Hypnotic and opioid anesthetic drug interactions on the CNS, focus on response surface modeling

This chapter will present the conceptual and applied approaches to capture the interaction of anesthetic hypnotic drugs with opioid drugs, as used in the clinical anesthetic state. The graphic and mathematical approaches used to capture hypnotic/opiate anesthetic drug interactions will be presented. This chapter is not a review article about interaction modeling, but focuses on specific drug interactions within a quite narrow field, anesthesia.

Response surface modeling of the interaction between propofol and sevoflurane

BACKGROUND: Propofol and sevoflurane display additivity for gamma-aminobutyric acid receptor activation, loss of consciousness, and tolerance of skin incision. Information about their interaction regarding electroencephalographic suppression is unavailable. This study examined this interaction as well as the interaction on the probability of tolerance of shake and shout and three noxious stimulations by using a response surface methodology. METHODS: Sixty patients preoperatively received different combined concentrations of propofol (0-12 microg/ml) and sevoflurane (0-3.5 vol.%) according to a crisscross design (274 concentration pairs, 3 to 6 per patient). After having reached pseudo-steady state, the authors recorded bispectral index, state and response entropy and the response to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy. For the analysis of the probability of tolerance by logistic regression, a Greco interaction model was used. For the separate analysis of bispectral index, state and response entropy suppression, a fractional Emax Greco model was used. All calculations were performed with NONMEM V (GloboMax LLC, Hanover, MD). RESULTS: Additivity was found for all endpoints, the Ce(50, PROP)/Ce(50, SEVO) for bispectral index suppression was 3.68 microg. ml(-1)/ 1.53 vol.%, for tolerance of shake and shout 2.34 microg . ml(-1)/ 1.03 vol.%, tetanic stimulation 5.34 microg . ml(-1)/ 2.11 vol.%, laryngeal mask airway insertion 5.92 microg. ml(-1) / 2.55 vol.%, and laryngoscopy 6.55 microg. ml(-1)/2.83 vol.%. CONCLUSION: For both electroencephalographic suppression and tolerance to stimulation, the interaction of propofol and sevoflurane was identified as additive. The response surface data can be used for more rational dose finding in case of sequential and coadministration of propofol and sevoflurane.

The influence of yield surface shape and damage in the depth-dependent response of bone tissue to nanoindentation using spherical and Berkovich indenters

Prevention and treatment of osteoporosis rely on understanding of the micromechanical behaviour of bone and its influence on fracture toughness and cell-mediated adaptation processes. Postyield properties may be assessed by nonlinear finite element simulations of nanoindentation using elastoplastic and damage models. This computational study aims at determining the influence of yield surface shape and damage on the depth-dependent response of bone to nanoindentation using spherical and conical tips. Yield surface shape and damage were shown to have a major impact on the indentation curves. Their influence on indentation modulus, hardness, their ratio as well as the elastic-to-total work ratio is well described by multilinear regressions for both tip shapes. For conical tips, indentation depth was not statistically significant (p<0.0001). For spherical tips, damage was not a significant parameter (p<0.0001). The gained knowledge can be used for developing an inverse method for identification of postelastic properties of bone from nanoindentation.

Quantitative analysis of imprint shape and its relation to mechanical properties measured by microindentation in bone

Microindentation in bone is a micromechanical testing technique routinely used to extract material properties related to bone quality. As the analysis of microindentation data is based on assumptions about the contact between sample and surface, the aim of this study was to quantify the topological variability of indentations in bone and examine its relationship with mechanical properties. Indentations were performed in dry human and ovine bone in axial and transverse directions and their topology was measured by atomic force microscopy. Statistical shape modeling of the residual imprint allowed to define a mean shape and to describe the variability in terms of 21 principal components related to imprint depth, surface curvature and roughness. The indentation profile of bone was found to be highly consistent and free of any pile up while differing mostly by depth between species and direction. A few of the topological parameters, in particular depth, showed significant but rather weak and inconsistent correlations to variations in mechanical properties. The mechanical response of bone as well as the residual imprint shape was highly consistent within each category. We could thus verify that bone is rather homogeneous in its micromechanical properties and that indentation results are not strongly influenced by small deviations from an ideally flat surface.

Wetting and spreading of a surfactant film on solid particles: influence of sharp edges and surface irregularities

In addition to particle size and surface chemistry, the shape of particles plays an important role in their wetting and displacement by the surfactant film in the lung. The role of particle shape was the subject of our investigations using a model system consisting of a modified Langmuir-Wilhelmy surface balance. We measured the influence of sharp edges (lines) and other highly curved surfaces, including sharp corners or spikes, of different particles on the spreading of a dipalmitoylphosphatidyl (DPPC) film. The edges of cylindrical sapphire plates (circular curved edges, 1.65 mm radius) were wetted at a surface tension of 10.7 mJ/m2 (standard error (SE) = 0.45, n = 20) compared with that of 13.8 mJ/m2 (SE = 0.20, n = 20) for cubic sapphire plates (straight linear edges, edge length 3 mm) (p < 0.05). The top surfaces of the sapphire plates (cubic and cylindrical) were wetted at 8.4 mJ/m2 (SE = 0.54, n = 20) and 9.1 mJ/m2 (SE = 0.50, n = 20), respectively, but the difference was not significant (p > 0.05). The surfaces of the plates showed significantly higher resistance to spreading compared to that of the edges, as substantially lower surface tensions were required to initiate wetting (p < 0.05). Similar results were found for talc particles, were the edges of macro- and microcrystalline particles were wetted at 7.2 mJ/m2 (SE = 0.52, n = 20) and 8.2 mJ/m2 (SE = 0.30, n = 20) (p > 0.05), respectively, whereas the surfaces were wetted at 3.8 mJ/m2 (SE = 0.89, n = 20) and 5.8 mJ/m2 (SE = 0.52, n = 20) (p < 0.05), respectively. Further experiments with pollen of malvaceae and maize (spiky and fine knobbly surfaces) were wetted at 10.0 mJ/m2 (SE = 0.52, n = 10) and 22.75 mJ/m2 (SE = 0.81, n = 10), respectively (p < 0.05). These results show that resistance to spreading of a DPPC film on various surfaces is dependent on the extent these surfaces are curved. This is seen with cubic sapphire plates which have at their corners a radius of curvature of about 0.75 microm, spiky malvaceae pollen with an even smaller radius on top of their spikes, or talc with various highly curved surfaces. These highly curved surfaces resisted wetting by the DPPC film to a higher degree than more moderately curved surfaces such as those of cylindrical sapphire plates, maize pollens, or polystyrene spheres, which have a surface free energy similar to that of talc but a smooth surface. The macroscopic plane surfaces of the particles demonstrated the greatest resistance to spreading. This was explained by the extremely fine grooves in the nanometer range, as revealed by electron microscopy. In summary, to understand the effects of airborne particles retained on the surfaces of the respiratory tract, and ultimately their pathological potential, not only the particle size and surface chemistry but also the particle shape should be taken in consideration.

The adsorption of biomolecules to multi-walled carbon nanotubes is influenced by both pulmonary surfactant lipids and surface chemistry

Background During production and processing of multi-walled carbon nanotubes (MWCNTs), they may be inhaled and may enter the pulmonary circulation. It is essential that interactions with involved body fluids like the pulmonary surfactant, the blood and others are investigated, particularly as these interactions could lead to coating of the tubes and may affect their chemical and physical characteristics. The aim of this study was to characterize the possible coatings of different functionalized MWCNTs in a cell free environment. Results To simulate the first contact in the lung, the tubes were coated with pulmonary surfactant and subsequently bound lipids were characterized. The further coating in the blood circulation was simulated by incubating the tubes in blood plasma. MWCNTs were amino (NH2)- and carboxyl (-COOH)-modified, in order to investigate the influence on the bound lipid and protein patterns. It was shown that surfactant lipids bind unspecifically to different functionalized MWCNTs, in contrast to the blood plasma proteins which showed characteristic binding patterns. Patterns of bound surfactant lipids were altered after a subsequent incubation in blood plasma. In addition, it was found that bound plasma protein patterns were altered when MWCNTs were previously coated with pulmonary surfactant. Conclusions A pulmonary surfactant coating and the functionalization of MWCNTs have both the potential to alter the MWCNTs blood plasma protein coating and to determine their properties and behaviour in biological systems.

Operator variability using different polishing methods and surface geometry of a nanohybrid composite

This study evaluated the operator variability of different finishing and polishing techniques. After placing 120 composite restorations (Tetric EvoCeram) in plexiglassmolds, the surface of the specimens was roughened in a standardized manner. Twelve operators with different experience levels polished the specimens using the following finishing/polishing procedures: method 1 (40 ?m diamond [40D], 15 ?m diamond [15D], 42 ?m silicon carbide polisher [42S], 6 ?m silicon carbide polisher [6S] and Occlubrush [O]); method 2 (40D, 42S, 6S and O); method 3 (40D, 42S, 6S and PoGo); method 4 (40D, 42S and PoGo) and method 5 (40D, 42S and O). The mean surface roughness (Ra) was measured with a profilometer. Differences between the methods were analyzed with non-parametric ANOVA and pairwise Wilcoxon signed rank tests (?=0.05). All the restorations were qualitatively assessed using SEM. Methods 3 and 4 showed the best polishing results and method 5 demonstrated the poorest. Method 5 was also most dependent on the skills of the operator. Except for method 5, all of the tested procedures reached a clinically acceptable surface polish of Ra?0.2 ?m. Polishing procedures can be simplified without increasing variability between operators and without jeopardizing polishing results.

Fine-tuning of substrate architecture and surface chemistry promotes muscle tissue development

Tissue engineering has been increasingly brought to the scientific spotlight in response to the tremendous demand for regeneration, restoration or substitution of skeletal or cardiac muscle after traumatic injury, tumour ablation or myocardial infarction. In vitro generation of a highly organized and contractile muscle tissue, however, crucially depends on an appropriate design of the cell culture substrate. The present work evaluated the impact of substrate properties, in particular morphology, chemical surface composition and mechanical properties, on muscle cell fate. To this end, aligned and randomly oriented micron (3.3±0.8 μm) or nano (237±98 nm) scaled fibrous poly(ε-caprolactone) non-wovens were processed by electrospinning. A nanometer-thick oxygen functional hydrocarbon coating was deposited by a radio frequency plasma process. C2C12 muscle cells were grown on pure and as-functionalized substrates and analysed for viability, proliferation, spatial orientation, differentiation and contractility. Cell orientation has been shown to depend strongly on substrate architecture, being most pronounced on micron-scaled parallel-oriented fibres. Oxygen functional hydrocarbons, representing stable, non-immunogenic surface groups, were identified as strong triggers for myotube differentiation. Accordingly, the highest myotube density (28±15% of total substrate area), sarcomeric striation and contractility were found on plasma-coated substrates. The current study highlights the manifold material characteristics to be addressed during the substrate design process and provides insight into processes to improve bio-interfaces.

Combined bone and soft-tissue augmentation surgery in temporo-orbital contour reconstruction

Temporal hollowing due to temporal muscle atrophy after standard skull base surgery is common. Various techniques have been previously described to correct the disfiguring defect. Most often reconstruction is performed using freehand molded polymethylmethacrylate cement. This method and material are insufficient in terms of aesthetic results and implant characteristics. We herein propose reconstruction of such defects with a polyetheretherketone (PEEK)-based patient-specific implant (PSI) including soft-tissue augmentation to preserve normal facial topography. We describe a patient who presented with a large temporo-orbital hemangioma that had been repaired with polymethylmethacrylate 25 years earlier. Because of a toxic skin atrophy fistula, followed by infection and meningitis, this initial implant had to be removed. The large, disfiguring temporo-orbital defect was reconstructed with a PEEK-based PSI. The lateral orbital wall and the temporal muscle atrophy were augmented with computer-aided design and surface modeling techniques. The operative procedure to implant and adopt the reconstructed PEEK-based PSI was simple, and an excellent cosmetic outcome was achieved. The postoperative clinical course was uneventful over a 5-year follow-up period. Polyetheretherketone-based combined bony and soft contour remodeling is a feasible and effective method for cranioplasty including combined bone and soft-tissue reconstruction of temporo-orbital defects. Manual reconstruction of this cosmetically delicate area carries an exceptional risk of disfiguring results. Augmentation surgery in this anatomic location needs accurate PSIs to achieve satisfactory cosmetic results. The cosmetic outcome achieved in this case is superior compared with previously reported techniques.

Mutagenesis and computer modeling studies of a GPCR conserved residue W5.43(194) in ligand recognition and signal transduction for CB2 receptor

W5.43(194), a conserved tryptophan residue among G-protein coupled receptors (GPCRs) and cannabinoid receptors (CB), was examined in the present report for its significance in CB2 receptor ligand binding and adenylyl cyclase (AC) activity. Computer modeling postulates that this site in CB2 may be involved in the affinity of WIN55212-2 and SR144528 through aromatic contacts. In the present study, we reported that a CB2 receptor mutant, W5.43(194)Y, which had a tyrosine (Y) substitution for tryptophan (W), retained the binding affinity for CB agonist CP55940, but reduced binding affinity for CB2 agonist WIN55212-2 and inverse agonist SR144528 by 8-fold and 5-fold, respectively; the CB2 W5.43(194)F and W5.43(194)A mutations significantly affect the binding activities of CP55940, WIN55212-2 and SR144528. Furthermore, we found that agonist-mediated inhibition of the forskolin-induced cAMP production was dramatically diminished in the CB2 mutant W5.43(194)Y, whereas W5.43(194)F and W5.43(194)A mutants resulted in complete elimination of downstream signaling, suggesting that W5.43(194) was essential for the full activation of CB2. These results indicate that both aromatic interaction and hydrogen bonding are involved in ligand binding for the residue W5.43(194), and the mutations of this tryptophan site may affect the conformation of the ligand binding pocket and therefore control the active conformation of the wild type CB2 receptor. W5.43(194)Y/F/A mutations also displayed noticeable enhancement of the constitutive activation probably attributed to the receptor conformational changes resulted from the mutations.