Summary

Background: In myasthenic patients, the time course of action of non-depolarizing neuromuscular blocking agents is prolonged and the sensitivity is increased. We used our antegrade perfused rat peroneal nerve anterior tibialis muscle model to investigate if this altered time course of effect and sensitivity can be explained by the decreased acetylcholine receptor concentration that is caused by the disease. Methods: Functional acetylcholine receptors were reduced by administration of α-bungarotoxin or by injecting monoclonal antibodies against rat acetylcholine receptors (experimental autoimmune myasthenia gravis). After induction of anaesthesia, the model was set up and perfusion of the tibialis anterior muscle with blood was started. After stabilization of the twitch, rocuronium or pancuronium were infused until 90% block was obtained. Twitch data and infusion data were recorded and used to calculate the time course of effect and potency. Results: The potency of neuromuscular blocking agents was increased and the offset of the neuromuscular block was prolonged in both the α-bungarotoxin groups and the experimental autoimmune myasthenia gravis groups compared to controls. Conclusion: This study shows that the increased sensitivity to neuromuscular-blocking agents in myasthenia gravis can be accounted for by a decreased number of acetylcholine receptors. It also shows that the antegrade perfused rat peroneal nerve anterior tibialis muscle model is a suitable model to study the effects of myasthenia gravis on the time course of effect of neuromuscular blocking agents.

Summary

Background and objective: The time course of action of mivacurium does not correlate with its rapid breakdown by plasma cholinesterase. Pharmacokinetic–pharmacodynamic (PK–PD) modelling was applied to obtain more insight in the concentration–effect relationship.

Methods: Fourteen patients between 25 and 55 yr, undergoing non-major surgery, American Society of Anesthesiologists Grade I–II, were included. All patients received thiopentone/fentanyl/isoflurane/oxygen/nitrous oxide anaesthesia. Neuromuscular block was monitored mechanomyographically using single twitch stimulation (0.1 Hz). Mivacurium was administered as a short-term infusion, mean (standard deviation) duration 4.7 (1.0) min and dose 145 (33) μg kg−1. Arterial blood samples were obtained, and plasma was analysed using high performance liquid chromatography. PK–PD modelling was performed using an iterative Bayesian two-stage approach, assuming that the trans–trans and cis–trans isomers are equally potent.

Results: A PK–PD model with an effect compartment linked to plasma did not fit to the data satisfactorily. A model using an interstitial space compartment between plasma and effect compartment fitted significantly better. Parameters (mean (percentage coefficient of variation)) of the best fitting model were: kip 0.374 min−1 (46%), kei 0.151 min−1 (36%), EC50 98 μg L−1 (29%) and γ 3.7 (22%).

Conclusions: The PK–PD behaviour of mivacurium could be described using a model with an interstitial space compartment interposed between plasma and effect compartment. This model shows that the time course of mivacurium is mainly governed by the concentration decline in this interposed compartment and only indirectly related to the rapid plasma clearance.

The rapid onset and offset of rapacuronium can be explained from its pharmacokinetic and pharmacodynamic characteristics. A unique property of rapacuronium is its high value for ke0, indicating a rapid access to the receptor site. The reason for this high ke0 may be related to the low intrinsic potency of rapacuronium, but this is not yet fully clarified.

Substrate curvature measurements were used to study stress changes during thermal cycling and isothermal tensile stress relaxation in 800 nm Al–0.5 wt% Cu and Al–1 wt% Si–0.5 wt% Cu films. For both compositions dislocation glide can describe the relaxation data well for temperatures up to 120 °C for Al–Si–Cu and up to 100 °C for Al–Cu. The average activation energy for Al–Si–Cu and Al–Cu is 1.7 ± 0.2 eV and 3.0 ± 0.3 eV, respectively. The athermal flow stress is the same for both and equal to 600 ± 200 MPa. This result is consistent with the obstacles for glide being Al2Cu precipitates, which, in the case of Al–Si–Cu, are fine and can be cut by the dislocations, and, in the case of Al–Cu, are strong and provide Orowan strengthening. Also, the stress changes during thermal cycling in the Al–Cu films are different from those in the Al–Si–Cu films. For Al–Cu films, the room temperature stress decreases after each thermal cycle, while for Al–Si–Cu stress changes during thermal cycling are stable from the second cycle on. These observations are supported by thorough transmission electron microscopy (TEM) studies.

In this work, the electromigration (EM)-behaviour of bamboo RIE and damascene Al(Cu) interconnects has been studied by drift experiments. For RIE lines, both lattice and interface EM can be operative, depending on the Cu-distribution. Cu-alloying only retains its retarding effect for Al-diffusion at metallic interfaces, while the accompanying presence of an incubation time was found to become rate-controlling for the EM-performance at operating conditions. Contrary to the case of polycrystalline lines, the higher EM-threshold still observed for bamboo damascene relative to RIE is now insufficient to compensate for the significantly increased Cudepletion rate in bamboo damascene due to both geometrical and metallurgical reasons.

The introduction of rapid thermal processing for silicide formation has triggered a lot of research to temperature uniformity and reproducibility in RTP systems. In addition to the temperature, the ambient control is to be taken into account. Although gasses are specified to a low level of contaminants, the RTP step needs to be optimised for optimal contaminant reduction. Besides, the process wafer itself is a source of contamination.

In this paper an overview will be given of the role of RTP ambient on the silicidation processes. The effect of the wafer on ambient purity will be highlighted. It will be shown that the use of a reactive capping layer during silicidation represents an adequate solution for both sources of contamination.

The electromigration (EM) behaviour of damascene Al(Cu)-interconnects has been studied for the first time by drift experiments and results directly compared to plasma-etched lines. For the latter EM is known to occur through sequential stages : an incubation period, needed for Cu-depletion, and an Al-drift stage. It is shown that using a damascene implementation, the incubation time significantly increases but the Al-drift velocity does as well. This is demonstrated to be an intrinsic effect, directly related to the technological nature of both metallization schemes. Implications on lifetime prediction at operating conditions are discussed.

Substrate curvature measurements were used to study stress relaxation in Al-Si-Cu films at temperatures between 45 and 165 °C. Dislocation glide with an average activation energy, resp. athermal flow stress of 1.7 ± 0.2 eV, resp. 600 ± 200 MPa could describe the relaxation data for temperatures up to 120 °C well. Stress relaxation at 92 °C was found to progress much slower in 1 μm wide nitride passivated lines than in thin films or unpassivated lines.