Modelling altered signalling of G-protein coupled receptors in inflamed environment to advance drug design.

We previously reported the successful design, synthesis and testing of the prototype opioid painkiller NFEPP that does not elicit adverse side effects. The design process of NFEPP was based on mathematical modelling of extracellular interactions between G-protein coupled receptors (GPCRs) and ligands, recognizing that GPCRs function differently under pathological versus healthy conditions. We now present an additional and novel stochastic model of GPCR function that includes intracellular dissociation of G-protein subunits and modulation of plasma membrane calcium channels and their dependence on parameters of inflamed and healthy tissue (pH, radicals). The model is validated against in vitro experimental data for the ligands NFEPP and fentanyl at different pH values and radical concentrations. We observe markedly reduced binding affinity and calcium channel inhibition for NFEPP at normal pH compared to lower pH, in contrast to the effect of fentanyl. For increasing radical concentrations, we find enhanced constitutive G-protein activation but reduced ligand binding affinity. Assessing the different effects, the results suggest that, compared to radicals, low pH is a more important determinant of overall GPCR function in an inflamed environment. Future drug design efforts should take this into account.

Long-term morbidity and quality of life after surgical repair of transposition of the great arteries: atrial versus arterial switch operation.

Since a growing number of patients after surgical repair of transposition of the great arteries (TGA) survive until adulthood the focus of attention has shifted to the management of associated long-term morbidity and quality of life (QoL). Therefore, we reviewed all patients that underwent surgical repair of TGA at our institution and compared long-term results after atrial and arterial switch operation. Between 1973 and 2000, a total of 302 patients underwent either atrial switch operation (n=222) or arterial switch operation (n=80). Mean follow-up was 14.5±10.1 years. The arterial switch repair was associated with a higher early mortality whereas long-term survival was comparable between both groups. Postoperative arrhythmias including loss of sinus rhythm and pacemaker implantation occurred significantly more often after atrial switch repair. There was a trend towards a more favourable outcome of the arterial switch group concerning freedom from re-interventions, severe systemic ventricular dysfunction and need for heart failure medication. However, also the arterial switch operation was associated with an increased incidence of loss of sinus rhythm and neo-aortic valve regurgitation during late follow-up. Health related QoL according to the SF-36 questionnaire was not significantly different between both groups and comparable to a healthy population.