholipase C stimulation of [3H]-2-deoxyglucose (DOG) uptake and 2) PKC inhibitors staurosporine and polymixin B inhibition of insulin effects on [3H]-2-DOG uptake. Although phorbol ester was much less effective than insulin in the diaphragm, phospholipase C provoked increases in [3H]-2-DOG uptake that equaled or exceeded those of insulin. In the soleus muscle, phorbol ester, like phospholipase C, was only slightly but not significantly less effective than insulin. Similar variability in effectiveness of phorbol ester has also been noted previously in rat adipocytes (weak) and BC3H1 myocytes (strong), whereas DAG, added exogenously or generated by phospholipase C treatment, stimulates glucose transport to a degree that is quantitatively more comparable to that of insulin in each of the four tissues. Differences in effectiveness of phorbol ester and DAG could not be readily explained by postulating that the latter acts independently of PKC, because DAG provoked the apparent translocation of the enzyme from cytosol to membranes in rat adipocytes, and effects of DAG on [3H]-2-DOG uptake were blocked by inhibitors of PKC in both rat adipocytes and BC3H1 myocytes. Collectively, our findings provide further support for the hypothesis that insulin increases DAG production and PKC activity, and these processes are important in the stimulation of glucose transport in rat skeletal muscle and other tissues.     

Low-artifact intravascular devices: MR imaging evaluation

Flow-phantom magnetic resonance (MR) imaging, with use of both spin-echo (SE) and gradient-echo (GRE) techniques at 1.5 T, was performed on the percutaneous Greenfield (beta-III titanium alloy [TMA wire]), Amplatz (MP32-N alloy), and Simon nitinol filters and TMA wire facsimiles of the bird's nest, Gunther, new retrievable, and Amplatz vena caval filters. SE imaging allowed detection of thrombi as small as 5 X 5 mm trapped within the percutaneous Greenfield, Simon nitinol, and TMA-wire facsimile filters; with the MP32-N Amplatz filter, a larger volume of thrombus (10 X 20-mm clots) was necessary for clot detection. GRE imaging allowed detection of intraluminal tilting of the percutaneous Greenfield and facsimile Amplatz (TMA-wire) filters. GRE imaging was useful for demonstrating postfilter turbulence due to clots, which was greatest for the Amplatz filter. Imaging of facsimile vascular devices made of tantalum or TMA wire did not cause the severe "black-hole" MR artifacts typical of the stainless-steel devices. SE and GRE imaging were very useful for determining caval patency in two patients with previously placed Mobin-Uddin filters. Noninvasive MR evaluation of blood vessels in the presence of a variety of low-artifact intravascular devices appears feasible.